A hot hole-programmed and low-temperature-formed SONOS flash memory

PubMed Central

2013-01-01

In this study, a high-performance TixZrySizO flash memory is demonstrated using a sol–gel spin-coating method and formed under a low annealing temperature. The high-efficiency charge storage layer is formed by depositing a well-mixed solution of titanium tetrachloride, silicon tetrachloride, and zirconium tetrachloride, followed by 60 s of annealing at 600°C. The flash memory exhibits a noteworthy hot hole trapping characteristic and excellent electrical properties regarding memory window, program/erase speeds, and charge retention. At only 6-V operation, the program/erase speeds can be as fast as 120:5.2 μs with a 2-V shift, and the memory window can be up to 8 V. The retention times are extrapolated to 106 s with only 5% (at 85°C) and 10% (at 125°C) charge loss. The barrier height of the TixZrySizO film is demonstrated to be 1.15 eV for hole trapping, through the extraction of the Poole-Frenkel current. The excellent performance of the memory is attributed to high trapping sites of the low-temperature-annealed, high-κ sol–gel film. PMID:23899050

Preparation of TiO2-ZnO and its activity test in sonophotocatalytic degradation of phenol

NASA Astrophysics Data System (ADS)

Fatimah, Is; Novitasari

2016-02-01

Synthesis of TiO2-ZnO and its activity test in Sono photocatalysis degradation of phenol has been conducted. The synthesis was performed by the sol-gel mechanism by using titanium isopropoxide and zinc acetate as precursors with the Ti: Zn ratio of 5:1. Characterization of material were conducted by x-ray diffraction analysis, surface area analysis and also diffuse reflectance UV-Visible spectrophotometry. The material obtained from the synthesis was tested in photocatalysis, Sono catalysis and Sono photocatalysis degradation of phenol solution. Results showed that material exhibited the activity of varied mechanism o- phenol degradation. In advance, the Sono photocatalysis degradation produced the synergy index of 1.169 compared to both photocatalysis and Sono catalysis.

Effect of acoustic parameters on the cavitation behavior of SonoVue microbubbles induced by pulsed ultrasound.

PubMed

Lin, Yutong; Lin, Lizhou; Cheng, Mouwen; Jin, Lifang; Du, Lianfang; Han, Tao; Xu, Lin; Yu, Alfred C H; Qin, Peng

2017-03-01

SonoVue microbubbles could serve as artificial nuclei for ultrasound-triggered stable and inertial cavitation, resulting in beneficial biological effects for future therapeutic applications. To optimize and control the use of the cavitation of SonoVue bubbles in therapy while ensuring safety, it is important to comprehensively understand the relationship between the acoustic parameters and the cavitation behavior of the SonoVue bubbles. An agarose-gel tissue phantom was fabricated to hold the SonoVue bubble suspension. 1-MHz transmitting transducer calibrated by a hydrophone was used to trigger the cavitation of SonoVue bubbles under different ultrasonic parameters (i.e., peak rarefactional pressure (PRP), pulse repetition frequency (PRF), and pulse duration (PD)). Another 7.5-MHz focused transducer was employed to passively receive acoustic signals from the exposed bubbles. The ultraharmonics and broadband intensities in the acoustic emission spectra were measured to quantify the extent of stable and inertial cavitation of SonoVue bubbles, respectively. We found that the onset of both stable and inertial cavitation exhibited a strong dependence on the PRP and PD and a relatively weak dependence on the PRF. Approximate 0.25MPa PRP with more than 20μs PD was considered to be necessary for ultraharmonics emission of SonoVue bubbles, and obvious broadband signals started to appear when the PRP exceeded 0.40MPa. Moreover, the doses of stable and inertial cavitation varied with the PRP. The stable cavitation dose initially increased with increasing PRP, and then decreased rapidly after 0.5MPa. By contrast, the inertial cavitation dose continuously increased with increasing PRP. Finally, the doses of both stable and inertial cavitation were positively correlated with PRF and PD. These results could provide instructive information for optimizing future therapeutic applications of SonoVue bubbles. Copyright © 2016 Elsevier B.V. All rights reserved.

Surface Charge Measurement of SonoVue, Definity and Optison: A Comparison of Laser Doppler Electrophoresis and Micro-Electrophoresis.

PubMed

Ja'afar, Fairuzeta; Leow, Chee Hau; Garbin, Valeria; Sennoga, Charles A; Tang, Meng-Xing; Seddon, John M

2015-11-01

Microbubble (MB) contrast-enhanced ultrasonography is a promising tool for targeted molecular imaging. It is important to determine the MB surface charge accurately as it affects the MB interactions with cell membranes. In this article, we report the surface charge measurement of SonoVue, Definity and Optison. We compare the performance of the widely used laser Doppler electrophoresis with an in-house micro-electrophoresis system. By optically tracking MB electrophoretic velocity in a microchannel, we determined the zeta potentials of MB samples. Using micro-electrophoresis, we obtained zeta potential values for SonoVue, Definity and Optison of -28.3, -4.2 and -9.5 mV, with relative standard deviations of 5%, 48% and 8%, respectively. In comparison, laser Doppler electrophoresis gave -8.7, +0.7 and +15.8 mV with relative standard deviations of 330%, 29,000% and 130%, respectively. We found that the reliability of laser Doppler electrophoresis is compromised by MB buoyancy. Micro-electrophoresis determined zeta potential values with a 10-fold improvement in relative standard deviation. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Sono-electro-magnetic therapy for treating chronic pelvic pain syndrome in men: a randomized, placebo-controlled, double-blind trial.

PubMed

Kessler, Thomas M; Mordasini, Livio; Weisstanner, Christian; Jüni, Peter; da Costa, Bruno R; Wiest, Roland; Thalmann, George N

2014-01-01

To assess the efficacy and safety of sono-electro-magnetic therapy compared to placebo in men with refractory CPPS. In a randomized, placebo-controlled, double-blind single center trial, we assessed the effect of sono-electro-magnetic therapy in men with treatment refractory CPPS. Sixty male patients were randomly assigned to treatment with either sono-electro-magnetic (n = 30) or placebo therapy (n = 30) for 12 weeks. The primary outcome was a change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) from baseline to 12 weeks. The 12-week difference between sono-electro-magnetic and placebo therapy in changes of the NIH-CPSI total score was -3.1 points (95% CI -6.8 to 0.6, p = 0.11). In secondary comparisons of NIH-CPSI sub-scores, we found differences between groups most pronounced for the quality-of-life sub-score (difference at 12 weeks -1.6, 95% CI -2.8 to -0.4, p = 0.015). In stratified analyses, the benefit of sono-electro-magnetic therapy appeared more pronounced among patients who had a symptom duration of 12 months or less (difference in NIH-CPSI total score -8.3, 95% CI -14.5 to 2.6) than in patients with a longer symptom duration (-0.8, 95% CI -4.6 to 3.1; p for interaction = 0.023). Sono-electro-magnetic therapy did not result in a significant improvement of symptoms in the overall cohort of treatment refractory CPPS patients compared to placebo treatment. Subgroup analysis indicates, however, that patients with a symptom-duration of 12 months or less may benefit from sono-electro-magnetic therapy, warranting larger randomized controlled trials in this subpopulation. ClinicalTrials.gov NCT00688506.

Characteristics and Echogenicity of Clinical Ultrasound Contrast Agents: An In Vitro and In Vivo Comparison Study.

PubMed

Hyvelin, Jean-Marc; Gaud, Emmanuel; Costa, Maria; Helbert, Alexandre; Bussat, Philippe; Bettinger, Thierry; Frinking, Peter

2017-05-01

To compare physicochemical characteristics and in vitro and in vivo contrast-enhanced ultrasound imaging performance of 3 commercially available ultrasound contrast agents: SonoVue (Bracco Imaging SpA, Colleretto Giacosa, Italy; also marketed as Lumason in the USA), Definity (Lantheus Medical Imaging, North Billerica, MA) and Optison (GE Healthcare AS, Oslo, Norway). Physicochemical characteristics were measured with a Multisizer Coulter Counter (Beckman Coulter, Fullerton, CA). Two ultrasound systems (Aplio 500; Toshiba Medical Systems Corp, Tochigi-ken, Japan; and Logiq E9; GE Healthcare, Little Chalfont, England) were used with different transducers. Contrast enhancement was measured in vitro by dose-ranging measurements using a custom-built beaker setup; in vivo imaging performances were compared in pigs (heart and liver) and rabbits (liver). Quantitative analyses were performed with VueBox quantification software (Bracco Suisse SA, Plan-les-Ouates, Switzerland). Measured physicochemical characteristics were in agreement with those provided by the manufacturers. In vitro data demonstrated that the performance of SonoVue was similar to or better than that of Definity but superior to Optison (normalized scattered power 2- to 10-fold higher with SonoVue). Similar results were obtained in vivo, although the duration of enhancement in the pig heart was longer for SonoVue compared to Definity, and quantitative analysis revealed higher enhancement for SonoVue (1.5-fold increase). For liver imaging, SonoVue and Definity showed similar contrast enhancement and duration of enhancement, but compared to Optison, both peak enhancement and duration of enhancement were superior for SonoVue (up to 2-fold increase). Imaging performance of SonoVue was similar to or slightly better than that of Definity, but it was superior to Optison for the conditions used in this study. © 2017 by the American Institute of Ultrasound in Medicine.

Investigation of Microbubble Cavitation-Induced Calcein Release from Cells In Vitro.

PubMed

Maciulevičius, Martynas; Tamošiūnas, Mindaugas; Jakštys, Baltramiejus; Jurkonis, Rytis; Venslauskas, Mindaugas Saulius; Šatkauskas, Saulius

2016-12-01

In the present study, microbubble (MB) cavitation signal analysis was performed together with calcein release evaluation in both pressure and exposure duration domains of the acoustic field. A passive cavitation detection system was used to simultaneously measure MB scattering and attenuation signals for subsequent extraction efficiency relative to MB cavitation activity. The results indicate that the decrease in the efficiency of extraction of calcein molecules from Chinese hamster ovary cells, as well as cell viability, is associated with MB cavitation activity and can be accurately predicted using inertial cavitation doses up to 0.18 V × s (R 2  > 0.9, p < 0.0001). No decrease in additional calcein release or cell viability was observed after complete MB sonodestruction was achieved. This indicates that the optimal exposure duration within which maximal sono-extraction efficiency is obtained coincides with the time necessary to achieve complete MB destruction. These results illustrate the importance of MB inertial cavitation in the sono-extraction process. To our knowledge, this study is the first to (i) investigate small molecule extraction from cells via sonoporation and (ii) relate the extraction process to the quantitative characteristics of MB cavitation acoustic spectra. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Study Trapped Charge Distribution in P-Channel Silicon-Oxide-Nitride-Oxide-Silicon Memory Device Using Dynamic Programming Scheme

NASA Astrophysics Data System (ADS)

Li, Fu-Hai; Chiu, Yung-Yueh; Lee, Yen-Hui; Chang, Ru-Wei; Yang, Bo-Jun; Sun, Wein-Town; Lee, Eric; Kuo, Chao-Wei; Shirota, Riichiro

2013-04-01

In this study, we precisely investigate the charge distribution in SiN layer by dynamic programming of channel hot hole induced hot electron injection (CHHIHE) in p-channel silicon-oxide-nitride-oxide-silicon (SONOS) memory device. In the dynamic programming scheme, gate voltage is increased as a staircase with fixed step amplitude, which can prohibits the injection of holes in SiN layer. Three-dimensional device simulation is calibrated and is compared with the measured programming characteristics. It is found, for the first time, that the hot electron injection point quickly traverses from drain to source side synchronizing to the expansion of charged area in SiN layer. As a result, the injected charges quickly spread over on the almost whole channel area uniformly during a short programming period, which will afford large tolerance against lateral trapped charge diffusion by baking.

[Comparative study of sleep patterns in nurses working day and night shifts].

PubMed

De Martino, Milva Maria Figueiredo

2002-08-01

To compare sleep patterns in nurses working day and night shifts in a hospital in Campinas (SP), Brazil. Fifty-nine nurses between 23 and 59 years of age participated in the study. For day shift workers, the pattern of nocturnal sleep was examined; for night shift workers, nocturnal and diurnal sleep patterns were examined. During 1 week, participants filled out a sleep diary right after waking up. The following items were assessed: time going to bed, falling asleep, and waking up; sleep latency; duration in hours of nocturnal and diurnal sleep; naps; quality of sleep; mode of waking up; and comparison between the sleep recorded in the diary with the usual sleep. Personal and professional information was also collected. Day shift workers went to bed at 23h36min, and night workers at 23h52min (P > 0.05). The nurses working a day schedule woke up earlier (7h3min) than those working a night schedule when they slept at night (8h30min) (P

Sono-photo-Fenton oxidation of bisphenol-A over a LaFeO3 perovskite catalyst.

PubMed

Dükkancı, Meral

2018-01-01

In this study, oxidation of bisphenol-A (IUPAC name - 2,2-(4,4-dihydroxyphenyl, BPA), which is an endocrine disrupting phenolic compound used in the polycarbonate plastic and epoxy resin industry, was investigated using sono-photo-Fenton process under visible light irradiation in the presence of an iron containing perovskite catalyst, LaFeO 3 . The catalyst prepared by sol-gel method, calcined at 500°C showed a catalytic activity in BPA oxidation using sono-photo-Fenton process with a degradation degree and a chemical oxygen demand (COD) reduction of 21.8% and 11.2%, respectively. Degradation of BPA was studied by using individual and combined advanced oxidation techniques including sonication, heterogeneous Fenton reaction and photo oxidation over this catalyst to understand the effect of each process on degradation of BPA. It was seen, the role of sonication was very important in hybrid sono-photo-Fenton process due to the pyrolysis and sonoluminescence effects caused by ultrasonic irradiation. The prepared LaFeO 3 perovskite catalyst was a good sonocatalyst rather than a photocatalyst. Sonication was not only the effective process to degrade BPA but also it was the cost effective process in terms of energy consumption. The studies show that the energy consumption is lower in the sono-Fenton process than those in the photo-Fenton and sono-photo- Fenton processes. Copyright © 2017 Elsevier B.V. All rights reserved.

Advanced oxidation of Reactive Blue 181 solution: a comparison between Fenton and Sono-Fenton process.

PubMed

Basturk, Emine; Karatas, Mustafa

2014-09-01

In this work, the decolorization of C.I. Reactive Blue 181 (RB181), an anthraquinone dye, by Ultrasound and Fe(2+) H2O2 processes was investigated. The effects of operating parameters, such as Fe(2+) dosage, H2O2 dosage, pH value, reaction time and temperature were examined. Process optimisation [pH, ferrous ion (Fe(2+)), hydrogen peroxide (H2O2), and reaction time], kinetic studies and their comparison were carried out for both of the processes. The Sono-Fenton process was performed by indirect sonication in an ultrasonic water bath, which was operated at a fixed 35-kHz frequency. The optimum conditions were determined as [Fe(2+)]=30 mg/L, [H2O2]=50 mg/L and pH=3 for the Fenton process and [Fe(2+)]=10 mg/L, [H2O2]=40 mg/L and pH=3 for the Sono-Fenton process. The colour removals were 88% and 93.5% by the Fenton and Sono-Fenton processes, respectively. The highest decolorization was achieved by the Sono-Fenton process because of the production of some oxidising agents as a result of sonication. The paper also discussed kinetic parameters. The decolorization kinetic of RB181 followed pseudo-second-order reaction (Fenton study) and Behnajady kinetics (Sono-Fenton study). Copyright © 2014 Elsevier B.V. All rights reserved.

Improving ovarian cancer imaging with LHRH-NBs: an experimental study.

PubMed

Li, Wenjuan; Zhang, Lingping; Zhu, Yuanfang; Zhang, Jinyi; Shen, Li; Huang, Shuying; Fang, Shanyu

2016-09-01

Our previous study used freeze-drying and biotin-avidin binding methods and obtained nontargeted nanobubbles (N-NBs) and ovarian cancer-targeting nanobubbles (LHRH-NBs, luteinizing hormone-releasing hormone nanobubbles). Our study also identified the physical and chemical properties of these two contrast agents, and validated the targeting ability and underlying mechanisms of LHRH-NBs in vitro. The present study investigated the imaging of N-NBs and LHRH-NBs in nude mice and their binding with tissues. The nude mice models of xenografts were divided into three groups, N-NB, LHRH-NB, and SonoVue. These contrast agents were injected via the caudal vein to observe the imaging of ovarian cancer. Fluorescence microscope was used to observe the penetration of N-NBs and LHRH-NBs through the vascular endothelial gaps. Immunofluorescence was used to observe the penetration of N-NBs and LHRH-NBs through vascular endothelial gaps and binding to the tumor cells. The imaging intensity and duration were not significantly different between N-NBs and LHRH-NBs. The imaging intensity in the N-NB and LHRH-NB groups was not significantly different compared with the SonoVue group; however, the imaging duration in the N-NB and LHRH-NB groups was significantly longer than in the SonoVue group (P < 0.001). Both N-NBs and LHRH-NBs penetrated through the vascular endothelial gaps. After penetrating through the vascular endothelial gapes, LHRH-NBs could target and bind to the tumor cells. N-NBs and LHRH-NBs are of good imaging effectiveness and relatively long imaging duration. LHRH-NB is a potent contrast agent for imaging ovarian cancer, while achieving targeted delivery of drugs to the site of ovarian cancer.

Sono-assisted adsorption of a textile dye on milk vetch-derived charcoal supported by silica nanopowder.

PubMed

Jorfi, Sahand; Darvishi Cheshmeh Soltani, Reza; Ahmadi, Mehdi; Khataee, Alireza; Safari, Mahdi

2017-02-01

This study was performed to assess the efficiency of silica nanopowder (SNP)/milk vetch-derived charcoal (MVDC) nanocomposite coupled with the ultrasonic irradiation named sono-adsorption process for treating water-contained Basic Red 46 (BR46) dye. Field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET) and Fourier transform infrared spectroscopy (FT-IR) were performed for the characterization of as-prepared adsorbent. The sono-assisted adsorption process was optimized using response surface optimization on the basis of central composite design by the application of quadratic model. Accordingly, the color removal can be retained more than 93% by an initial BR46 concentration of 8 mg/L, sonication time of 31 min, adsorbent dosage of 1.2 g/L and initial pH of 9. The pseudo-second order kinetic model described the sono-assisted adsorption of BR46 reasonably well (R 2  > 0.99). The intra-particular diffusion kinetic model pointed out that the sono-assisted adsorption of BR46 onto SNP/MVDC nanocomposite was diffusion controlled as well as that ultrasonication enhanced the diffusion rate. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Population health surveillance of the general population living near Turin (Northern Italy) incinerator (SPoTT): methodology of the study].

PubMed

Bena, Antonella; Chiusolo, Monica; Orengia, Manuela; Cadum, Ennio; Farina, Elena; Musmeci, Loredana; Procopio, Enrico; Salamina, Giuseppe

2016-01-01

Si intende qui descrivere il sistema di sorveglianza sugli effetti sulla salute (SpoTT) dell'inquinamento ambientale nelle aree circostanti l'inceneritore di Torino. SPoTT ha 3 linee di attività: 1. monitoraggio epidemiologico degli effetti a breve termine attraverso analisi temporali e misura della correlazione tra livelli giornalieri di emissioni dell'impianto e andamento degli eventi individuati dagli archivi dei dimessi (SDO), di pronto soccorso e di mortalità; sono coinvolti coloro che nel 2013-2018 risiedevano nell'area di ricaduta delle emissioni; 2. sorveglianza epidemiologica degli effetti a lungo termine, stimando tassi standardizzati di mortalità e morbosità; a ogni soggetto è attribuito il valore stimato di esposizione cumulato nel tempo caratteristico della residenza anagrafica; le informazioni sulla salute sono reperite dagli archivi SDO, di mortalità e dai certificati di assistenza al parto; sono studiati due decenni pre-post l'avvio dell'impianto: 2003-2012 e 2013-2022; 3. monitoraggio biologico con misurazione pre-post di metalli, PCDD/F, PCB, OH-IPA; sono coinvolti 196 residenti esposti e 196 di controllo di 35-69 anni, campionati a caso dalle anagrafi comunali; sono effettuate misure di funzionalità endocrina e respiratoria, pressione arteriosa, rischio cardiovascolare; l'esposizione cumulativa sarà stimata per ciascuna persona campionata integrando l'indirizzo di residenza, il tempo di permanenza in ciascun indirizzo e i dati ricavati dai modelli di ricaduta; sarà costituita una biobanca per future indagini di laboratorio; sono coinvolti anche 20 allevatori e i lavoratori dell'impianto. Una quarta linea di attività, non descritta in questo articolo, riguarda il monitoraggio della salute dei lavoratori addetti all'impianto. SPoTT è il primo studio in Italia su inceneritori e salute che adotta un disegno di studio longitudinale di adeguata potenza sia per i residenti sia per i lavoratori. I primi risultati sono attesi nel corso del 2016.

Development of Next Generation Memory Test Experiment for Deployment on a Small Satellite

NASA Technical Reports Server (NTRS)

MacLeod, Todd; Ho, Fat D.

2012-01-01

The original Memory Test Experiment successfully flew on the FASTSAT satellite launched in November 2010. It contained a single Ramtron 512K ferroelectric memory. The memory device went through many thousands of read/write cycles and recorded any errors that were encountered. The original mission length was schedule to last 6 months but was extended to 18 months. New opportunities exist to launch a similar satellite and considerations for a new memory test experiment should be examined. The original experiment had to be designed and integrated in less than two months, so the experiment was a simple design using readily available parts. The follow-on experiment needs to be more sophisticated and encompass more technologies. This paper lays out the considerations for the design and development of this follow-on flight memory experiment. It also details the results from the original Memory Test Experiment that flew on board FASTSAT. Some of the design considerations for the new experiment include the number and type of memory devices to be used, the kinds of tests that will be performed, other data needed to analyze the results, and best use of limited resources on a small satellite. The memory technologies that are considered are FRAM, FLASH, SONOS, Resistive Memory, Phase Change Memory, Nano-wire Memory, Magneto-resistive Memory, Standard DRAM, and Standard SRAM. The kinds of tests that could be performed are read/write operations, non-volatile memory retention, write cycle endurance, power measurements, and testing Error Detection and Correction schemes. Other data that may help analyze the results are GPS location of recorded errors, time stamp of all data recorded, radiation measurements, temperature, and other activities being perform by the satellite. The resources of power, volume, mass, temperature, processing power, and telemetry bandwidth are extremely limited on a small satellite. Design considerations must be made to allow the experiment to not interfere with the satellite s primary mission.

Development of a Sono-Assembled, Bifunctional Soy Peptide Nanoparticle for Cellular Delivery of Hydrophobic Active Cargoes.

PubMed

Zhang, Yuanhong; Zhao, Mouming; Ning, Zhengxiang; Yu, Shujuan; Tang, Ning; Zhou, Feibai

2018-04-25

Soy proteins are prone to aggregate upon proteolysis, hindering their sustainable development in food processing. Here, a continuous work on the large insoluble peptide aggregates was carried out, aiming to develop a new type of soy peptide-based nanoparticle (SPN) for active cargo delivery. Sono-assembled SPN in spherical appearance and core-shell structure maintained by noncovalent interactions was successfully fabricated, exhibiting small particle size (103.95 nm) in a homogeneous distribution state (PDI = 0.18). Curcumin as a model cargo was efficiently encapsulated into SPN upon sonication, showing high water dispersity (129.6 mg/L, 10 4 higher than its water solubility) and storage stability. Additionally, the pepsin-resistant SPN contributed to the controlled release of curcumin at the intestinal phase and thus significantly improved the bioaccessibility. Encapsulated curcumin was effective in protecting glutamate-induced toxicity in PC12 cells, where the matrix SPN can simultaneously reduce lipid peroxidation and elevate antioxidant enzymes levels, innovatively demonstrating its bifunctionality during cellular delivery.

Sono assisted electrocoagulation process for the removal of pollutant from pulp and paper industry effluent.

PubMed

Asaithambi, P; Aziz, Abdul Raman Abdul; Sajjadi, Baharak; Daud, Wan Mohd Ashri Bin Wan

2017-02-01

In the present work, the efficiency of the sonication, electrocoagulation, and sono-electrocoagulation process for removal of pollutants from the industrial effluent of the pulp and paper industry was compared. The experimental results showed that the sono-electrocoagulation process yielded higher pollutant removal percentage compared to the sonication and electrocoagulation process alone. The effect of the operating parameters in the sono-electrocoagulation process such as electrolyte concentration (1-5 g/L), current density (1-5 A/dm 2 ), effluent pH (3-11), COD concentration (1500-6000 mg/L), inter-electrode distance (1-3 cm), and electrode combination (Fe and Al) on the color removal, COD removal, and power consumption were studied. The maximum color and COD removal percentages of 100 and 95 %, respectively, were obtained at the current density of 4 A/dm 2 , electrolyte concentration of 4 g/L, effluent pH of 7, COD concentration of 3000 mg/L, electrode combination of Fe/Fe, inter-electrode distance of 1 cm, and reaction time of 4 h, respectively. The color and COD removal percentages were analyzed by using an UV/Vis spectrophotometer and closed reflux method. The results showed that the sono-electrocoagulation process could be used as an efficient and environmental friendly technique for complete pollutant removal.

Functions of Discourse Markers "Ano and Sono" in Written Dialogue.

ERIC Educational Resources Information Center

Fujita, Yasuko

Through examination of the discourse markers "ano" and "sono" in Japanese, this paper explores how these linguistic devices function differently in conversation. The focus of this analysis is the mental and social functions through which a speaker attempts to achieve an interpersonal rapport with a listener. In particular, the…

Enhanced sonochemical degradation of azure B dye by the electroFenton process.

PubMed

Martínez, Susana Silva; Uribe, Edgar Velasco

2012-01-01

The degradation of azure B dye (C15H16ClN3S; AB) has been studied by Fenton, sonolysis and sono-electroFenton processes employing ultrasound at 23 kHz and the electrogeneration of H2O2 at the reticulated vitreous carbon electrode. It was found that the dye degradation followed apparent first-order kinetics in all the degradation processes tested. The rate constant was affected by both the pH of the solution and initial concentration of Fe2+, with the highest degradation obtained at pH between 2.6 and 3. The first-order rate constant decreased in the following order: sono-electroFenton>Fenton>sonolysis. The rate constant for AB degradation by sono-electroFenton is ∼10-fold that of sonolysis and ∼2-fold the one obtained by Fenton under silent conditions. The chemical oxygen demand was abated ∼68% and ∼85% by Fenton and sono-electroFenton respectively, achieving AB concentration removal over 90% with both processes. Copyright © 2011 Elsevier B.V. All rights reserved.

Engineering design and prototype development of a full scale ultrasound system for virgin olive oil by means of numerical and experimental analysis.

PubMed

Clodoveo, Maria Lisa; Moramarco, Vito; Paduano, Antonello; Sacchi, Raffaele; Di Palmo, Tiziana; Crupi, Pasquale; Corbo, Filomena; Pesce, Vito; Distaso, Elia; Tamburrano, Paolo; Amirante, Riccardo

2017-07-01

The aim of the virgin olive oil extraction process is mainly to obtain the best quality oil from fruits, by only applying mechanical actions while guaranteeing the highest overall efficiency. Currently, the mechanical methods used to extract virgin oils from olives are basically of two types: the discontinuous system (obsolete) and the continuous one. Anyway the system defined as "continuous" is composed of several steps which are not all completely continuous, due to the presence of the malaxer, a device that works in batch. The aim of the paper was to design, realize and test the first full scale sono-exchanger for the virgin olive oil industry, to be placed immediately after the crusher and before the malaxer. The innovative device is mainly composed of a triple concentric pipe heat exchanger combined with three ultrasound probes. This mechanical solution allows both the cell walls (which release the oil droplets) along with the minor compounds to be destroyed more effectively and the heat exchange between the olive paste and the process water to be accelerated. This strategy represents the first step towards the transformation of the malaxing step from a batch operation into a real continuous process, thus improving the working capacity of the industrial plants. Considering the heterogeneity of the olive paste, which is composed of different tissues, the design of the sono-exchanger required a thorough fluid dynamic analysis. The thermal effects of the sono-exchanger were monitored by measuring the temperature of the product at the inlet and the outlet of the device; in addition, the measurement of the pigments concentration in the product allowed monitoring the mechanical effects of the sono-exchanger. The effects of the innovative process were also evaluated in terms of extra virgin olive oil yields and quality, evaluating the main legal parameters, the polyphenol and tocopherol content. Moreover, the activity of the polyphenol oxidase enzyme in the olive paste was measured. Copyright © 2017 Elsevier B.V. All rights reserved.

Acoustic Characterization and Enhanced Ultrasound Imaging of Long-Circulating Lipid-Coated Microbubbles.

PubMed

Li, Hongbo; Yang, Yanye; Zhang, Meimei; Yin, Liping; Tu, Juan; Guo, Xiasheng; Zhang, Dong

2018-05-01

A long-circulating lipid-coated ultrasound (US) contrast agent was fabricated to achieve a longer wash-out time and gain more resistance against higher-mechanical index sonication. Systemic physical, acoustic, and in vivo imaging experiments were performed to better understand the underlying mechanism enabling the improvement of contrast agent performance by adjusting the physical and acoustic properties of contrast agent microbubbles. By simply altering the gas core, a kind of US contrast agent microbubble was synthesized with a similar lipid-coating shell as SonoVue microbubbles (Bracco SpA, Milan, Italy) to achieve a longer wash-out time and higher inertial cavitation threshold. To bridge the structure-performance relationship of the synthesized microbubbles, the imaging performance of the microbubbles was assessed in vivo with SonoVue as a control group. The size distribution and inertial cavitation threshold of the synthesized microbubbles were characterized, and the shell parameters of the microbubbles were determined by acoustic attenuation measurements. All of the measurements were compared with SonoVue microbubbles. The synthesized microbubbles had a spherical shape, a smooth, consistent membrane, and a uniform distribution, with an average diameter of 1.484 μm. According to the measured attenuation curve, the synthesized microbubbles resonated at around 2.8 MHz. Although the bubble's shell elasticity (0.2 ± 0.09 N/m) was comparable with SonoVue, it had relatively greater viscosity and inertial cavitation because of the different gas core. Imaging studies showed that the synthesized microbubbles had a longer circulation time and a better chance of fighting against rapid collapse than SonoVue. Nano/micrometer long-circulating lipid-coated microbubbles could be fabricated by simply altering the core composition of SonoVue microbubbles with a higher-molecular weight gas. The smaller diameter and higher inertial cavitation threshold of the synthesized microbubbles might make it easier to access deep-seated organs and give prolonged imaging enhancement in the liver. © 2017 by the American Institute of Ultrasound in Medicine.

Enhanced photo-, sono- and sonophotocatalysis of methylene blue via SnO2 nanoparticle supported on nanographene platelets (NGP)

NASA Astrophysics Data System (ADS)

Paramarta, V.; Taufik, A.; Saleh, R.

2017-07-01

In our previous study, we have reported the catalytic (photo- and sono-) performance of SnO2 nanoparticles in methylene blue (MB) removal from aqueous solution. In this study, SnO2/nanographene platelets (NGP) composites were fabricated by depositing SnO2 nanoparticle onto nanographene platelets surface to develop photo-, sono-, and sonophotocatalysts, SnO2 nanoparticle, and SnO2/NGP composites were successfully synthesized using the sol-gel and coprecipitation method, respectively. The nanographene platelets (NGP) content was varied from 5, 10, and 15 weight percentages (wt.%). The optical properties and thermal stability of the samples were characterized using X-ray Diffraction (XRD), Fourier Transform Infrared (FTIR), and Thermal Gravimetric Analysis (TGA). The catalytic ability of the samples was investigated using photo-, sono-, and sonophoto degradation of MB which was observed when nanographene platelets (NGP) were added into SnO2 nanocomposite. The photo-, sono- and sonophotocatalytic activities of SnO2/NGP composites on dyes were analyzed by measuring the change in absorbance of dyes under UV-spectrophotometer. The degradation of the organic dyes has been calculated by monitoring the degradation in concentration of the dyes before and after irradiation of UV light, ultrasound, and both of them respectively. The influence of other parameters such as catalyst dosage, pH, and scavenger have also been investigated. The results showed that SnO2/NGP composite with 10 weight percent (wt.%) has better catalytic performance than pure SnO2 nanoparticle. The reusability tests have also been done to ensure the stability of the used catalysts.

Intraoperative Ultrasound to Assess for Pancreatic Duct Injuries

DTIC Science & Technology

2015-04-01

cholecystocholangiopancreatography is often nondiagnostic, gastroenterologists may not be available for endoscopic retrograde cholangiopancreatography (ERCP...10MHz.We use the SonoSite MicroMaxx SLT 10-5 MHz 52mm broadband linear array intraoperative US probe ( FUJIFILM SonoSite, Inc., Bothell, WA). The duct...Intraoperative US Availability Is gastroenterology available? Is the fluoroscopic and endoscopic equipment available? Is MRCP available? Is a

Sono-photocatalytic production of hydrogen by interface modified metal oxide insulators.

PubMed

Senevirathne, Rushdi D; Abeykoon, Lahiru K; De Silva, Nuwan L; Yan, Chang-Feng; Bandara, Jayasundera

2018-07-01

Dielectric oxide materials are well-known insulators that have many applications in catalysis as well as in device manufacturing industries. However, these dielectric materials cannot be employed directly in photochemical reactions that are initiated by the absorption of UV-Vis photons. Despite their insensitivity to solar energy, dielectric materials can be made sono-photoactive even for low energy IR photons by modifications of the interfacial properties of dielectric materials by noble metals and metal oxides. In this investigation, by way of interface modification of dielectric MgO nanoparticles by Ag metal and Ag 2 O nanoparticles, IR photon initiated sono-photocatalytic activity of MgO is reported. The observed photocatalytic activity is found to be the synergic action of both IR light and sonication effect and sonication assisted a multi-step, sub-bandgap excitation of electrons in the MgO is proposed for the observed catalytic activity of Ag/Ag 2 O coated MgO nanoparticles. Our investigation reveals that other dielectric materials such as silver coated SiO 2 and Al 2 O 3 also exhibit IR active sono-photocatalytic activity. Copyright © 2018 Elsevier B.V. All rights reserved.

Estimation of intra-operator variability in perfusion parameter measurements using DCE-US

PubMed Central

Gauthier, Marianne; Leguerney, Ingrid; Thalmensi, Jessie; Chebil, Mohamed; Parisot, Sarah; Peronneau, Pierre; Roche, Alain; Lassau, Nathalie

2011-01-01

AIM: To investigate intra-operator variability of semi-quantitative perfusion parameters using dynamic contrast-enhanced ultrasonography (DCE-US), following bolus injections of SonoVue®. METHODS: The in vitro experiments were conducted using three in-house sets up based on pumping a fluid through a phantom placed in a water tank. In the in vivo experiments, B16F10 melanoma cells were xenografted to five nude mice. Both in vitro and in vivo, images were acquired following bolus injections of the ultrasound contrast agent SonoVue® (Bracco, Milan, Italy) and using a Toshiba Aplio® ultrasound scanner connected to a 2.9-5.8 MHz linear transducer (PZT, PLT 604AT probe) (Toshiba, Japan) allowing harmonic imaging (“Vascular Recognition Imaging”) involving linear raw data. A mathematical model based on the dye-dilution theory was developed by the Gustave Roussy Institute, Villejuif, France and used to evaluate seven perfusion parameters from time-intensity curves. Intra-operator variability analyses were based on determining perfusion parameter coefficients of variation (CV). RESULTS: In vitro, different volumes of SonoVue® were tested with the three phantoms: intra-operator variability was found to range from 2.33% to 23.72%. In vivo, experiments were performed on tumor tissues and perfusion parameters exhibited values ranging from 1.48% to 29.97%. In addition, the area under the curve (AUC) and the area under the wash-out (AUWO) were two of the parameters of great interest since throughout in vitro and in vivo experiments their variability was lower than 15.79%. CONCLUSION: AUC and AUWO appear to be the most reliable parameters for assessing tumor perfusion using DCE-US as they exhibited the lowest CV values. PMID:21512654

Estimation of intra-operator variability in perfusion parameter measurements using DCE-US.

PubMed

Gauthier, Marianne; Leguerney, Ingrid; Thalmensi, Jessie; Chebil, Mohamed; Parisot, Sarah; Peronneau, Pierre; Roche, Alain; Lassau, Nathalie

2011-03-28

To investigate intra-operator variability of semi-quantitative perfusion parameters using dynamic contrast-enhanced ultrasonography (DCE-US), following bolus injections of SonoVue(®). The in vitro experiments were conducted using three in-house sets up based on pumping a fluid through a phantom placed in a water tank. In the in vivo experiments, B16F10 melanoma cells were xenografted to five nude mice. Both in vitro and in vivo, images were acquired following bolus injections of the ultrasound contrast agent SonoVue(®) (Bracco, Milan, Italy) and using a Toshiba Aplio(®) ultrasound scanner connected to a 2.9-5.8 MHz linear transducer (PZT, PLT 604AT probe) (Toshiba, Japan) allowing harmonic imaging ("Vascular Recognition Imaging") involving linear raw data. A mathematical model based on the dye-dilution theory was developed by the Gustave Roussy Institute, Villejuif, France and used to evaluate seven perfusion parameters from time-intensity curves. Intra-operator variability analyses were based on determining perfusion parameter coefficients of variation (CV). In vitro, different volumes of SonoVue(®) were tested with the three phantoms: intra-operator variability was found to range from 2.33% to 23.72%. In vivo, experiments were performed on tumor tissues and perfusion parameters exhibited values ranging from 1.48% to 29.97%. In addition, the area under the curve (AUC) and the area under the wash-out (AUWO) were two of the parameters of great interest since throughout in vitro and in vivo experiments their variability was lower than 15.79%. AUC and AUWO appear to be the most reliable parameters for assessing tumor perfusion using DCE-US as they exhibited the lowest CV values.

[Effectiveness of school-based interventions to prevent traffic accidents: an overview of secondary literature].

PubMed

Guerriero, Chiara; Verdina, Federico; Ferri, Chiara; Pizzaguerra, Martina; Silvestri, Silvia; Tober, Nastassja; Ristagno, Quenya; Costa, Alessandro; Cerasuolo, Michele; Faggiano, Fabrizio; Allara, Elias

2016-01-01

INTRODUZIONE: gli incidenti stradali sono l'ottava causa di morte al mondo e la prima tra i giovani di 15-29 anni. In Italia il Piano nazionale sicurezza stradale raccomanda l'educazione scolastica per la prevenzione degli incidenti stradali; ad oggi non esistono documenti che raccolgano evidenze di efficacia sugli interventi educativi stradali e le rapportino al contesto italiano. OBIETTIVI: riassumere e discutere ciò che è noto in letteratura riguardo agli interventi scolastici per la prevenzione degli incidenti stradali. METODI: sono state ricercate linee guida e revisioni sistematiche usando i seguenti criteri di inclusione: popolazione di età inferiore ai 25 anni di entrambi i sessi; interventi scolastici di educazione stradale; effetti su indicatori primari di esito come riduzione degli incidenti stradali, astinenza dalla guida sotto l'effetto di alcol e dall'accettare passaggi in macchina da guidatori che sono sotto l'effetto di alcol; effetti su indicatori secondari di esito come conoscenze e competenze sui comportamenti di guida sicura. RISULTATI: sono state identificate due revisioni sistematiche. L'educazione stradale nelle scuole non mostra evidenza di efficacia (rischio relativo 1,03; IC95% 0,98-1,08) nel ridurre gli incidenti. Programmi scolastici più specifici mostrano risultati solo in parte convincenti per l'adozione di comportamenti sicuri come l'astinenza dal guidare sotto l'effetto di alcol e dall'accettare passaggi in macchina da guidatori che sono sotto l'effetto di alcol. DISCUSSIONE: le revisioni incluse non hanno trovato programmi efficaci nella riduzione degli incidenti stradali o dei fattori che possano determinarli. Nell'attesa di studi più recenti, appare opportuno promuovere l'implementazione di interventi misti, scolastici e di comunità, che hanno mostrato maggiori prove di efficacia.

Low Power Resistive Oxygen Sensor Based on Sonochemical SrTi0.6Fe0.4O2.8 (STFO40)

PubMed Central

Stratulat, Alisa; Serban, Bogdan-Catalin; de Luca, Andrea; Avramescu, Viorel; Cobianu, Cornel; Brezeanu, Mihai; Buiu, Octavian; Diamandescu, Lucian; Feder, Marcel; Ali, Syed Zeeshan; Udrea, Florin

2015-01-01

The current paper reports on a sonochemical synthesis method for manufacturing nanostructured (typical grain size of 50 nm) SrTi0.6Fe0.4O2.8 (Sono-STFO40) powder. This powder is characterized using X ray-diffraction (XRD), Mössbauer spectroscopy and Scanning Electron Microscopy (SEM), and results are compared with commercially available SrTi0.4Fe0.6O2.8 (STFO60) powder. In order to manufacture resistive oxygen sensors, both Sono-STFO40 and STFO60 are deposited, by dip-pen nanolithography (DPN) method, on an SOI (Silicon-on-Insulator) micro-hotplate, employing a tungsten heater embedded within a dielectric membrane. Oxygen detection tests are performed in both dry (RH = 0%) and humid (RH = 60%) nitrogen atmosphere, varying oxygen concentrations between 1% and 16% (v/v), at a constant heater temperature of 650 °C. The oxygen sensor, based on the Sono-STFO40 sensing layer, shows good sensitivity, low power consumption (80 mW), and short response time (25 s). These performance are comparable to those exhibited by state-of-the-art O2 sensors based on STFO60, thus proving Sono-STFO40 to be a material suitable for oxygen detection in harsh environments. PMID:26205267

Sono-elastography for Differentiating Benign and Malignant Cervical Lymph Nodes: A Systematic Review and Meta-Analysis

PubMed Central

Ghajarzadeh, Mahsa; Mohammadifar, Mehdi; Azarkhish, Kamran; Emami-Razavi, Seyed Hassan

2014-01-01

We did this systematic review to determine diagnostic accuracy of sono-elastography in evaluating cervical lymph nodes (LNs). A highly sensitive search for sono-elastography and LNs was performed in MEDLINE, Cochrane Library, ACP Journal Club, EMBASE, Health Technology assessment, and ISI web of knowledge for studies published prior to December 2012. SPSS version 18 (SPSS Inc., Chicago, IL, USA) used for descriptive analysis and meta-disk version 1.4 applied for meta-analysis. Forest plots for pooled estimates and summery of receiver operating characteristic plots for different cut-offs were produced. The literature and manual search yielded 69 articles, of which 10 were eligible to include. A total of 578 individuals with a total number of 936 cervical LNs was evaluated (502 malignant and 434 benign). The summary sensitivity of the scoring and strain ratio (SR) measurements for the differentiation of benign and malignant LNs were 0.76 (95% CI: 0.71–0.8) and 0.83 (95% CI: 0.78–0.87). The summary specificities were 0.8 (95% confidence interval [CI]: 0.75–0.84) and 0.84 (95% CI: 0.79–0.88), respectively. Area under the curve for scoring system was 0.86 (standard error [SE] = 0.03) and 0.95 (SE = 0.02) for SR measurement. Sono-elastograohy has high accuracy in differentiating benign and malignant cervical LNs. PMID:25709787

Sono-elastography for Differentiating Benign and Malignant Cervical Lymph Nodes: A Systematic Review and Meta-Analysis.

PubMed

Ghajarzadeh, Mahsa; Mohammadifar, Mehdi; Azarkhish, Kamran; Emami-Razavi, Seyed Hassan

2014-12-01

We did this systematic review to determine diagnostic accuracy of sono-elastography in evaluating cervical lymph nodes (LNs). A highly sensitive search for sono-elastography and LNs was performed in MEDLINE, Cochrane Library, ACP Journal Club, EMBASE, Health Technology assessment, and ISI web of knowledge for studies published prior to December 2012. SPSS version 18 (SPSS Inc., Chicago, IL, USA) used for descriptive analysis and meta-disk version 1.4 applied for meta-analysis. Forest plots for pooled estimates and summery of receiver operating characteristic plots for different cut-offs were produced. The literature and manual search yielded 69 articles, of which 10 were eligible to include. A total of 578 individuals with a total number of 936 cervical LNs was evaluated (502 malignant and 434 benign). The summary sensitivity of the scoring and strain ratio (SR) measurements for the differentiation of benign and malignant LNs were 0.76 (95% CI: 0.71-0.8) and 0.83 (95% CI: 0.78-0.87). The summary specificities were 0.8 (95% confidence interval [CI]: 0.75-0.84) and 0.84 (95% CI: 0.79-0.88), respectively. Area under the curve for scoring system was 0.86 (standard error [SE] = 0.03) and 0.95 (SE = 0.02) for SR measurement. Sono-elastograohy has high accuracy in differentiating benign and malignant cervical LNs.

Ultrasound (US), Ultraviolet light (UV) and combination (US+UV) assisted semiconductor catalysed degradation of organic pollutants in water: oscillation in the concentration of hydrogen peroxide formed in situ.

PubMed

Jyothi, K P; Yesodharan, Suguna; Yesodharan, E P

2014-09-01

Application of Advanced Oxidation Processes (AOP) such as sono, photo and sonophoto catalysis in the purification of polluted water under ambient conditions involve the formation and participation of Reactive Oxygen Species (ROS) like ·OH, HO2·, O2(-), H2O2 etc. Among these, H2O2 is the most stable and is also a precursor for the reactive free radicals. Current investigations on the ZnO mediated sono, photo and sonophoto catalytic degradation of phenol pollutant in water reveal that H2O2 formed in situ cannot be quantitatively correlated with the degradation of the pollutant. The concentration of H2O2 formed does not increase corresponding to phenol degradation and reaches a plateau or varies in a wave-like fashion (oscillation) with well defined crests and troughs, indicating concurrent formation and decomposition. The concentration at which decomposition overtakes formation or formation overtakes decomposition is sensitive to the reaction conditions. Direct photolysis of H2O2 in the absence of catalyst or the presence of pre-equilibrated (with the adsorption of H2O2) catalyst in the absence of light does not lead to the oscillation. The phenomenon is more pronounced in sonocatalysis, the intensity of oscillation being in the order sonocatalysis>photocatalysis⩾sonophotocatalysis while the degradation of phenol follows the order sonophotocatalysis>photocatalysis>sonocatalysis>sonolysis>photolysis. In the case of sonocatalysis, the oscillation continues for some more time after discontinuing the US irradiation indicating that the reactive free radicals as well as the trapped electrons and holes which interact with H2O2 have longer life time (memory effect). Copyright © 2014 Elsevier B.V. All rights reserved.

Il ruolo svolto dall’attività lavorativa sull’ipertensione arteriosa

PubMed Central

Barbini, N.; Gorini, G.; Ferrucci, L.; Biggeri, A.

2009-01-01

RIASSUNTO Introduzione I parametri di pressione arteriosa, sistolica (PAS) o diastolica (PAD) hanno costituito I’oggetto di numerosi studi, alcuni dei quali stabiliscono un’associazione tra I’aumnto di tali parametri e la mortalità, in particolare alle età medie. I fattori di rischio di ipertensione più frequentemente studiati sono il consumo di alcol, il fumo e I’origine etnica in riferimento sia alle differenze genetiche che nella condotta alimentare, mentre i fattori di origine professionale sono stati presi in considerazione più raramente e in maniera poco approfondita, inoltre sono state riferite notevoli differenze nelle pressioni arteriose medie di individui che svolgono professioni diverse. Sembra infatti che i “colletti blu” siano più a rischio dei “colletti bianchi”. Obiettivi Il nostro scopo è valutare se determinati rischi o vincoli connessi con l’attività professionale o determinati stili di vita rappresentano un fattore di rischio per l’ipertensione arteriosa in considerazioni dell’aumentare dell’età. Elementi specifici che rendano conto di questa relazione non sono stati ancora completamente chiariti e soprattutto i dati sulla popolazione italiana sono molto limitati. Metodi La metodologia di ricerca utilizzata è stata quella dell’indagine francese ESTEV (Derriennic, Touranchet, Volkoff) - VISAT (Marquie, Janson), studio epidemiologico longitudinale su oltre 23000 lavoratori attivata in Francia nel 1990 al fine di indagare gli effetti a lungo termine delle condizioni di lavoro, riferite all’intera vita professionale, sia sull’invecchiamento sia sulla salute dei lavoratori. Analoga indagine è stata avviata in Italia, nel 2000, in 6 Regioni, prendendo in esame i lavoratori dipendenti di diversi settori produttivi appartenenti a 5 coorti di età: da 32 a 52 anni con intervallo di 5 anni. Le rilevazioni sono state effettuate dai medici del lavoro di azienda attraverso 3 questionari: 1. sulle condizioni professionali (esposizione a determinati rischi o vincoli); 2. sugli stili di vita e la salute percepita secondo il Nottingham Health Profile; 3. sulle condizioni oggettive di salute. Per il presente lavoro saranno considerati solo alcuni parametri utili all’approfondimento epidemiologico nel settore cardiocircolatorio. Essi riguarderanno: 1) le condizioni di lavoro, 2) la valutazione soggettiva del lavoro, 3) costrizioni specifiche del lavoro vissute come più gravose con l’avanzare dell’età. Relativamente all’ipertensione, sono stati considerati ipertesi i soggetti che presentavano una PAS ≥160 mm/Hg e/o una PAD ≥90 mm/Hg nonché coloro in cura antipertensiva. Risultati I risultati si riferiscono a 1104 lavoratori, di cui 76% uomini e 24% donne. La prevalenza di ipertensione si è dimostrata più elevata nei maschi (33% Vs 22%). Le stime del rischio hanno evidenziato una associazione statisticamente significativa con alcuni fattori lavorativi come mantenere posture difficili (O.R. 1.71), lavorare in presenza di calore (O.R. 1.43), a contatto con agenti chimici (O.R, 1.31). stare a lungo seduti (O.R. 1.48), fare più cose contemporaneamente (O.R. 1.41), essere interrotti nel proprio lavoro (O.R. 1,35). non poter distogilere gli occhi dal lavoro (O.R.1.61). Conclusioni Noi abbiamo osservato che alcune caratteristiche fisiche del lavoro, ma soprattutto quelle di tipo organizzativo sono fortemente associate all’ipertensione arteriosa. Un elemento importante è sembrata la valutazione soggettiva del valore che i lavoratori danno del proprio lavoro: tale elemento è fortemente connesso con I’organizzazione del lavoro, pertanto è un possibile target di prevenzione (fattore di rischio modificabile). PMID:17886759

Needle echogenicity in ultrasound-guided lumbar spine injections: a cadaveric study.

PubMed

Gofeld, Michael; Krashin, Daniel L; Ahn, Sangmin

2013-01-01

Echogenicity of regional anesthesia needles has been tested on different preclinical models; however, previous studies were done in an ideal experimental setting utilizing high-frequency insonation and superficially located targets. Because steep-angle deep injections are typically required for spinal and other chronic pain procedures, and low-frequency transducers are used, further feasibility study is warranted. To determine effectiveness of steep-angle deep injections, typically required for spinal and other chronic pain procedures. Experimental laboratory study. Willed Body Program, University of Washington. In-plane lumbar spine procedures with 50° and 70° angles were performed on a human cadaver. The images and video clips of a non-echogenic (Quincke-type) and echogenic (SonoPlex, StimuQuick, and EchoStim) needle placements were presented to 3 blinded assessors who rated the needle visibility on a 4-point scale. The data was statistically analyzed to determine the differences in visibility between the needles with and without the digital image enhancement, and to compare the video clips to captured images. ANOVA analysis demonstrated that overall SonoPlex was significantly better (P = 0.02) than other needles. SonoPlex maintained its superiority in the subset of facet joint injections (P = 0.02), followed by Quincke-type, then the StimuQuik, and EchoStim needles. In deep procedures, EchoStim was comparable with SonoPlex (P = 0.03), and they both were better than the other 2 needles. The enhanced images received higher rates, with a 0.6 point mean improved rating (P = 0). This study is limited by choice of needles, number of experiments performed, and potential postmortem changes of echogenicity. The SonoPlex needle appeared to have better echogenicity in this study. While non-echogenic Quincke-type needle visibility was adequate in superficial placements, it was limited in deep injections. An imaging enhancement is effective in improving needle visibility and should be used whenever possible.

Preparation of nanobubbles carrying androgen receptor siRNA and their inhibitory effects on androgen-independent prostate cancer when combined with ultrasonic irradiation.

PubMed

Wang, Luofu; Zhang, Miao; Tan, Kaibin; Guo, Yanli; Tong, Haipeng; Fan, Xiaozhou; Fang, Kejing; Li, Rui

2014-01-01

The objective of this study was to investigate nanobubbles carrying androgen receptor (AR) siRNA and their in vitro and in vivo anti-tumor effects, when combined with ultrasonic irradiation, on androgen-independent prostate cancer (AIPC). Nanobubbles carrying AR siRNA were prepared using poly-L-lysine and electrostatic adsorption methods. Using C4-2 cell activity as a testing index, the optimal irradiation parameters (including the nanobubble number/cell number ratio, mechanical index [MI], and irradiation time) were determined and used for transfection of three human prostate cancer cell lines (C4-2, LNCaP, and PC-3 cells). The AR expression levels were investigated with RT-PCR and Western blot analysis. Additionally, the effects of the nanobubbles and control microbubbles named SonoVue were assessed via imaging in a C4-2 xenograft model. Finally, the growth and AR expression of seven groups of tumor tissues were assessed using the C4-2 xenograft mouse model. The nanobubbles had an average diameter of 609.5±15.6 nm and could effectively bind to AR siRNA. Under the optimized conditions of a nanobubble number/cell number ratio of 100∶1, an MI of 1.2, and an irradiation time of 2 min, the highest transfection rates in C4-2, LNCaP, and PC-3 cells were 67.4%, 74.0%, and 63.96%, respectively. In the C4-2 and LNCaP cells, treatment with these binding nanobubbles plus ultrasonic irradiation significantly inhibited cell growth and resulted in the suppression of AR mRNA and protein expression. Additionally, contrast-enhanced ultrasound showed that the nanobubbles achieved stronger signals than the SonoVue control in the central hypovascular area of the tumors. Finally, the anti-tumor effect of these nanobubbles plus ultrasonic irradiation was most significant in the xenograft tumor model compared with the other groups. Nanobubbles carrying AR siRNA could be potentially used as gene vectors in combination with ultrasonic irradiation for the treatment of AIPC.

Preparation of Nanobubbles Carrying Androgen Receptor siRNA and Their Inhibitory Effects on Androgen-Independent Prostate Cancer when Combined with Ultrasonic Irradiation

PubMed Central

Tan, Kaibin; Guo, Yanli; Tong, Haipeng; Fan, Xiaozhou; Fang, Kejing; Li, Rui

2014-01-01

Objective The objective of this study was to investigate nanobubbles carrying androgen receptor (AR) siRNA and their in vitro and in vivo anti-tumor effects, when combined with ultrasonic irradiation, on androgen-independent prostate cancer (AIPC). Materials and Methods Nanobubbles carrying AR siRNA were prepared using poly-L-lysine and electrostatic adsorption methods. Using C4-2 cell activity as a testing index, the optimal irradiation parameters (including the nanobubble number/cell number ratio, mechanical index [MI], and irradiation time) were determined and used for transfection of three human prostate cancer cell lines (C4-2, LNCaP, and PC-3 cells). The AR expression levels were investigated with RT-PCR and Western blot analysis. Additionally, the effects of the nanobubbles and control microbubbles named SonoVue were assessed via imaging in a C4-2 xenograft model. Finally, the growth and AR expression of seven groups of tumor tissues were assessed using the C4-2 xenograft mouse model. Results The nanobubbles had an average diameter of 609.5±15.6 nm and could effectively bind to AR siRNA. Under the optimized conditions of a nanobubble number/cell number ratio of 100∶1, an MI of 1.2, and an irradiation time of 2 min, the highest transfection rates in C4-2, LNCaP, and PC-3 cells were 67.4%, 74.0%, and 63.96%, respectively. In the C4-2 and LNCaP cells, treatment with these binding nanobubbles plus ultrasonic irradiation significantly inhibited cell growth and resulted in the suppression of AR mRNA and protein expression. Additionally, contrast-enhanced ultrasound showed that the nanobubbles achieved stronger signals than the SonoVue control in the central hypovascular area of the tumors. Finally, the anti-tumor effect of these nanobubbles plus ultrasonic irradiation was most significant in the xenograft tumor model compared with the other groups. Conclusion Nanobubbles carrying AR siRNA could be potentially used as gene vectors in combination with ultrasonic irradiation for the treatment of AIPC. PMID:24798477

Treating soil-washing fluids polluted with oxyfluorfen by sono-electrolysis with diamond anodes.

PubMed

Vieira Dos Santos, E; Sáez, C; Cañizares, P; Martínez-Huitle, C A; Rodrigo, M A

2017-01-01

This works is focused on the treatment by sono-electrolysis of the liquid effluents produced during the Surfactant-Aided Soil-Washing (SASW) of soils spiked with herbicide oxyfluorfen. Results show that this combined technology is very efficient and attains the complete mineralization of the waste, regardless of the surfactant/soil radio applied in the SASW process (which is the main parameter of the soil remediation process and leads to very different wastes). Both the surfactant and the herbicide are completely degraded, even when single electrolysis is used; and only two intermediates are detected by HPLC in very low concentrations. Conversely, the efficiency of single sonolysis approach, for the oxidation of pollutant, is very low and just small changes in the herbicides and surfactant concentrations are observed during the tests carried out. Sono-electrolysis with diamond electrodes achieved higher degradation rates than those obtained by single sonolysis and/or single electrolysis with diamond anodes. A key role of sulfate is developed, when it is released after the electrochemical degradation of surfactant. The efficient catalytic effect observed which can be explained by the anodic formation of persulfate and the later, a sono-activation is attained to produce highly efficient sulfate radicals. The effect of irradiating US is more importantly observed in the pesticide than in the surfactant, in agreement with the well-known behavior of these radicals which are known to oxidize more efficiently aromatic compounds than aliphatic species. Copyright © 2016 Elsevier B.V. All rights reserved.

Enhancing the anaerobic digestion potential of dairy waste activated sludge by two step sono-alkalization pretreatment.

PubMed

Rani, R Uma; Kumar, S Adish; Kaliappan, S; Yeom, Ick-Tae; Banu, J Rajesh

2014-05-01

High efficiency resource recovery from dairy waste activated sludge (WAS) has been a focus of attention. An investigation into the influence of two step sono-alkalization pretreatment (using different alkaline agents, pH and sonic reaction times) on sludge reduction potential in a semi-continuous anaerobic reactor was performed for the first time in literature. Firstly, effect of sludge pretreatment was evaluated by COD solubilization, suspended solids reduction and biogas production. At optimized condition (4172 kJ/kg TS of supplied energy for NaOH - pH 10), COD solubilization, suspended solids reduction and biogas production was 59%, 46% and 80% higher than control. In order to clearly describe the hydrolysis of waste activated sludge during sono-alkalization pretreatment by a two step process, concentrations of ribonucleic acid (RNA) and bound extracellular polymeric substance (EPS) were also measured. Secondly, semi-continuous process performance was studied in a lab-scale semi-continuous anaerobic reactor (5L), with 4 L working volume. With three operated SRTs, the SRT of 15 d was found to be most appropriate for economic operation of the reactor. Combining pretreatment with anaerobic digestion led to 58% and 62% of suspended solids and volatile solids reduction, respectively, with an improvement of 83% in biogas production. Thus, two step sono-alkalization pretreatment laid the basis in enhancing the anaerobic digestion potential of dairy WAS. Copyright © 2013 Elsevier B.V. All rights reserved.

FEM simulation of a sono-reactor accounting for vibrations of the boundaries.

PubMed

Louisnard, O; Gonzalez-Garcia, J; Tudela, I; Klima, J; Saez, V; Vargas-Hernandez, Y

2009-02-01

The chemical effects of acoustic cavitation are obtained in sono-reactors built-up from a vessel and an ultrasonic source. In this paper, simulations of an existing sono-reactor are carried out, using a linear acoustics model, accounting for the vibrations of the solid walls. The available frequency range of the generator (19-21 kHz) is systematically scanned. Global quantities are plotted as a function of frequency in order to obtain response curves, exhibiting several resonance peaks. In absence of the precise knowledge of the bubbles size distribution and spatial location, the attenuation coefficient of the wave is taken as a variable, but spatially uniform parameter, and its influence is studied. The concepts of acoustic energy, intensity, active power, and source impedance are recalled, along with the general balance equation for acoustic energy, which is used as a convergence check of the simulations. It is shown that the interface between the liquid and the solid walls cannot be correctly represented by the simple approximations of either infinitely soft, or infinitely hard boundaries. Moreover, the liquid-solid coupling allows the cooling jacket to receive a noticeable part of the input power, although it is not in direct contact with the sonotrode. It may therefore undergo cavitation and this feature opens the perspective to design sono-reactors which avoid direct contact between the working liquid and the sonotrode. Besides, the possibility to shift the main pressure antinode far from the sonotrode area by exciting a resonance of the system is examined.

Colour Doppler and microbubble contrast agent ultrasonography do not improve cancer detection rate in transrectal systematic prostate biopsy sampling.

PubMed

Taverna, Gianluigi; Morandi, Giovanni; Seveso, Mauro; Giusti, Guido; Benetti, Alessio; Colombo, Piergiuseppe; Minuti, Francesco; Grizzi, Fabio; Graziotti, Pierpaolo

2011-12-01

What's known on the subject? and What does the study add? Transrectal gray-scale ultrasonography guided prostate biopsy sampling is the method for diagnosing prostate cancer (PC) in patients with an increased prostate specific antigen level and/or abnormal digital rectal examination. Several imaging strategies have been proposed to optimize the diagnostic value of biopsy sampling, although at the first biopsy nearly 10-30% of PC still remains undiagnosed. This study compares the PC detection rate when employing Colour Doppler ultransongraphy with or without the injection of SonoVue™ microbubble contrast agent, versus the transrectal ultrasongraphy-guided systematic biopsy sampling. The limited accuracy, sensitivity, specificity and the additional cost of using the contrast agent do not justify its routine application in PC detection. • To compare prostate cancer (PC) detection rate employing colour Doppler ultrasonography with or without SonoVue™ contrast agent with transrectal ultrasonography-guided systematic biopsy sampling. • A total of 300 patients with negative digital rectal examination and transrectal grey-scale ultrasonography, with PSA values ranging between 2.5 and 9.9 ng/mL, were randomized into three groups: 100 patients (group A) underwent transrectal ultrasonography-guided systematic bioptic sampling; 100 patients (group B) underwent colour Doppler ultrasonography, and 100 patients (group C) underwent colour Doppler ultrasonography before and during the injection of SonoVue™. • Contrast-enhanced targeted biopsies were sampled into hypervascularized areas of peripheral, transitional, apical or anterior prostate zones. • All the patients included in Groups B and C underwent a further 13 systematic prostate biopsies. The cancer detection rate was calculated for each group. • In 88 (29.3%) patients a histological diagnosis of PC was made, whereas 22 (7.4%) patients were diagnosed with high-grade prostatic intraepithelial neoplasia or atypical small acinar proliferation. • No significant differences were found among the three groups for cancer detection rate (P= 0.329). • Additionally, low sensitivity, specificity and accuracy of colour Doppler with or without SonoVue™ contrast agent were found. • Prostate cancer detection rate does not significantly improve with the use of colour Doppler ultrasonography with or without SonoVue™. • Although no collateral effects have been highlighted, the combined use of colour Doppler ultrasonography and SonoVue™ determines adjunctive costs and increases the mean time for taking a single prostate biopsy. © 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.

Sleep-disordered breathing in patients with COPD and mild hypoxemia: prevalence and predictive variables.

PubMed

Silva, José Laerte Rodrigues; Conde, Marcus Barreto; Corrêa, Krislainy de Sousa; Rabahi, Helena; Rocha, Arthur Alves; Rabahi, Marcelo Fouad

2017-01-01

To infer the prevalence and variables predictive of isolated nocturnal hypoxemia and obstructive sleep apnea (OSA) in patients with COPD and mild hypoxemia. This was a cross-sectional study involving clinically stable COPD outpatients with mild hypoxemia (oxygen saturation = 90-94%) at a clinical center specializing in respiratory diseases, located in the city of Goiânia, Brazil. The patients underwent clinical evaluation, spirometry, polysomnography, echocardiography, arterial blood gas analysis, six-minute walk test assessment, and chest X-ray. The sample included 64 patients with COPD and mild hypoxemia; 39 (61%) were diagnosed with sleep-disordered breathing (OSA, in 14; and isolated nocturnal hypoxemia, in 25). Correlation analysis showed that PaO2 correlated moderately with mean sleep oxygen saturation (r = 0.45; p = 0.0002), mean rapid eye movement (REM) sleep oxygen saturation (r = 0.43; p = 0.001), and mean non-REM sleep oxygen saturation (r = 0.42; p = 0.001). A cut-off point of PaO2 ≤ 70 mmHg in the arterial blood gas analysis was significantly associated with sleep-disordered breathing (OR = 4.59; 95% CI: 1.54-13.67; p = 0.01). The model showed that, for identifying sleep-disordered breathing, the cut-off point had a specificity of 73.9% (95% CI: 51.6-89.8%), a sensitivity of 63.4% (95% CI: 46.9-77.9%), a positive predictive value of 81.3% (95% CI: 67.7-90.0%), and a negative predictive value of 53.1% (95% CI: 41.4-64.4%), with an area under the ROC curve of 0.69 (95% CI: 0.57-0.80), correctly classifying the observations in 67.2% of the cases. In our sample of patients with COPD and mild hypoxemia, the prevalence of sleep-disordered breathing was high (61%), suggesting that such patients would benefit from sleep studies. Inferir a prevalência e as variáveis preditivas de hipoxemia noturna e apneia obstrutiva do sono (AOS) em pacientes portadores de DPOC com hipoxemia leve. Estudo transversal realizado em pacientes ambulatoriais, clinicamente estáveis, portadores de DPOC e hipoxemia leve (saturação de oxigênio = 90-94%) em um centro clínico especializado no atendimento de doenças respiratórias em Goiânia (GO). Os pacientes foram submetidos à avaliação clínica, espirometria, polissonografia, ecocardiografia, gasometria arterial, teste de caminhada de seis minutos e radiografia de tórax. Foram avaliados 64 pacientes com DPOC e hipoxemia leve, e 39 (61%) apresentaram distúrbios respiratórios do sono (14 com AOS e 25 com hipoxemia noturna isolada). A análise de correlação mostrou moderada correlação da PaO2 com saturação média do sono (r = 0,45; p = 0,0002), saturação média do sono rapid eye movement (REM; r = 0,43; p = 0,001) e saturação média do sono não-REM (r = 0,42; p = 0,001). Um ponto de corte de PaO2 ≤ 70 mmHg (OR = 4,59; IC95%: 1,54-13,67; p = 0,01) na gasometria arterial foi significativamente associada com distúrbios respiratórios do sono. O modelo mostrou que, para identificar distúrbios respiratórios do sono, o ponto de corte teve uma especificidade de 73,9% (IC95%: 51,6-89,8%), uma sensibilidade de 63,4% (IC95%: 46,9-77,9%) e valores preditivos positivo e negativo de 81,3% (IC95%: 67,7-90,0%) e 53,1% (IC95%: 41,4-64,4%), respectivamente. A área sob a curva ROC foi de 0,69 (IC95%: 0,57-0,80), e a proporção de observações corretamente classificadas foi de 67,2% dos casos. A elevada prevalência de distúrbios respiratórios do sono em portadores de DPOC e hipoxemia leve nesta amostra (61%) sugere que esses pacientes podem se beneficiar da realização de estudos do sono.

Targeted nanobubbles in low-frequency ultrasound-mediated gene transfection and growth inhibition of hepatocellular carcinoma cells.

PubMed

Wu, Bolin; Qiao, Qiang; Han, Xue; Jing, Hui; Zhang, Hao; Liang, Hongjian; Cheng, Wen

2016-09-01

The use of SonoVue combined with ultrasound exposure increases the transfection efficiency of short interfering RNA (siRNA). The objective of this study was to prepare targeted nanobubbles (TNB) conjugated with NET-1 siRNA and an antibody GPC3 to direct nanobubbles to hepatocellular carcinoma cells. SMMC-7721 human hepatocellular carcinoma cells were treated with six different groups. The transfection efficiency and cellular apoptosis were measured by flow cytometry. The protein and messenger RNA (mRNA) expression were measured by Western blot and quantitative real-time PCR, respectively. The migration and invasion potential of the cells were determined by Transwell analysis. The results show that US-guided siRNA-TNB transfection effectively enhanced gene silencing. In summary, siRNA-TNB may be an effective delivery vector to mediate highly effective RNA interference in tumor treatment.

[National epidemiological surveillance systems of mesothelioma cases].

PubMed

Ferrante, Pierpaolo; Binazzi, Alessandra; Branchi, Claudia; Marinaccio, Alessandro

2016-01-01

INTRODUZIONE: sebbene la relazione causale tra esposizione ad amianto e malattie neoplastiche sia ben nota, in molti Paesi il consumo del materiale è ancora rilevante e crescente. A causa della lunga latenza, nei Paesi dove è stato bandito (come in Italia) è oggi in corso un'epidemia di malattie correlate ad amianto. OBIETTIVI: descrivere i sistemi di sorveglianza dei mesoteliomi attivi nel mondo mediante un'analisi comparativa. è stata condotta una revisione bibliografica della letteratura disponibile sui sistemi di sorveglianza epidemiologica dei mesoteliomi attivi nel mondo, comparando metodi e risultati disponibili. RISULTATI: sistemi di ricerca dei casi incidenti e di analisi anamnestica dei soggetti ammalati sono attivi solo in Italia, Francia e Corea del Sud. I Paesi presso i quali sono attivi sistemi di rilevazione e controllo dei casi incidenti di mesotelioma sono quelli in cui vige il bando dell'amianto e che hanno sperimentato consumi rilevanti in passato. Non sono stati istituiti sistemi epidemiologici di sorveglianza in molti Paesi dove il consumo di amianto è ancora importante (inclusi Russia, Cina, India e Brasile). CONCLUSIONI: si conferma l'importanza dei sistemi di sorveglianza epidemiologica dei mesoteliomi per la sanità pubblica, il sostegno alle politiche di welfare e la prevenzione dei rischi. Lo sviluppo di progetti per tendere a una maggiore uniformità nei metodi di ricerca dei casi, di classificazione delle diagnosi e dell'esposizione e nelle tecniche di analisi dei dati potrebbe consentire una maggiore fruibilità dei dati aggregati. La disponibilità di dati internazionali confrontabili può essere di stimolo all'adozione di provvedimenti di bando internazionale.

Use of a decision-analytic model to support the use of a new oral US contrast agent in patients with abdominal pain.

PubMed

Bree, R L; Arnold, R J; Pettit, K G; Kaniecki, D J; O'haeri, C; LaFrance, N D; Toaff, A L

2001-03-01

The authors performed this study to compare the cost and diagnostic abilities of ultrasound (US) performed with and without the use of an oral contrast material recently approved by the U.S. Food and Drug Administration. An interactive decision-analytic model was constructed to compare US performed with and without contrast material (SonoRx; Bracco Diagnostics) for the evaluation of patients with abdominal pain who were suspected of having pancreatic disease. The model considered all resources that might be used to evaluate a patient suspected of having pancreatic disease (eg, US, computed tomography [CT], endoscopic retrograde cholangiopancreatography, fine-needle aspiration biopsy, and open biopsy). The literature and an expert panel were the clinical data sources. Cost estimates were based on Medicare and non-Medicare reimbursements. The primary cost-effectiveness measure was the cost to achieve a diagnosis. SonoRx-enhanced US was less expensive than unenhanced US ($714 vs $808, respectively, with Medicare costs; $1,612 vs $1,878, respectively, with non-Medicare costs) and as effective (0.785 vs 0.782, respectively). SonoRx-enhanced US was more cost-effective than unenhanced US ($909 vs $1,034, respectively, with Medicare costs; $2,052 vs $2,401, respectively, with non-Medicare costs). This relationship was maintained throughout extensive sensitivity analyses. SonoRx-enhanced US is more cost-effective than unenhanced US, primarily because it avoids the need for CT. CT may be avoided owing to the higher probability of obtaining optimal US scans with oral contrast material.

Education in children's sleep hygiene: which approaches are effective? A systematic review.

PubMed

Halal, Camila S E; Nunes, Magda L

2014-01-01

To analyze the interventions aimed at the practice of sleep hygiene, as well as their applicability and effectiveness in the clinical scenario, so that they may be used by pediatricians and family physicians for parental advice. A search of the PubMed database was performed using the following descriptors: sleep hygiene OR sleep education AND children or school-aged. In the LILACS and SciELO databases, the descriptors in Portuguese were: higiene E sono, educação E sono, educação E sono E crianças, e higiene E sono E infância, with no limitations of the publication period. In total, ten articles were reviewed, in which the main objectives were to analyze the effectiveness of behavioral approaches and sleep hygiene techniques on children's sleep quality and parents' quality of life. The techniques used were one or more of the following: positive routines; controlled comforting and gradual extinction or sleep remodeling; as well as written diaries to monitor children's sleep patterns. All of the approaches yielded positive results. Although behavioral approaches to pediatric sleep hygiene are easy to apply and adhere to, there have been very few studies evaluating the effectiveness of the available techniques. This review demonstrated that these methods are effective in providing sleep hygiene for children, thus reflecting on parents' improved quality of life. It is of utmost importance that pediatricians and family physicians are aware of such methods in order to adequately advise patients and their families. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Mechanistic investigations in sono-hybrid techniques for rice straw pretreatment.

PubMed

Suresh, Kelothu; Ranjan, Amrita; Singh, Shuchi; Moholkar, Vijayanand S

2014-01-01

This paper reports comparative study of two chemical techniques (viz. dilute acid/alkali treatment) and two physical techniques (viz. hot water bath and autoclaving) coupled with sonication, termed as sono-hybrid techniques, for hydrolysis of rice straw. The efficacy of each sono-hybrid technique was assessed on the basis of total sugar and reducing sugar release. The system of biomass pretreatment is revealed to be mass transfer controlled. Higher sugar release is obtained during dilute acid treatment than dilute alkali treatment. Autoclaving alone was found to increase sugar release marginally as compared to hot water bath. Sonication of the biomass solution after autoclaving and stirring resulted in significant rise of sugar release, which is attributed to strong convection generated during sonication that assists effective transport of sugar molecules. Discrimination between individual contributions of ultrasound and cavitation to mass transfer enhancement reveals that contribution of ultrasound (through micro-streaming) is higher. Micro-turbulence as well as acoustic waves generated by cavitation did not contribute much to enhancing of mass transfer in the system. Copyright © 2013 Elsevier B.V. All rights reserved.

The evolving roles of memory immune cells in transplantation

PubMed Central

Chen, Wenhao; Ghobrial, Rafik M.; Li, Xian C.

2015-01-01

Memory cells are the products of immune responses but also exert significant impact on subsequent immunity and immune tolerance, thus placing them in a unique position in transplant research. Memory cells are heterogeneous, including not only memory T cells but also memory B cells and innate memory cells. Memory cells are a critical component of protective immunity against invading pathogens, especially in immunosuppressed patients, but they also mediate graft loss and tolerance resistance. Recent studies suggest that some memory cells unexpectedly act as regulatory cells, promoting rather than hindering transplant survival. This functional diversity makes therapeutic targeting of memory cells a challenging task in transplantation. In this article we highlight recent advances in our understanding of memory cells, focusing on diversity of memory cells and mechanisms involved in their induction and functions. We also provide a broad overview on the challenges and opportunities in targeting memory cells in the induction of transplant tolerance. PMID:26102615

CD4 memory T cells develop and acquire functional competence by sequential cognate interactions and stepwise gene regulation

PubMed Central

Kaji, Tomohiro; Hijikata, Atsushi; Ishige, Akiko; Kitami, Toshimori; Watanabe, Takashi; Ohara, Osamu; Yanaka, Noriyuki; Okada, Mariko; Shimoda, Michiko; Taniguchi, Masaru

2016-01-01

Memory CD4+ T cells promote protective humoral immunity; however, how memory T cells acquire this activity remains unclear. This study demonstrates that CD4+ T cells develop into antigen-specific memory T cells that can promote the terminal differentiation of memory B cells far more effectively than their naive T-cell counterparts. Memory T cell development requires the transcription factor B-cell lymphoma 6 (Bcl6), which is known to direct T-follicular helper (Tfh) cell differentiation. However, unlike Tfh cells, memory T cell development did not require germinal center B cells. Curiously, memory T cells that develop in the absence of cognate B cells cannot promote memory B-cell recall responses and this defect was accompanied by down-regulation of genes associated with homeostasis and activation and up-regulation of genes inhibitory for T-cell responses. Although memory T cells display phenotypic and genetic signatures distinct from Tfh cells, both had in common the expression of a group of genes associated with metabolic pathways. This gene expression profile was not shared to any great extent with naive T cells and was not influenced by the absence of cognate B cells during memory T cell development. These results suggest that memory T cell development is programmed by stepwise expression of gatekeeper genes through serial interactions with different types of antigen-presenting cells, first licensing the memory lineage pathway and subsequently facilitating the functional development of memory T cells. Finally, we identified Gdpd3 as a candidate genetic marker for memory T cells. PMID:26714588

Interconnected subsets of memory follicular helper T cells have different effector functions.

PubMed

Asrir, Assia; Aloulou, Meryem; Gador, Mylène; Pérals, Corine; Fazilleau, Nicolas

2017-10-10

Follicular helper T cells regulate high-affinity antibody production. Memory follicular helper T cells can be local in draining lymphoid organs and circulate in the blood, but the underlying mechanisms of this subdivision are unresolved. Here we show that both memory follicular helper T subsets sustain B-cell responses after reactivation. Local cells promote more plasma cell differentiation, whereas circulating cells promote more secondary germinal centers. In parallel, local memory B cells are homogeneous and programmed to become plasma cells, whereas circulating memory B cells are able to rediversify. Local memory follicular helper T cells have higher affinity T-cell receptors, which correlates with expression of peptide MHC-II at the surface of local memory B cells only. Blocking T-cell receptor-peptide MHC-II interactions induces the release of local memory follicular helper T cells in the circulating compartment. Our studies show that memory follicular helper T localization is highly intertwined with memory B cells, a finding that has important implications for vaccine design.Tfh cells can differentiate into memory cells. Here the authors describe distinct functional and phenotypic profiles of these memory Tfh cells dependent on their anatomical localization to the lymphoid organs or to the circulation.

T inflammatory memory CD8 T cells participate to antiviral response and generate secondary memory cells with an advantage in XCL1 production.

PubMed

Jubin, Virginie; Ventre, Erwan; Leverrier, Yann; Djebali, Sophia; Mayol, Katia; Tomkowiak, Martine; Mafille, Julien; Teixeira, Marie; Teoh, Denise Y-L; Lina, Bruno; Walzer, Thierry; Arpin, Christophe; Marvel, Jacqueline

2012-06-01

Besides the classically described subsets of memory CD8 T cells generated under infectious conditions, are T inflammatory memory cells generated under sterile priming conditions, such as sensitization to allergens. Although not fully differentiated as pathogen-induced memory cells, they display memory properties that distinguish them from naive CD8 T cells. Given these memory cells are generated in an antigen-specific context that is devoid of pathogen-derived danger signals and CD4 T cell help, we herein questioned whether they maintained their activation and differentiation potential, could be recruited in an immune response directed against a pathogen expressing their cognate antigen and further differentiate in fully competent secondary memory cells. We show that T inflammatory memory cells can indeed take part to the immune response triggered by a viral infection, differentiate into secondary effectors and further generate typical central memory CD8 T cells and effector memory CD8 T cells. Furthermore, the secondary memory cells they generate display a functional advantage over primary memory cells in their capacity to produce TNF-α and the XCL1 chemokine. These results suggest that cross-reactive stimulations and differentiation of cells directed against allergens or self into fully competent pathogen-induced memory cells might have incidences in inflammatory immuno-pathologies.

Memory. Engram cells retain memory under retrograde amnesia.

PubMed

Ryan, Tomás J; Roy, Dheeraj S; Pignatelli, Michele; Arons, Autumn; Tonegawa, Susumu

2015-05-29

Memory consolidation is the process by which a newly formed and unstable memory transforms into a stable long-term memory. It is unknown whether the process of memory consolidation occurs exclusively through the stabilization of memory engrams. By using learning-dependent cell labeling, we identified an increase of synaptic strength and dendritic spine density specifically in consolidated memory engram cells. Although these properties are lacking in engram cells under protein synthesis inhibitor-induced amnesia, direct optogenetic activation of these cells results in memory retrieval, and this correlates with retained engram cell-specific connectivity. We propose that a specific pattern of connectivity of engram cells may be crucial for memory information storage and that strengthened synapses in these cells critically contribute to the memory retrieval process. Copyright © 2015, American Association for the Advancement of Science.

Mechanical memory

DOEpatents

Gilkey, Jeffrey C [Albuquerque, NM; Duesterhaus, Michelle A [Albuquerque, NM; Peter, Frank J [Albuquerque, NM; Renn, Rosemarie A [Alburquerque, NM; Baker, Michael S [Albuquerque, NM

2006-08-15

A first-in-first-out (FIFO) microelectromechanical memory apparatus (also termed a mechanical memory) is disclosed. The mechanical memory utilizes a plurality of memory cells, with each memory cell having a beam which can be bowed in either of two directions of curvature to indicate two different logic states for that memory cell. The memory cells can be arranged around a wheel which operates as a clocking actuator to serially shift data from one memory cell to the next. The mechanical memory can be formed using conventional surface micromachining, and can be formed as either a nonvolatile memory or as a volatile memory.

Mechanical memory

DOEpatents

Gilkey, Jeffrey C [Albuquerque, NM; Duesterhaus, Michelle A [Albuquerque, NM; Peter, Frank J [Albuquerque, NM; Renn, Rosemarie A [Albuquerque, NM; Baker, Michael S [Albuquerque, NM

2006-05-16

A first-in-first-out (FIFO) microelectromechanical memory apparatus (also termed a mechanical memory) is disclosed. The mechanical memory utilizes a plurality of memory cells, with each memory cell having a beam which can be bowed in either of two directions of curvature to indicate two different logic states for that memory cell. The memory cells can be arranged around a wheel which operates as a clocking actuator to serially shift data from one memory cell to the next. The mechanical memory can be formed using conventional surface micromachining, and can be formed as either a nonvolatile memory or as a volatile memory.

Engram Cells Retain Memory Under Retrograde Amnesia

PubMed Central

Ryan, Tomás J.; Roy, Dheeraj S.; Pignatelli, Michele; Arons, Autumn; Tonegawa, Susumu

2017-01-01

Memory consolidation is the process by which a newly formed and unstable memory transforms into a stable long-term memory. It is unknown whether the process of memory consolidation occurs exclusively by the stabilization of memory engrams. By employing learning-dependent cell labeling, we identified an increase of synaptic strength and dendritic spine density specifically in consolidated memory engram cells. While these properties are lacking in the engram cells under protein synthesis inhibitor-induced amnesia, direct optogenetic activation of these cells results in memory retrieval, and this correlates with the retained engram cell-specific connectivity. We propose that a specific pattern of connectivity of engram cells may be crucial for memory information storage and that strengthened synapses in these cells critically contribute to the memory retrieval process. PMID:26023136

Relationship of ultrasound signal intensity with SonoVue concentration at body temperature in vitro

NASA Astrophysics Data System (ADS)

Yang, Xin; Li, Jing; He, Xiaoling; Wu, Kaizhi; Yuan, Yun; Ding, Mingyue

2014-04-01

In this paper, the relationship between image intensity and ultrasound contrast agent (UCA) concentration is investigated. Experiments are conducted in water bath using a silicon tube filled with UCA (SonoVue) at different concentrations (100μl/l to 6000μl/l) at around 37 °C to simulate the temperature in human body. The mean gray-scale intensity within the region of interest (ROI) is calculated to obtain the plot of signal intensity to UCA concentration. The results show that the intensity firstly exhibits a linear increase to the peak at approximately 1500μl/l then appears a downward trend due to the multiple scattering (MS) effects.

Sono-bromination of aromatic compounds based on the ultrasonic advanced oxidation processes.

PubMed

Fujita, Mitsue; Lévêque, Jean-Marc; Komatsu, Naoki; Kimura, Takahide

2015-11-01

A novel, mild "sono-halogenation" of various aromatic compounds with potassium halide was investigated under ultrasound in a biphasic carbon tetrachloride/water medium. The feasibility study was first undertaken with the potassium bromide and then extended to chloride and iodide analogues. This methodology could be considered as a new expansion of the ultrasonic advanced oxidation processes (UAOPs) into a synthetic aspect as the developed methodology is linked to the sonolytic disappearance of carbon tetrachloride. Advantages of the present method are not only that the manipulation of the bromination is simple and green, but also that the halogenating agents used are readily available, inexpensive, and easy-handling. Copyright © 2015 Elsevier B.V. All rights reserved.

Duration of ultrasound-mediated enhanced plasma membrane permeability.

PubMed

Lammertink, Bart; Deckers, Roel; Storm, Gert; Moonen, Chrit; Bos, Clemens

2015-03-30

Ultrasound (US) induced cavitation can be used to enhance the intracellular delivery of drugs by transiently increasing the cell membrane permeability. The duration of this increased permeability, termed temporal window, has not been fully elucidated. In this study, the temporal window was investigated systematically using an endothelial- and two breast cancer cell lines. Model drug uptake was measured as a function of time after sonication, in the presence of SonoVue™ microbubbles, in HUVEC, MDA-MB-468 and 4T1 cells. In addition, US pressure amplitude was varied in MDA-MB-468 cells to investigate its effect on the temporal window. Cell membrane permeability of HUVEC and MDA-MB-468 cells returned to control level within 1-2 h post-sonication, while 4T1 cells needed over 3h. US pressure affected the number of cells with increased membrane permeability, as well as the temporal window in MDA-MB-468 cells. This study shows that the duration of increased membrane permeability differed between the cell lines and US pressures used here. However, all were consistently in the order of 1-3 h after sonication. Copyright © 2014 Elsevier B.V. All rights reserved.

Analysis of antigen-specific B-cell memory directly ex vivo.

PubMed

McHeyzer-Williams, Louise J; McHeyzer-Williams, Michael G

2004-01-01

Helper T-cell-regulated B-cell memory develops in response to initial antigen priming as a cellular product of the germinal center (GC) reaction. On antigen recall, memory response precursors expand rapidly with exaggerated differentiation into plasma cells to produce the high-titer, high-affinity antibody(Ab) that typifies the memory B-cell response in vivo. We have devised a high-resolution flow cytometric strategy to quantify the emergence and maintenance of antigen-specific memory B cells directly ex vivo. Extended cell surface phenotype establishes a level of cellular diversity not previously appreciated for the memory B-cell compartment. Using an "exclusion transfer" strategy, we ascertain the capacity of two distinct memory B-cell populations to transfer antigen-specific memory into naive adoptive hosts. Finally, we sequence expressed messenger ribonucleic acid (mRNA) from single cells within the population to estimate the level of somatic hypermutation as the best molecular indicator of B-cell memory. In this chapter, we describe the methods used in each of these four sections that serve to provide high-resolution quantification of antigen-specific B-cell memory responses directly ex vivo.

Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8 T cells.

PubMed

Drobek, Ales; Moudra, Alena; Mueller, Daniel; Huranova, Martina; Horkova, Veronika; Pribikova, Michaela; Ivanek, Robert; Oberle, Susanne; Zehn, Dietmar; McCoy, Kathy D; Draber, Peter; Stepanek, Ondrej

2018-05-11

Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute 10-20% of all peripheral CD8 + T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing T-cell receptor repertoires and using retrogenic monoclonal T-cell populations, we demonstrate that the virtual memory T-cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells. First, virtual memory T cells originate exclusively from strongly self-reactive T cells. Second, the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T-cell compartment via modulating the self-reactivity of individual T cells. Although virtual memory T cells descend from the highly self-reactive clones and acquire a partial memory program, they are not more potent in inducing experimental autoimmune diabetes than naïve T cells. These data underline the importance of the variable level of self-reactivity in polyclonal T cells for the generation of functional T-cell diversity. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

Cancer immunotherapy and immunological memory.

PubMed

Murata, Kenji; Tsukahara, Tomohide; Torigoe, Toshihiko

2016-01-01

Human immunological memory is the key distinguishing hallmark of the adaptive immune system and plays an important role in the prevention of morbidity and the severity of infection. The differentiation system of T cell memory has been clarified using mouse models. However, the human T cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. We believe that only human studies can elucidate the human immune system. The importance of immunological memory in cancer immunotherapy has been pointed out, and the trafficking properties and long-lasting anti-tumor capacity of memory T cells play a crucial role in the control of malignant tumors. Adoptive cell transfer of less differentiated T cells has consistently demonstrated superior anti-tumor capacity relative to more differentiated T cells. Therefore, a human T cell population with the characteristics of stem cell memory is thought to be attractive for peptide vaccination and adoptive cell transfer. A novel human memory T cell population that we have identified is closer to the naive state than previous memory T cells in the T cell differentiation lineage, and has the characteristics of stem-like chemoresistance. Here we introduce this novel population and describe the fundamentals of immunological memory in cancer immunotherapy.

Experimental realization of a multiplexed quantum memory with 225 individually accessible memory cells.

PubMed

Pu, Y-F; Jiang, N; Chang, W; Yang, H-X; Li, C; Duan, L-M

2017-05-08

To realize long-distance quantum communication and quantum network, it is required to have multiplexed quantum memory with many memory cells. Each memory cell needs to be individually addressable and independently accessible. Here we report an experiment that realizes a multiplexed DLCZ-type quantum memory with 225 individually accessible memory cells in a macroscopic atomic ensemble. As a key element for quantum repeaters, we demonstrate that entanglement with flying optical qubits can be stored into any neighboring memory cells and read out after a programmable time with high fidelity. Experimental realization of a multiplexed quantum memory with many individually accessible memory cells and programmable control of its addressing and readout makes an important step for its application in quantum information technology.

Effector CD8 T cells dedifferentiate into long-lived memory cells.

PubMed

Youngblood, Ben; Hale, J Scott; Kissick, Haydn T; Ahn, Eunseon; Xu, Xiaojin; Wieland, Andreas; Araki, Koichi; West, Erin E; Ghoneim, Hazem E; Fan, Yiping; Dogra, Pranay; Davis, Carl W; Konieczny, Bogumila T; Antia, Rustom; Cheng, Xiaodong; Ahmed, Rafi

2017-12-21

Memory CD8 T cells that circulate in the blood and are present in lymphoid organs are an essential component of long-lived T cell immunity. These memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogens, but also have many properties in common with naive cells, including pluripotency and the ability to migrate to the lymph nodes and spleen. Thus, memory cells embody features of both naive and effector cells, fuelling a long-standing debate centred on whether memory T cells develop from effector cells or directly from naive cells. Here we show that long-lived memory CD8 T cells are derived from a subset of effector T cells through a process of dedifferentiation. To assess the developmental origin of memory CD8 T cells, we investigated changes in DNA methylation programming at naive and effector cell-associated genes in virus-specific CD8 T cells during acute lymphocytic choriomeningitis virus infection in mice. Methylation profiling of terminal effector versus memory-precursor CD8 T cell subsets showed that, rather than retaining a naive epigenetic state, the subset of cells that gives rise to memory cells acquired de novo DNA methylation programs at naive-associated genes and became demethylated at the loci of classically defined effector molecules. Conditional deletion of the de novo methyltransferase Dnmt3a at an early stage of effector differentiation resulted in reduced methylation and faster re-expression of naive-associated genes, thereby accelerating the development of memory cells. Longitudinal phenotypic and epigenetic characterization of the memory-precursor effector subset of virus-specific CD8 T cells transferred into antigen-free mice revealed that differentiation to memory cells was coupled to erasure of de novo methylation programs and re-expression of naive-associated genes. Thus, epigenetic repression of naive-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells while key effector genes remain demethylated, demonstrating that memory T cells arise from a subset of fate-permissive effector T cells.

Distinct T helper cell dependence of memory B-cell proliferation versus plasma cell differentiation.

PubMed

Zabel, Franziska; Fettelschoss, Antonia; Vogel, Monique; Johansen, Pål; Kündig, Thomas M; Bachmann, Martin F

2017-03-01

Several memory B-cell subclasses with distinct functions have been described, of which the most effective is the class-switched (CS) memory B-cell population. We have previously shown, using virus-like particles (VLPs), that the proliferative potential of these CS memory B cells is limited and they fail to re-enter germinal centres (GCs). However, VLP-specific memory B cells quickly differentiated into secondary plasma cells (PCs) with the virtue of elevated antibody production compared with primary PCs. Whereas the induction of VLP + memory B cells was strongly dependent on T helper cells, we were wondering whether re-stimulation of VLP + memory B cells and their differentiation into secondary PCs would also require T helper cells. Global absence of T helper cells led to strongly impaired memory B cell proliferation and PC differentiation. In contrast, lack of interleukin-21 receptor-dependent follicular T helper cells or CD40 ligand signalling strongly affected proliferation of memory B cells, but differentiation into mature secondary PCs exhibiting increased antibody production was essentially normal. This contrasts with primary B-cell responses, where a strong dependence on CD40 ligand but limited importance of interleukin-21 receptor was seen. Hence, T helper cell dependence differs between primary and secondary B-cell responses as well as between memory B-cell proliferation and PC differentiation. © 2016 John Wiley & Sons Ltd.

[Analysis of factors predicting early unplanned readmissions].

PubMed

Di Domenico, Gabriella; Tersigni, Ivan; Federico, Bruno; Leuter, Cinzia

2016-01-01

OBIETTIVI: determinare i fattori associati ai ricoveri ripetuti per identificare i pazienti a rischio di riospedalizzazione entro i 30 giorni dalla dimissione. DISEGNO: analisi retrospettiva delle dimissioni nell'anno 2013 attraverso le schede di dimissione ospedaliera (SDO). 3.900 pazienti ricoverati presso il presidio ospedaliero "Fabrizio Spaziani" di Frosinone. PRINCIPALI MISURE DI OUTCOME: analisi bivariata per l'analisi dell'associazione tra variabili. La regressione logistica è stata utilizzata per identificare i fattori di rischio associati al ricovero ripetuto. RISULTATI: tra i 3.900 pazienti considerati, il 12,8% ha avuto una riammissione non programmata entro un mese dalla dimissione precedente per le stesse categorie diagnostiche principali (MCD). Sono state rilevate differenze statisticamente significative tra i pazienti con e senza ricovero ripetuto per età, durata della degenza, titolo di studio, condizione occupazionale e diagnosi. I fattori che aumentano la probabilità di una riospedalizzazione sono il vivere da solo, la condizione di pensionato o casalinga, una degenza più lunga e alcune diagnosi, fra cui malattie dell'apparato respiratorio, del sistema nervoso e dell'apparato urinario. CONCLUSIONE: alcune caratteristiche sociodemografiche e la diagnosi dei pazienti ospedalizzati sono associate al rischio di riospedalizzazione entro 30 giorni dalla dimissione. I dati disponibili nell'archivio delle SDO possono essere utilizzati per un'identificazione dei pazienti a rischio sui quali definire specifici piani di dimissione.

[Trattamento della dipendenza da alcol. Alcol e persone senza fissa dimora: punto di vista sociale].

PubMed

Alessandrini, Giovanni; Ciccarelli, Rosaria; Battagliese, Gemma; Cereatti, Federica; Gencarelli, Simona; Messina, Marisa Patrizia; Vitali, Mario; De Rosa, Francesca; Ledda, Roberta; Mancini, Serena; Attilia, Maria Luisa

2018-01-01

RIASSUNTO. Il fenomeno delle persone senza fissa dimora sta assumendo in questi anni una rilevanza sociale devastante, con una prevalenza stimata in USA e in Europa compresa tra il 5,6% e il 13,9%. Queste persone hanno una scarsa qualità di vita, una limitata o assente vita sociale, sono spesso disoccupate o lavorano solo saltuariamente. Sono a rischio di problemi con la legge, sono spesso affette da dipendenza da droghe, da patologie psichiatriche e internistiche. L'alcol spesso non rappresenta la causa della loro condizione sociale, ma solo la conseguenza, contribuendo in questo modo al loro degrado bio-psico-sociale. Nel 2009 lo US Department of Housing and Urban Development's Homelessness Assistance Programs e nel 2010 la European Consensus Conference on Homelessness hanno segnato un grande passo avanti nella riabilitazione sociale di queste persone, utilizzando il concetto del "case management". In particolare lo Standard Case Management si è dimostrato in grado di migliorare la stabilità abitativa, di ridurre l'uso di droghe e di rimuovere le barriere lavorative. L'Assertive Community Treatment si è dimostrato, invece, in grado di migliorare la stabilità abitativa e ha un rapporto costo/beneficio migliore per i pazienti affetti da doppia diagnosi.

Technical and social evaluation of arsenic mitigation in rural Bangladesh.

PubMed

Shafiquzzaman, Md; Azam, Md Shafiul; Mishima, Iori; Nakajima, Jun

2009-10-01

Technical and social performances of an arsenic-removal technology--the sono arsenic filter--in rural areas of Bangladesh were investigated. Results of arsenic field-test showed that filtered water met the Bangladesh standard (< 50 microg/L) after two years of continuous use. A questionnaire was administrated among 198 sono arsenic filter-user and 230 non-user families. Seventy-two percent of filters (n = 198) were working at the time of the survey. Another 28% of the filters were abandoned due to breakage. The abandonment percentage (28%) was lower than other mitigation options currently implemented in Bangladesh. Households were reluctant to repair the broken filters on their own. High cost, problems with maintenance of filters, weak sludge-disposal guidance, and slow flow rate were the other demerits of the filter. These results indicate that the implementation approaches of the sono arsenic filter suffered from lack of ownership and long-term sustainability. Continuous use of arsenic-contaminated tubewells by the non-user households demonstrated the lack of alternative water supply in the survey area. Willingness of households to pay (about 30%) and preference of household filter (50%) suggest the need to develop a low-cost household arsenic filter. Development of community-based organization would be also necessary to implement a long-term, sustainable plan for household-based technology.

Vaccine-elicited SIV and HIV envelope-specific IgA and IgG memory B cells in rhesus macaque peripheral blood correlate with functional antibody responses and reduced viremia

PubMed Central

Brocca-Cofano, Egidio; McKinnon, Katherine; Demberg, Thorsten; Venzon, David; Hidajat, Rachmat; Xiao, Peng; Daltabuit-Test, Mara; Patterson, L. Jean; Robert-Guroff, Marjorie

2011-01-01

An effective HIV vaccine requires strong systemic and mucosal, cellular and humoral immunity. Numerous non-human primate studies have investigated memory T cells, but not memory B cells. Humoral immunologic memory is mediated by long-lived antibody-secreting plasma cells and differentiation of memory B cells into short-lived plasma blasts following re-exposure to immunizing antigen. Here we studied memory B cells in vaccinated rhesus macaques. PBMC were stimulated polyclonally using CD40 Ligand, IL-21 and CpG to induce B cell proliferation and differentiation into antibody secreting cells (ASC). Flow cytometry was used for phenotyping and evaluating proliferation by CFSE dilution. B cell responses were quantified by ELISPOT. Methodology was established using PBMC of vaccinated elite-controller macaques that exhibited strong, multi-functional antibody activities. Subsequently, memory B cells elicited by two replicating Ad-recombinant prime/envelope boost regimens were retrospectively evaluated pre- and post- SIV and SHIV challenges. The vaccine regimens induced SIV and HIV Env-specific IgG and IgA memory B cells. Prior to challenge, IgA memory B cells were more numerous than IgG memory B cells, reflecting the mucosal priming immunizations. Pre- and post-challenge memory B cells were correlated with functional antibody responses including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated viral inhibition (ADCVI) and transcytosis inhibition. Post-challenge, Env-specific IgG and IgA memory B cells were correlated with reduced chronic viremia. We conclude that functional antibody responses elicited by our prime/boost regimen were effectively incorporated into the memory B cell pool where they contributed to control of viremia following re-exposure to the immunizing antigen. PMID:21382487

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

PubMed Central

Kurtulus, S; Sholl, A; Toe, J; Tripathi, P; Raynor, J; Li, K-P; Pellegrini, M; Hildeman, D A

2015-01-01

During the effector CD8+ T-cell response, transcriptional differentiation programs are engaged that promote effector T cells with varying memory potential. Although these differentiation programs have been used to explain which cells die as effectors and which cells survive and become memory cells, it is unclear if the lack of cell death enhances memory. Here, we investigated effector CD8+ T-cell fate in mice whose death program has been largely disabled because of the loss of Bim. Interestingly, the absence of Bim resulted in a significant enhancement of effector CD8+ T cells with more memory potential. Bim-driven control of memory T-cell development required T-cell-specific, but not dendritic cell-specific, expression of Bim. Both total and T-cell-specific loss of Bim promoted skewing toward memory precursors, by enhancing the survival of memory precursors, and limiting the availability of IL-15. Decreased IL-15 availability in Bim-deficient mice facilitated the elimination of cells with less memory potential via the additional pro-apoptotic molecules Noxa and Puma. Combined, these data show that Bim controls memory development by limiting the survival of pre-memory effector cells. Further, by preventing the consumption of IL-15, Bim limits the role of Noxa and Puma in causing the death of effector cells with less memory potential. PMID:25124553

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins.

PubMed

Kurtulus, S; Sholl, A; Toe, J; Tripathi, P; Raynor, J; Li, K-P; Pellegrini, M; Hildeman, D A

2015-01-01

During the effector CD8+ T-cell response, transcriptional differentiation programs are engaged that promote effector T cells with varying memory potential. Although these differentiation programs have been used to explain which cells die as effectors and which cells survive and become memory cells, it is unclear if the lack of cell death enhances memory. Here, we investigated effector CD8+ T-cell fate in mice whose death program has been largely disabled because of the loss of Bim. Interestingly, the absence of Bim resulted in a significant enhancement of effector CD8+ T cells with more memory potential. Bim-driven control of memory T-cell development required T-cell-specific, but not dendritic cell-specific, expression of Bim. Both total and T-cell-specific loss of Bim promoted skewing toward memory precursors, by enhancing the survival of memory precursors, and limiting the availability of IL-15. Decreased IL-15 availability in Bim-deficient mice facilitated the elimination of cells with less memory potential via the additional pro-apoptotic molecules Noxa and Puma. Combined, these data show that Bim controls memory development by limiting the survival of pre-memory effector cells. Further, by preventing the consumption of IL-15, Bim limits the role of Noxa and Puma in causing the death of effector cells with less memory potential.

CD8 T cell memory: it takes all kinds

PubMed Central

Hamilton, Sara E.; Jameson, Stephen C.

2012-01-01

Understanding the mechanisms that regulate the differentiation and maintenance of CD8+ memory T cells is fundamental to the development of effective T cell-based vaccines. Memory cell differentiation is influenced by the cytokines that accompany T cell priming, the history of previous antigen encounters, and the tissue sites into which memory cells migrate. These cues combine to influence the developing CD8+ memory pool, and recent work has revealed the importance of multiple transcription factors, metabolic molecules, and surface receptors in revealing the type of memory cell that is generated. Paired with increasingly meticulous subsetting and sorting of memory populations, we now know the CD8+ memory pool to be phenotypically and functionally heterogeneous in nature. This includes both recirculating and tissue-resident memory populations, and cells with varying degrees of inherent longevity and protective function. These data point to the importance of tailored vaccine design. Here we discuss how the diversity of the memory CD8+ T cell pool challenges the notion that “one size fits all” for pathogen control, and how distinct memory subsets may be suited for distinct aspects of protective immunity. PMID:23230436

The use of contrasted transvaginal sonography in the diagnosis of gynecologic diseases: a preliminary study.

PubMed

Testa, Antonia Carla; Ferrandina, Gabriella; Fruscella, Erika; Van Holsbeke, Caroline; Ferrazzi, Enrico; Leone, Francesco P G; Arduini, Domenico; Exacoustos, Caterina; Bokor, Daniela; Scambia, Giovanni; Timmerman, Dirk

2005-09-01

The purpose of this study was to evaluate the efficacy of a new contrast-dedicated ultrasound technology, contrast-tuned imaging (CnTI), implemented on an endovaginal probe and using the second-generation contrast agent SonoVue (Bracco International BV, Amsterdam, the Netherlands), compared with the standard ultrasound examination in different gynecologic diseases. Eighty-nine patients were enrolled in the study in 4 different clinical centers. The study included 40 patients with uncertain pelvic adnexal masses, 10 patients with pelvic masses indicative of recurrences of gynecologic tumors, 26 patients with uterine pathologic features, and 13 patients with cervical lesions. Application of CnTI technology after the SonoVue injection gave a picture of the intralesional microvascularization dramatically different from that obtained during color Doppler examination. Of the 40 pelvic masses, 15 (37.5%) were considered benign and 25 (62.5%) were considered malignant at B-mode and color Doppler examinations. Contrast-enhanced sonography showed no intralesional contrast perfusion in 11 (73%) of 15 cases, and all these were benign at final diagnosis. Of the 4 (27%) cases that had perfusion, 2 were malignant. Conversely, of the 25 cases with positive findings at color Doppler examination and therefore expected to show the appearance of contrast tissue-filling morphologic characteristics, 13 (52%) were malignant at final diagnosis. For evaluation of uterine pathologic features, the CnTI-SonoVue technology did not appear to be superior to the B-mode and color Doppler examinations; however, for the evaluation of cervical cancer, CnTI-SonoVue technology revealed a better definition of the margins of the neoplastic lesions in 4 (40%) of 10 cases. In the evaluation of uncertain pelvic masses, the CnTI technology led to an improvement in the ability of the practitioner to differentiate benign from malignant adnexal lesions.

Influence of temperature, needle gauge and injection rate on the size distribution, concentration and acoustic responses of ultrasound contrast agents at high frequency.

PubMed

Sun, Chao; Panagakou, Ioanna; Sboros, Vassilis; Butler, Mairead B; Kenwright, David; Thomson, Adrian J W; Moran, Carmel M

2016-08-01

This paper investigated the influence of needle gauge (19G and 27G), injection rate (0.85ml·min(-1), 3ml·min(-1)) and temperature (room temperature (RT) and body temperature (BT)) on the mean diameter, concentration, acoustic attenuation, contrast to tissue ratio (CTR) and normalised subharmonic intensity (NSI) of three ultrasound contrast agents (UCAs): Definity, SonoVue and MicroMarker (untargeted). A broadband substitution technique was used to acquire the acoustic properties over the frequency range 17-31MHz with a preclinical ultrasound scanner Vevo770 (Visualsonics, Canada). Significant differences (P<0.001-P<0.05) between typical in vitro setting (19G needle, 3ml·min(-1) at RT) and typical in vivo setting (27G needle, 0.85ml·min(-1) at BT) were found for SonoVue and MicroMarker. Moreover we found that the mean volume-based diameter and concentration of both SonoVue and Definity reduced significantly when changing from typical in vitro to in vivo experimental set-ups, while those for MicroMarker did not significantly change. From our limited measurements of Definity, we found no significant change in attenuation, CTR and NSI with needle gauge. For SonoVue, all the measured acoustic properties (attenuation, CTR and NSI) reduced significantly when changing from typical in vitro to in vivo experimental conditions, while for MicroMarker, only the NSI reduced, with attenuation and CTR increasing significantly. These differences suggest that changes in physical compression and temperature are likely to alter the shell structure of the UCAs resulting in measureable and significant changes in the physical and high frequency acoustical properties of the contrast agents under typical in vitro and preclinical in vivo experimental conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

Experimental realization of a multiplexed quantum memory with 225 individually accessible memory cells

PubMed Central

Pu, Y-F; Jiang, N.; Chang, W.; Yang, H-X; Li, C.; Duan, L-M

2017-01-01

To realize long-distance quantum communication and quantum network, it is required to have multiplexed quantum memory with many memory cells. Each memory cell needs to be individually addressable and independently accessible. Here we report an experiment that realizes a multiplexed DLCZ-type quantum memory with 225 individually accessible memory cells in a macroscopic atomic ensemble. As a key element for quantum repeaters, we demonstrate that entanglement with flying optical qubits can be stored into any neighboring memory cells and read out after a programmable time with high fidelity. Experimental realization of a multiplexed quantum memory with many individually accessible memory cells and programmable control of its addressing and readout makes an important step for its application in quantum information technology. PMID:28480891

Comparison microbial killing efficacy between sonodynamic therapy and photodynamic therapy

NASA Astrophysics Data System (ADS)

Drantantiyas, Nike Dwi Grevika; Astuti, Suryani Dyah; Nasution, Aulia M. T.

2016-11-01

Biofilm is a way used by bacteria to survive from their environmental conditions by forming colony of bacteria. Specific characteristic in biofilm formation is the availability of matrix layer, known as extracellular polymer substance. Treatment using antibiotics may lead bacteria to be to resistant. Other treatments to reduce microbial, like biofilm, can be performed by using photodynamic therapy. Successful of this kind of therapy is induced by penetration of light and photosensitizer into target cells. The sonodynamic therapy offers greater penetrating capability into tissues. This research aimed to use sonodynamic therapy in reducing biofilm. Moreover, it compares also the killing efficacy of photodynamic therapy, sonodynamic therapy, and the combination of both therapeutic schemes (known as sono-photodynamic) to achieve higher microbial killing efficacy. Samples used are Staphylococcus aureus biofilm. Treatments were divided into 4 groups, i.e. group under ultrasound treatment with variation of 5 power levels, group of light treatment with exposure of 75s, group of combined ultrasound-light with variation of ultrasound power levels, and group of combined lightultrasound with variation of ultrasound power levels. Results obtained for each treatment, expressed in % efficacy of log CFU/mL, showed that the treatment of photo-sonodynamic provides greater killing efficacy in comparison to either sonodynamic and sono-photodynamic. The photo-sonodynamic shows also greater efficacy to photodynamic. So combination of light-ultrasound (photo-sonodynamic) can effectively kill microbial biofilm. The combined therapy will provide even better efficacy using exogenous photosensitizer.

Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells.

PubMed

Wang, Yifeng; Shi, Jingwen; Yan, Jiacong; Xiao, Zhengtao; Hou, Xiaoxiao; Lu, Peiwen; Hou, Shiyue; Mao, Tianyang; Liu, Wanli; Ma, Yuanwu; Zhang, Lianfeng; Yang, Xuerui; Qi, Hai

2017-08-01

Germinal centers (GCs) support high-affinity, long-lived humoral immunity. How memory B cells develop in GCs is not clear. Through the use of a cell-cycle-reporting system, we identified GC-derived memory precursor cells (GC-MP cells) that had quit cycling and reached G0 phase while in the GC, exhibited memory-associated phenotypes with signs of affinity maturation and localized toward the GC border. After being transferred into adoptive hosts, GC-MP cells reconstituted a secondary response like genuine memory B cells. GC-MP cells expressed the interleukin 9 (IL-9) receptor and responded to IL-9. Acute treatment with IL-9 or antibody to IL-9 accelerated or retarded the positioning of GC-MP cells toward the GC edge and exit from the GC, and enhanced or inhibited the development of memory B cells, which required B cell-intrinsic responsiveness to IL-9. Follicular helper T cells (T FH cells) produced IL-9, and deletion of IL-9 from T cells or, more specifically, from GC T FH cells led to impaired memory formation of B cells. Therefore, the GC development of memory B cells is promoted by T FH cell-derived IL-9.

Phenotypic and Functional Alterations in Circulating Memory CD8 T Cells with Time after Primary Infection.

PubMed

Martin, Matthew D; Kim, Marie T; Shan, Qiang; Sompallae, Ramakrishna; Xue, Hai-Hui; Harty, John T; Badovinac, Vladimir P

2015-10-01

Memory CD8 T cells confer increased protection to immune hosts upon secondary viral, bacterial, and parasitic infections. The level of protection provided depends on the numbers, quality (functional ability), and location of memory CD8 T cells present at the time of infection. While primary memory CD8 T cells can be maintained for the life of the host, the full extent of phenotypic and functional changes that occur over time after initial antigen encounter remains poorly characterized. Here we show that critical properties of circulating primary memory CD8 T cells, including location, phenotype, cytokine production, maintenance, secondary proliferation, secondary memory generation potential, and mitochondrial function change with time after infection. Interestingly, phenotypic and functional alterations in the memory population are not due solely to shifts in the ratio of effector (CD62Llo) and central memory (CD62Lhi) cells, but also occur within defined CD62Lhi memory CD8 T cell subsets. CD62Lhi memory cells retain the ability to efficiently produce cytokines with time after infection. However, while it is was not formally tested whether changes in CD62Lhi memory CD8 T cells over time occur in a cell intrinsic manner or are due to selective death and/or survival, the gene expression profiles of CD62Lhi memory CD8 T cells change, phenotypic heterogeneity decreases, and mitochondrial function and proliferative capacity in either a lymphopenic environment or in response to antigen re-encounter increase with time. Importantly, and in accordance with their enhanced proliferative and metabolic capabilities, protection provided against chronic LCMV clone-13 infection increases over time for both circulating memory CD8 T cell populations and for CD62Lhi memory cells. Taken together, the data in this study reveal that memory CD8 T cells continue to change with time after infection and suggest that the outcome of vaccination strategies designed to elicit protective memory CD8 T cells using single or prime-boost immunizations depends upon the timing between antigen encounters.

Memory T and memory B cells share a transcriptional program of self-renewal with long-term hematopoietic stem cells

PubMed Central

Luckey, Chance John; Bhattacharya, Deepta; Goldrath, Ananda W.; Weissman, Irving L.; Benoist, Christophe; Mathis, Diane

2006-01-01

The only cells of the hematopoietic system that undergo self-renewal for the lifetime of the organism are long-term hematopoietic stem cells and memory T and B cells. To determine whether there is a shared transcriptional program among these self-renewing populations, we first compared the gene-expression profiles of naïve, effector and memory CD8+ T cells with those of long-term hematopoietic stem cells, short-term hematopoietic stem cells, and lineage-committed progenitors. Transcripts augmented in memory CD8+ T cells relative to naïve and effector T cells were selectively enriched in long-term hematopoietic stem cells and were progressively lost in their short-term and lineage-committed counterparts. Furthermore, transcripts selectively decreased in memory CD8+ T cells were selectively down-regulated in long-term hematopoietic stem cells and progressively increased with differentiation. To confirm that this pattern was a general property of immunologic memory, we turned to independently generated gene expression profiles of memory, naïve, germinal center, and plasma B cells. Once again, memory-enriched and -depleted transcripts were also appropriately augmented and diminished in long-term hematopoietic stem cells, and their expression correlated with progressive loss of self-renewal function. Thus, there appears to be a common signature of both up- and down-regulated transcripts shared between memory T cells, memory B cells, and long-term hematopoietic stem cells. This signature was not consistently enriched in neural or embryonic stem cell populations and, therefore, appears to be restricted to the hematopoeitic system. These observations provide evidence that the shared phenotype of self-renewal in the hematopoietic system is linked at the molecular level. PMID:16492737

Increased numbers of preexisting memory CD8 T cells and decreased T-bet expression can restrain terminal differentiation of secondary effector and memory CD8 T cells.

PubMed

Joshi, Nikhil S; Cui, Weiguo; Dominguez, Claudia X; Chen, Jonathan H; Hand, Timothy W; Kaech, Susan M

2011-10-15

Memory CD8 T cells acquire effector memory cell properties after reinfection and may reach terminally differentiated, senescent states ("Hayflick limit") after multiple infections. The signals controlling this process are not well understood, but we found that the degree of secondary effector and memory CD8 T cell differentiation was intimately linked to the amount of T-bet expressed upon reactivation and preexisting memory CD8 T cell number (i.e., primary memory CD8 T cell precursor frequency) present during secondary infection. Compared with naive cells, memory CD8 T cells were predisposed toward terminal effector (TE) cell differentiation because they could immediately respond to IL-12 and induce T-bet, even in the absence of Ag. TE cell formation after secondary (2°) or tertiary infections was dependent on increased T-bet expression because T-bet(+/-) cells were resistant to these phenotypic changes. Larger numbers of preexisting memory CD8 T cells limited the duration of 2° infection and the amount of IL-12 produced, and consequently, this reduced T-bet expression and the proportion of 2° TE CD8 T cells that formed. Together, these data show that over repeated infections, memory CD8 T cell quality and proliferative fitness is not strictly determined by the number of serial encounters with Ag or cell divisions, but is a function of the CD8 T cell differentiation state, which is genetically controlled in a T-bet-dependent manner. This differentiation state can be modulated by preexisting memory CD8 T cell number and the intensity of inflammation during reinfection. These results have important implications for vaccinations involving prime-boost strategies.

Mutation in the Fas Pathway Impairs CD8+ T Cell Memory1

PubMed Central

Dudani, Renu; Russell, Marsha; van Faassen, Henk; Krishnan, Lakshmi; Sad, Subash

2014-01-01

Fas death pathway is important for lymphocyte homeostasis, but the role of Fas pathway in T cell memory development is not clear. We show that whereas the expansion and contraction of CD8+ T cell response against Listeria monocytogenes were similar for wild-type (WT) and Fas ligand (FasL) mutant mice, the majority of memory CD8+ T cells in FasL mutant mice displayed an effector memory phenotype in the long-term in comparison with the mainly central memory phenotype displayed by memory CD8+ T cells in WT mice. Memory CD8+ T cells in FasL mutant mice expressed reduced levels of IFN-γ and displayed poor homeostatic and Ag-induced proliferation. Impairment in CD8+ T cell memory in FasL mutant hosts was not due to defective programming or the expression of mutant FasL on CD8+ T cells, but was caused by perturbed cytokine environment in FasL mutant mice. Although adoptively transferred WT memory CD8+ T cells mediated protection against L. monocytogenes in either the WT or FasL mutant hosts, FasL mutant memory CD8+ T cells failed to mediate protection even in WT hosts. Thus, in individuals with mutation in Fas pathway, impairment in the function of the memory CD8+ T cells may increase their susceptibility to recurrent/latent infections. PMID:18292515

IgG1 memory B cells keep the memory of IgE responses.

PubMed

He, Jin-Shu; Subramaniam, Sharrada; Narang, Vipin; Srinivasan, Kandhadayar; Saunders, Sean P; Carbajo, Daniel; Wen-Shan, Tsao; Hidayah Hamadee, Nur; Lum, Josephine; Lee, Andrea; Chen, Jinmiao; Poidinger, Michael; Zolezzi, Francesca; Lafaille, Juan J; Curotto de Lafaille, Maria A

2017-09-21

The unique differentiation of IgE cells suggests unconventional mechanisms of IgE memory. IgE germinal centre cells are transient, most IgE cells are plasma cells, and high affinity IgE is produced by the switching of IgG1 cells to IgE. Here we investigate the function of subsets of IgG1 memory B cells in IgE production and find that two subsets of IgG1 memory B cells, CD80 + CD73 + and CD80 - CD73 - , contribute distinctively to the repertoires of high affinity pathogenic IgE and low affinity non-pathogenic IgE. Furthermore, repertoire analysis indicates that high affinity IgE and IgG1 plasma cells differentiate from rare CD80 + CD73 + high affinity memory clones without undergoing further mutagenesis. By identifying the cellular origin of high affinity IgE and the clonal selection of high affinity memory B cells into the plasma cell fate, our findings provide fundamental insights into the pathogenesis of allergies, and on the mechanisms of antibody production in memory B cell responses.IgE is an important mediator of protective immunity as well as allergic reaction, but how high affinity IgE antibodies are produced in memory responses is not clear. Here the authors show that IgE can be generated via class-switch recombination in IgG1 memory B cells without additional somatic hypermutation.

The CD8+ memory T-cell state of readiness is actively maintained and reversible

PubMed Central

Allam, Atef; Conze, Dietrich B.; Giardino Torchia, Maria Letizia; Munitic, Ivana; Yagita, Hideo; Sowell, Ryan T.; Marzo, Amanda L.

2009-01-01

The ability of the adaptive immune system to respond rapidly and robustly upon repeated antigen exposure is known as immunologic memory, and it is thought that acquisition of memory T-cell function is an irreversible differentiation event. In this study, we report that many phenotypic and functional characteristics of antigen-specific CD8 memory T cells are lost when they are deprived of contact with dendritic cells. Under these circumstances, memory T cells reverted from G1 to the G0 cell-cycle state and responded to stimulation like naive T cells, as assessed by proliferation, dependence upon costimulation, and interferon-γ production, without losing cell surface markers associated with memory. The memory state was maintained by signaling via members of the tumor necrosis factor receptor superfamily, CD27 and 4-1BB. Foxo1, a transcription factor involved in T-cell quiescence, was reduced in memory cells, and stimulation of naive CD8 cells via CD27 caused Foxo1 to be phosphorylated and emigrate from the nucleus in a phosphatidylinositol-3 kinase–dependent manner. Consistent with these results, maintenance of G1 in vivo was compromised in antigen-specific memory T cells in vesicular stomatitis virus-infected CD27-deficient mice. Therefore, sustaining the functional phenotype of T memory cells requires active signaling and maintenance. PMID:19617575

The role of cytokines in T-cell memory in health and disease.

PubMed

Raeber, Miro E; Zurbuchen, Yves; Impellizzieri, Daniela; Boyman, Onur

2018-05-01

Upon stimulation with their cognate antigen, naive T cells undergo proliferation and differentiation into effector cells, followed by apoptosis or survival as precursors of long-lived memory cells. These phases of a T-cell response and the ensuing maintenance of memory T cells are shaped by cytokines, most notably interleukin-2 (IL-2), IL-7, and IL-15 that share the common γ chain (γ c ) cytokine receptor. Steady-state production of IL-7 and IL-15 is necessary for background proliferation and homeostatic survival of CD4 + and CD8 + memory T cells. During immune responses, augmented levels of IL-2, IL-15, IL-21, IL-12, IL-18, and type-I interferons determine the memory potential of antigen-specific effector CD8 + cells, while increased IL-2 and IL-15 cause bystander proliferation of heterologous CD4 + and CD8 + memory T cells. Limiting availability of γ c cytokines, reduction in regulatory T cells or IL-10, and persistence of inflammation or cognate antigen can result in memory T cells, which fail to become cytokine-dependent long-lived cells. Conversely, increased IL-7 and IL-15 can expand memory T cells, including pathogenic tissue-resident memory T cells, as seen in lymphopenia and certain chronic-inflammatory disorders and malignancies. These abovementioned factors impact immunotherapy and vaccines directed at memory T cells in cancer and chronic infection. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Akt signaling is critical for memory CD8+ T-cell development and tumor immune surveillance.

PubMed

Rogel, Anne; Willoughby, Jane E; Buchan, Sarah L; Leonard, Henry J; Thirdborough, Stephen M; Al-Shamkhani, Aymen

2017-02-14

Memory CD8 + T cells confer long-term immunity against tumors, and anticancer vaccines therefore should maximize their generation. Multiple memory CD8 + T-cell subsets with distinct functional and homing characteristics exist, but the signaling pathways that regulate their development are ill defined. Here we examined the role of the serine/threonine kinase Akt in the generation of protective immunity by CD8 + T cells. Akt is known to be activated by the T-cell antigen receptor and the cytokine IL-2, but its role in T-cell immunity in vivo has not been explored. Using CD8 + T cells from pdk1 K465E/K465E knockin mice, we found that decreased Akt activity inhibited the survival of T cells during the effector-to-memory cell transition and abolished their differentiation into C-X-C chemokine receptor 3 (CXCR3) lo CD43 lo effector-like memory cells. Consequently, antitumor immunity by CD8 + T cells that display defective Akt signaling was substantially diminished during the memory phase. Reduced memory T-cell survival and altered memory cell differentiation were associated with up-regulation of the proapoptotic protein Bim and the T-box transcription factor eomesodermin, respectively. These findings suggest an important role for effector-like memory CD8 + T cells in tumor immune surveillance and identify Akt as a key signaling node in the development of protective memory CD8 + T-cell responses.

Akt signaling is critical for memory CD8+ T-cell development and tumor immune surveillance

PubMed Central

Rogel, Anne; Willoughby, Jane E.; Buchan, Sarah L.; Leonard, Henry J.; Thirdborough, Stephen M.; Al-Shamkhani, Aymen

2017-01-01

Memory CD8+ T cells confer long-term immunity against tumors, and anticancer vaccines therefore should maximize their generation. Multiple memory CD8+ T-cell subsets with distinct functional and homing characteristics exist, but the signaling pathways that regulate their development are ill defined. Here we examined the role of the serine/threonine kinase Akt in the generation of protective immunity by CD8+ T cells. Akt is known to be activated by the T-cell antigen receptor and the cytokine IL-2, but its role in T-cell immunity in vivo has not been explored. Using CD8+ T cells from pdk1K465E/K465E knockin mice, we found that decreased Akt activity inhibited the survival of T cells during the effector-to-memory cell transition and abolished their differentiation into C-X-C chemokine receptor 3 (CXCR3)loCD43lo effector-like memory cells. Consequently, antitumor immunity by CD8+ T cells that display defective Akt signaling was substantially diminished during the memory phase. Reduced memory T-cell survival and altered memory cell differentiation were associated with up-regulation of the proapoptotic protein Bim and the T-box transcription factor eomesodermin, respectively. These findings suggest an important role for effector-like memory CD8+ T cells in tumor immune surveillance and identify Akt as a key signaling node in the development of protective memory CD8+ T-cell responses. PMID:28137869

Memory vs memory-like: The different facets of CD8+ T-cell memory in HCV infection.

PubMed

Hofmann, Maike; Wieland, Dominik; Pircher, Hanspeter; Thimme, Robert

2018-05-01

Memory CD8 + T cells are essential in orchestrating protection from re-infection. Hallmarks of virus-specific memory CD8 + T cells are the capacity to mount recall responses with rapid induction of effector cell function and antigen-independent survival. Growing evidence reveals that even chronic infection does not preclude virus-specific CD8 + T-cell memory formation. However, whether this kind of CD8 + T-cell memory that is established during chronic infection is indeed functional and provides protection from re-infection is still unclear. Human chronic hepatitis C virus infection represents a unique model system to study virus-specific CD8 + T-cell memory formation during and after cessation of persisting antigen stimulation. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis.

PubMed

Abdelsamed, Hossam A; Moustaki, Ardiana; Fan, Yiping; Dogra, Pranay; Ghoneim, Hazem E; Zebley, Caitlin C; Triplett, Brandon M; Sekaly, Rafick-Pierre; Youngblood, Ben

2017-06-05

Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell-mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (T EM ), and longer-lived central memory (T CM ) and stem cell memory (T SCM ) CD8 T cells identified effector molecules with demethylated promoters and poised for expression. Effector-loci demethylation was heritably preserved during IL-7- and IL-15-mediated in vitro cell proliferation. Conversely, cytokine-driven proliferation of T CM and T SCM memory cells resulted in phenotypic conversion into T EM cells and was coupled to increased methylation of the CCR7 and Tcf7 loci. Furthermore, haploidentical donor memory CD8 T cells undergoing in vivo proliferation in lymphodepleted recipients also maintained their effector-associated demethylated status but acquired T EM -associated programs. These data demonstrate that effector-associated epigenetic programs are preserved during cytokine-driven subset interconversion of human memory CD8 T cells. © 2017 Abdelsamed et al.

CD4 T-Cell Memory Generation and Maintenance

PubMed Central

Gasper, David J.; Tejera, Melba Marie; Suresh, M.

2014-01-01

Immunologic memory is the adaptive immune system's powerful ability to remember a previous antigen encounter and react with accelerated vigor upon antigen re-exposure. It provides durable protection against reinfection with pathogens and is the foundation for vaccine-induced immunity. Unlike the relatively restricted immunologic purview of memory B cells and CD8 T cells, the field of CD4 T-cell memory must account for multiple distinct lineages with diverse effector functions, the issue of lineage commitment and plasticity, and the variable distribution of memory cells within each lineage. Here, we discuss the evidence for lineage-specific CD4 T-cell memory and summarize the known factors contributing to memory-cell generation, plasticity, and long-term maintenance. PMID:24940912

IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking

PubMed Central

Nolz, Jeffrey C.; Harty, John T.

2014-01-01

Memory and naive CD8+ T cells exhibit distinct trafficking patterns. Specifically, memory but not naive CD8+ T cells are recruited to inflamed tissues in an antigen-independent manner. However, the molecular mechanisms that regulate memory CD8+ T cell trafficking are largely unknown. Here, using murine models of infection and T cell transfer, we found that memory but not naive CD8+ T cells dynamically regulate expression of core 2 O-glycans, which interact with P- and E-selectins to modulate trafficking to inflamed tissues. Following infection, antigen-specific effector CD8+ T cells strongly expressed core 2 O-glycans, but this glycosylation pattern was lost by most memory CD8+ T cells. After unrelated infection or inflammatory challenge, memory CD8+ T cells synthesized core 2 O-glycans independently of antigen restimulation. The presence of core 2 O-glycans subsequently directed these cells to inflamed tissue. Memory and naive CD8+ T cells exhibited the opposite pattern of epigenetic modifications at the Gcnt1 locus, which encodes the enzyme that initiates core 2 O-glycan synthesis. The open chromatin configuration in memory CD8+ T cells permitted de novo generation of core 2 O-glycans in a TCR-independent, but IL-15–dependent, manner. Thus, IL-15 stimulation promotes antigen-experienced memory CD8+ T cells to generate core 2 O-glycans, which subsequently localize them to inflamed tissues. These findings suggest that CD8+ memory T cell trafficking potentially can be manipulated to improve host defense and immunotherapy. PMID:24509081

Enhancement of Immune Memory Responses to Respiratory Infection

DTIC Science & Technology

2017-08-01

induction of highly specific B and T cell responses against viral infections. Despite recent progress in vaccine development, the molecular mechanisms...highly expressed in memory B cells in mice, and Atg7 is required for maintenance of long-term memory B cells needed to protect against influenza...infection. Human influenza-specific memory B cells also have high levels of autophagy, but whether autophagy protects memory B cell survival in humans

Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cells

PubMed Central

Tsuda, Hidetoshi; Su, Charles A.; Tanaka, Toshiaki; Ayasoufi, Katayoun; Min, Booki; Valujskikh, Anna; Fairchild, Robert L.

2018-01-01

Recipient endogenous memory T cells with donor reactivity pose an important barrier to successful transplantation and costimulatory blockade–induced graft tolerance. Longer ischemic storage times prior to organ transplantation increase early posttransplant inflammation and negatively impact early graft function and long-term graft outcome. Little is known about the mechanisms enhancing endogenous memory T cell activation to mediate tissue injury within the increased inflammatory environment of allografts subjected to prolonged cold ischemic storage (CIS). Endogenous memory CD4+ and CD8+ T cell activation is markedly increased within complete MHC-mismatched cardiac allografts subjected to prolonged versus minimal CIS, and the memory CD8+ T cells directly mediate CTLA-4Ig–resistant allograft rejection. Memory CD8+ T cell activation within allografts subjected to prolonged CIS requires memory CD4+ T cell stimulation of graft DCs to produce p40 homodimers, but not IL-12 p40/p35 heterodimers. Targeting p40 abrogates memory CD8+ T cell proliferation within the allografts and their ability to mediate CTLA-4Ig–resistant allograft rejection. These findings indicate a critical role for memory CD4+ T cell–graft DC interactions to increase the intensity of endogenous memory CD8+ T cell activation needed to mediate rejection of higher-risk allografts subjected to increased CIS. PMID:29467328

Ultrasound active nanoscaled lipid formulations for thrombus lysis.

PubMed

Becker, Andreas; Marxer, Elena; Brüssler, Jana; Hoormann, Anne Sophia; Kuhnt, Daniela; Bakowsky, Udo; Nimsky, Christopher

2011-04-01

In the present study, we investigated the sonothrombolytic effect of new nanoscaled lipid formulations in human blood clots, using diagnostic ultrasound. Human blood clots of 1 ml were incubated with 1 μl of the different lipid dispersions DPPC/CH, DPPC/PEG40S, DSPC/PEG40S and the commercially available ultrasound contrast agent SonoVue®. Clots were stored for 3 days at 5 °C to obtain maximal clot retraction and lytic resistance. Each clot weight was determined before and after continuous insonation for 1h of insonation at 1.4 MHz. The pressure in the insonation chamber was 80 mm Hg to mimic middle arterial blood pressure. There were no significant differences in thrombus weight before insonation. All nanoscaled formulations and SonoVue® were able to reduce thrombus weight compared to the weight loss of clots that were not insonated but kept under pressure for one hour (p < 0.001). We found a highly significant weight reduction with DSPC/PEG40S compared to SonoVue® (p = 0.007). Nanoscaled DSPC/PEG40S dispersion could be a promising formulation in ultrasound enhanced thrombolysis even without thrombolytic drugs. Stable cavitation is a crucial parameter in fragmentation of thrombus architecture. Further studies of physicochemical properties of DSPC/PEG40S are necessary to corroborate our hypothesis. Copyright © 2010 Elsevier B.V. All rights reserved.

Pregnancy persistently affects memory T cell populations.

PubMed

Kieffer, Tom E C; Faas, Marijke M; Scherjon, Sicco A; Prins, Jelmer R

2017-02-01

Pregnancy is an immune challenge to the maternal immune system. The effects of pregnancy on maternal immunity and particularly on memory T cells during and after pregnancy are not fully known. This observational study aims to show the short term and the long term effects of pregnancy on the constitution, size and activation status of peripheral human memory T-lymphocyte populations. Effector memory (EM) and central memory (CM) T-lymphocytes were analyzed using flow cytometry of peripheral blood from 14 nulligravid, 12 primigravid and 15 parous women that were on average 18 months postpartum. The short term effects were shown by the significantly higher CD4+ EM cell and activated CD4+ memory cell proportions in primigravid women compared to nulligravid women. The persistent effects found in this study were the significantly higher proportions of CD4+ EM, CD4+ CM and activated memory T cells in parous women compared to nulligravid women. In contrast to CD4+ cells, activation status of CD8+ memory cells did not differ between the groups. This study shows that pregnancy persistently affects the pre-pregnancy CD4+ memory cell pool in human peripheral blood. During pregnancy, CD4+ T-lymphocytes might differentiate into EM cells followed by persistent higher proportions of CD4+ CM and EM cells postpartum. The persistent effects of pregnancy on memory T cells found in this study support the hypothesis that memory T cells are generated during pregnancy and that these cells could be involved in the lower complication risks in multiparous pregnancies in humans. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Development of memory CD8+ T cells and their recall responses during blood-stage infection with Plasmodium berghei ANKA.

PubMed

Miyakoda, Mana; Kimura, Daisuke; Honma, Kiri; Kimura, Kazumi; Yuda, Masao; Yui, Katsuyuki

2012-11-01

Conditions required for establishing protective immune memory vary depending on the infecting microbe. Although the memory immune response against malaria infection is generally thought to be relatively slow to develop and can be lost rapidly, experimental evidence is insufficient. In this report, we investigated the generation, maintenance, and recall responses of Ag-specific memory CD8(+) T cells using Plasmodium berghei ANKA expressing OVA (PbA-OVA) as a model system. Mice were transferred with OVA-specific CD8(+) T (OT-I) cells and infected with PbA-OVA or control Listeria monocytogenes expressing OVA (LM-OVA). Central memory type OT-I cells were maintained for >2 mo postinfection and recovery from PbA-OVA. Memory OT-I cells produced IFN-γ as well as TNF-α upon activation and were protective against challenge with a tumor expressing OVA, indicating that functional memory CD8(+) T cells can be generated and maintained postinfection with P. berghei ANKA. Cotransfer of memory OT-I cells with naive OT-I cells to mice followed by infection with PbA-OVA or LM-OVA revealed that clonal expansion of memory OT-I cells was limited during PbA-OVA infection compared with expansion of naive OT-I cells, whereas it was more rapid during LM-OVA infection. The expression of inhibitory receptors programmed cell death-1 and LAG-3 was higher in memory-derived OT-I cells than naive-derived OT-I cells during infection with PbA-OVA. These results suggest that memory CD8(+) T cells can be established postinfection with P. berghei ANKA, but their recall responses during reinfection are more profoundly inhibited than responses of naive CD8(+) T cells.

Hoxb4 overexpression in CD4 memory phenotype T cells increases the central memory population upon homeostatic proliferation.

PubMed

Frison, Héloïse; Giono, Gloria; Thébault, Paméla; Fournier, Marilaine; Labrecque, Nathalie; Bijl, Janet J

2013-01-01

Memory T cell populations allow a rapid immune response to pathogens that have been previously encountered and thus form the basis of success in vaccinations. However, the molecular pathways underlying the development and maintenance of these cells are only starting to be unveiled. Memory T cells have the capacity to self renew as do hematopoietic stem cells, and overlapping gene expression profiles suggested that these cells might use the same self-renewal pathways. The transcription factor Hoxb4 has been shown to promote self-renewal divisions of hematopoietic stem cells resulting in an expansion of these cells. In this study we investigated whether overexpression of Hoxb4 could provide an advantage to CD4 memory phenotype T cells in engrafting the niche of T cell deficient mice following adoptive transfer. Competitive transplantation experiments demonstrated that CD4 memory phenotype T cells derived from mice transgenic for Hoxb4 contributed overall less to the repopulation of the lymphoid organs than wild type CD4 memory phenotype T cells after two months. These proportions were relatively maintained following serial transplantation in secondary and tertiary mice. Interestingly, a significantly higher percentage of the Hoxb4 CD4 memory phenotype T cell population expressed the CD62L and Ly6C surface markers, characteristic for central memory T cells, after homeostatic proliferation. Thus Hoxb4 favours the maintenance and increase of the CD4 central memory phenotype T cell population. These cells are more stem cell like and might eventually lead to an advantage of Hoxb4 T cells after subjecting the cells to additional rounds of proliferation.

Silent memory engrams as the basis for retrograde amnesia

PubMed Central

Roy, Dheeraj S.; Muralidhar, Shruti; Smith, Lillian M.

2017-01-01

Recent studies identified neuronal ensembles and circuits that hold specific memory information (memory engrams). Memory engrams are retained under protein synthesis inhibition-induced retrograde amnesia. These engram cells can be activated by optogenetic stimulation for full-fledged recall, but not by stimulation using natural recall cues (thus, amnesia). We call this state of engrams “silent engrams” and the cells bearing them “silent engram cells.” The retention of memory information under amnesia suggests that the time-limited protein synthesis following learning is dispensable for memory storage, but may be necessary for effective memory retrieval processes. Here, we show that the full-fledged optogenetic recall persists at least 8 d after learning under protein synthesis inhibition-induced amnesia. This long-term retention of memory information correlates with equally persistent retention of functional engram cell-to-engram cell connectivity. Furthermore, inactivation of the connectivity of engram cell ensembles with its downstream counterparts, but not upstream ones, prevents optogenetic memory recall. Consistent with the previously reported lack of retention of augmented synaptic strength and reduced spine density in silent engram cells, optogenetic memory recall under amnesia is stimulation strength-dependent, with low-power stimulation eliciting only partial recall. Finally, the silent engram cells can be converted to active engram cells by overexpression of α-p-21–activated kinase 1, which increases spine density in engram cells. These results indicate that memory information is retained in a form of silent engram under protein synthesis inhibition-induced retrograde amnesia and support the hypothesis that memory is stored as the specific connectivity between engram cells. PMID:29078397

Silent memory engrams as the basis for retrograde amnesia.

PubMed

Roy, Dheeraj S; Muralidhar, Shruti; Smith, Lillian M; Tonegawa, Susumu

2017-11-14

Recent studies identified neuronal ensembles and circuits that hold specific memory information (memory engrams). Memory engrams are retained under protein synthesis inhibition-induced retrograde amnesia. These engram cells can be activated by optogenetic stimulation for full-fledged recall, but not by stimulation using natural recall cues (thus, amnesia). We call this state of engrams "silent engrams" and the cells bearing them "silent engram cells." The retention of memory information under amnesia suggests that the time-limited protein synthesis following learning is dispensable for memory storage, but may be necessary for effective memory retrieval processes. Here, we show that the full-fledged optogenetic recall persists at least 8 d after learning under protein synthesis inhibition-induced amnesia. This long-term retention of memory information correlates with equally persistent retention of functional engram cell-to-engram cell connectivity. Furthermore, inactivation of the connectivity of engram cell ensembles with its downstream counterparts, but not upstream ones, prevents optogenetic memory recall. Consistent with the previously reported lack of retention of augmented synaptic strength and reduced spine density in silent engram cells, optogenetic memory recall under amnesia is stimulation strength-dependent, with low-power stimulation eliciting only partial recall. Finally, the silent engram cells can be converted to active engram cells by overexpression of α-p-21-activated kinase 1, which increases spine density in engram cells. These results indicate that memory information is retained in a form of silent engram under protein synthesis inhibition-induced retrograde amnesia and support the hypothesis that memory is stored as the specific connectivity between engram cells.

Pathogen stimulation history impacts donor-specific CD8+ T cell susceptibility to costimulation/integrin blockade-based therapy

PubMed Central

Badell, IR; Kitchens, WH; Wagener, ME; Lukacher, AE; Larsen, CP; Ford, ML

2017-01-01

Recent studies have shown that the quantity of donor-reactive memory T cells is an important factor in determining the relative heterologous immunity barrier posed during transplantation. Here, we hypothesized that the quality of T cell memory also potently influences the response to costimulation blockade-based immunosuppression. Using a murine skin graft model of CD8+ memory T cell-mediated costimulation blockade resistance, we elicited donor-reactive memory T cells using three distinct types of pathogen infections. Strikingly, we observed differential efficacy of a costimulation and integrin blockade regimen based on the type of pathogen used to elicit the donor-reactive memory T cell response. Intriguingly, the most immunosuppression-sensitive memory T cell populations were composed primarily of central memory cells that possessed greater recall potential, exhibited a less differentiated phenotype, and contained more multi-cytokine producers. These data therefore demonstrate that the memory T cell barrier is dependent on the specific type of pathogen infection via which the donor-reactive memory T cells are elicited, and suggest that the immune stimulation history of a given transplant patient may profoundly influence the relative barrier posed by heterologous immunity during transplantation. PMID:26228897

A Memory B Cell Crossmatch Assay for Quantification of Donor-Specific Memory B Cells in the Peripheral Blood of HLA-Immunized Individuals.

PubMed

Karahan, G E; de Vaal, Y J H; Krop, J; Wehmeier, C; Roelen, D L; Claas, F H J; Heidt, S

2017-10-01

Humoral responses against mismatched donor HLA are routinely measured as serum HLA antibodies, which are mainly produced by bone marrow-residing plasma cells. Individuals with a history of alloimmunization but lacking serum antibodies may harbor circulating dormant memory B cells, which may rapidly become plasma cells on antigen reencounter. Currently available methods to detect HLA-specific memory B cells are scarce and insufficient in quantifying the complete donor-specific memory B cell response due to their dependence on synthetic HLA molecules. We present a highly sensitive and specific tool for quantifying donor-specific memory B cells in peripheral blood of individuals using cell lysates covering the complete HLA class I and class II repertoire of an individual. Using this enzyme-linked immunospot (ELISpot) assay, we found a median frequency of 31 HLA class I and 89 HLA class II-specific memory B cells per million IgG-producing cells directed at paternal HLA in peripheral blood samples from women (n = 22) with a history of pregnancy, using cell lysates from spouses. The donor-specific memory B cell ELISpot can be used in HLA diagnostic laboratories as a cross-match assay to quantify donor-specific memory B cells in patients with a history of sensitizing events. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Protective Capacity of Memory CD8+ T Cells is Dictated by Antigen Exposure History and Nature of the Infection

PubMed Central

Nolz, Jeffrey C.; Harty, John T.

2011-01-01

SUMMARY Infection or vaccination confers heightened resistance to pathogen re-challenge due to quantitative and qualitative differences between naïve and primary memory T cells. Herein, we show that secondary (boosted) memory CD8+ T cells were better than primary memory CD8+ T cells in controlling some, but not all acute infections with diverse pathogens. However, secondary memory CD8+ T cells were less efficient than an equal number of primary memory cells at preventing chronic LCMV infection and are more susceptible to functional exhaustion. Importantly, localization of memory CD8+ T cells within lymph nodes, which is reduced by antigen re-stimulation, was critical for both viral control in lymph nodes and for the sustained CD8+ T cell response required to prevent chronic LCMV infection. Thus, repeated antigen-stimulation shapes memory CD8+ T cell populations to either enhance or decrease per cell protective immunity in a pathogen-specific manner, a concept of importance in vaccine design against specific diseases. PMID:21549619

Induction and Maintenance of CX3CR1-Intermediate Peripheral Memory CD8+ T Cells by Persistent Viruses and Vaccines.

PubMed

Gordon, Claire Louse; Lee, Lian Ni; Swadling, Leo; Hutchings, Claire; Zinser, Madeleine; Highton, Andrew John; Capone, Stefania; Folgori, Antonella; Barnes, Eleanor; Klenerman, Paul

2018-04-17

The induction and maintenance of T cell memory is critical to the success of vaccines. A recently described subset of memory CD8 + T cells defined by intermediate expression of the chemokine receptor CX3CR1 was shown to have self-renewal, proliferative, and tissue-surveillance properties relevant to vaccine-induced memory. We tracked these cells when memory is sustained at high levels: memory inflation induced by cytomegalovirus (CMV) and adenovirus-vectored vaccines. In mice, both CMV and vaccine-induced inflationary T cells showed sustained high levels of CX3R1 int cells exhibiting an effector-memory phenotype, characteristic of inflationary pools, in early memory. In humans, CX3CR1 int CD8 + T cells were strongly induced following adenovirus-vectored vaccination for hepatitis C virus (HCV) (ChAd3-NSmut) and during natural CMV infection and were associated with a memory phenotype similar to that in mice. These data indicate that CX3CR1 int cells form an important component of the memory pool in response to persistent viruses and vaccines in both mice and humans. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Identification of Nascent Memory CD8 T Cells and Modeling of Their Ontogeny.

PubMed

Crauste, Fabien; Mafille, Julien; Boucinha, Lilia; Djebali, Sophia; Gandrillon, Olivier; Marvel, Jacqueline; Arpin, Christophe

2017-03-22

Primary immune responses generate short-term effectors and long-term protective memory cells. The delineation of the genealogy linking naive, effector, and memory cells has been complicated by the lack of phenotypes discriminating effector from memory differentiation stages. Using transcriptomics and phenotypic analyses, we identify Bcl2 and Mki67 as a marker combination that enables the tracking of nascent memory cells within the effector phase. We then use a formal approach based on mathematical models describing the dynamics of population size evolution to test potential progeny links and demonstrate that most cells follow a linear naive→early effector→late effector→memory pathway. Moreover, our mathematical model allows long-term prediction of memory cell numbers from a few early experimental measurements. Our work thus provides a phenotypic means to identify effector and memory cells, as well as a mathematical framework to investigate their genealogy and to predict the outcome of immunization regimens in terms of memory cell numbers generated. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Studies on B-cell memory. III. T-dependent aspect of B memory generation in mice immunized with T-independent type-2(TI-2) antigen.

PubMed

Hosokawa, T; Tanaka, Y; Aoike, A; Kawai, K; Muramatsu, S

1984-09-01

The time course of B-cell memory development to a dinitrophenyl (DNP) T-independent type-2 (TI-2) antigen was investigated by adoptive cell transfer. Strong IgM and IgG memory developed in BALB/c mice after immunization with DNP-dextran, to be recalled by challenge with either T-dependent (TD) antigen or TI-2 antigen. However, only weak IgM memory and very feeble IgG memory were detected in athymic nude mice receiving the same immunization as euthymic mice. Once memory was established under probable T cell influence, its recall by TI-2 antigen challenge seemed independent of T cell help and did not require sharing of carriers between priming and challenge antigens. The following may be concluded. (i) Long-term IgM and IgG memory is induced by TI-2 antigen priming in the presence of functional T cells. (ii) The class switch from IgM to IgG in the memory B cell pool is driven effectively by TI-2 antigen and is probably T cell-dependent.

Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory

PubMed Central

Kaji, Tomohiro; Ishige, Akiko; Hikida, Masaki; Taka, Junko; Hijikata, Atsushi; Kubo, Masato; Nagashima, Takeshi; Takahashi, Yoshimasa; Kurosaki, Tomohiro; Okada, Mariko; Ohara, Osamu

2012-01-01

One component of memory in the antibody system is long-lived memory B cells selected for the expression of somatically mutated, high-affinity antibodies in the T cell–dependent germinal center (GC) reaction. A puzzling observation has been that the memory B cell compartment also contains cells expressing unmutated, low-affinity antibodies. Using conditional Bcl6 ablation, we demonstrate that these cells are generated through proliferative expansion early after immunization in a T cell–dependent but GC-independent manner. They soon become resting and long-lived and display a novel distinct gene expression signature which distinguishes memory B cells from other classes of B cells. GC-independent memory B cells are later joined by somatically mutated GC descendants at roughly equal proportions and these two types of memory cells efficiently generate adoptive secondary antibody responses. Deletion of T follicular helper (Tfh) cells significantly reduces the generation of mutated, but not unmutated, memory cells early on in the response. Thus, B cell memory is generated along two fundamentally distinct cellular differentiation pathways. One pathway is dedicated to the generation of high-affinity somatic antibody mutants, whereas the other preserves germ line antibody specificities and may prepare the organism for rapid responses to antigenic variants of the invading pathogen. PMID:23027924

Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? Vaccination Strategies Based on NK Cell and ILC Memory.

PubMed

Cooper, Megan A; Fehniger, Todd A; Colonna, Marco

2017-12-18

Studies over the last decade have decisively shown that innate immune natural killer (NK) cells exhibit enhanced long-lasting functional responses following a single activation event. With the increased recognition of memory and memory-like properties of NK cells, questions have arisen with regard to their ability to effectively mediate vaccination responses in humans. Moreover, recently discovered innate lymphoid cells (ILCs) could also potentially exhibit memory-like functions. Here, we review different forms of NK cell memory, and speculate about the ability of these cells and ILCs to meaningfully contribute to vaccination responses. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

An engram found? Evaluating the evidence from fruit flies.

PubMed

Gerber, Bertram; Tanimoto, Hiromu; Heisenberg, Martin

2004-12-01

Is it possible to localize a memory trace to a subset of cells in the brain? If so, it should be possible to show: first, that neuronal plasticity occurs in these cells. Second, that neuronal plasticity in these cells is sufficient for memory. Third, that neuronal plasticity in these cells is necessary for memory. Fourth, that memory is abolished if these cells cannot provide output during testing. And fifth, that memory is abolished if these cells cannot receive input during training. With regard to olfactory learning in flies, we argue that the notion of the olfactory memory trace being localized to the Kenyon cells of the mushroom bodies is a reasonable working hypothesis.

Ventromedial prefrontal cortex pyramidal cells have a temporal dynamic role in recall and extinction of cocaine-associated memory.

PubMed

Van den Oever, Michel C; Rotaru, Diana C; Heinsbroek, Jasper A; Gouwenberg, Yvonne; Deisseroth, Karl; Stuber, Garret D; Mansvelder, Huibert D; Smit, August B

2013-11-13

In addicts, associative memories related to the rewarding effects of drugs of abuse can evoke powerful craving and drug seeking urges, but effective treatment to suppress these memories is not available. Detailed insight into the neural circuitry that mediates expression of drug-associated memory is therefore of crucial importance. Substantial evidence from rodent models of addictive behavior points to the involvement of the ventromedial prefrontal cortex (vmPFC) in conditioned drug seeking, but specific knowledge of the temporal role of vmPFC pyramidal cells is lacking. To this end, we used an optogenetics approach to probe the involvement of vmPFC pyramidal cells in expression of a recent and remote conditioned cocaine memory. In mice, we expressed Channelrhodopsin-2 (ChR2) or Halorhodopsin (eNpHR3.0) in pyramidal cells of the vmPFC and studied the effect of activation or inhibition of these cells during expression of a cocaine-contextual memory on days 1-2 (recent) and ∼3 weeks (remote) after conditioning. Whereas optical activation of pyramidal cells facilitated extinction of remote memory, without affecting recent memory, inhibition of pyramidal cells acutely impaired recall of recent cocaine memory, without affecting recall of remote memory. In addition, we found that silencing pyramidal cells blocked extinction learning at the remote memory time-point. We provide causal evidence of a critical time-dependent switch in the contribution of vmPFC pyramidal cells to recall and extinction of cocaine-associated memory, indicating that the circuitry that controls expression of cocaine memories reorganizes over time.

Memory CD4 T cell subsets are kinetically heterogeneous and replenished from naive T cells at high levels

PubMed Central

Gossel, Graeme; Hogan, Thea; Cownden, Daniel

2017-01-01

Characterising the longevity of immunological memory requires establishing the rules underlying the renewal and death of peripheral T cells. However, we lack knowledge of the population structure and how self-renewal and de novo influx contribute to the maintenance of memory compartments. Here, we characterise the kinetics and structure of murine CD4 T cell memory subsets by measuring the rates of influx of new cells and using detailed timecourses of DNA labelling that also distinguish the behaviour of recently divided and quiescent cells. We find that both effector and central memory CD4 T cells comprise subpopulations with highly divergent rates of turnover, and show that inflows of new cells sourced from the naive pool strongly impact estimates of memory cell lifetimes and division rates. We also demonstrate that the maintenance of CD4 T cell memory subsets in healthy mice is unexpectedly and strikingly reliant on this replenishment. DOI: http://dx.doi.org/10.7554/eLife.23013.001 PMID:28282024

Antigen-Induced but Not Innate Memory CD8 T Cells Express NKG2D and Are Recruited to the Lung Parenchyma upon Viral Infection.

PubMed

Grau, Morgan; Valsesia, Séverine; Mafille, Julien; Djebali, Sophia; Tomkowiak, Martine; Mathieu, Anne-Laure; Laubreton, Daphné; de Bernard, Simon; Jouve, Pierre-Emmanuel; Ventre, Erwan; Buffat, Laurent; Walzer, Thierry; Leverrier, Yann; Marvel, Jacqueline

2018-05-15

The pool of memory-phenotype CD8 T cells is composed of Ag-induced (AI) and cytokine-induced innate (IN) cells. IN cells have been described as having properties similar to those of AI memory cells. However, we found that pathogen-induced AI memory cells can be distinguished in mice from naturally generated IN memory cells by surface expression of NKG2D. Using this marker, we described the increased functionalities of AI and IN memory CD8 T cells compared with naive cells, as shown by comprehensive analysis of cytokine secretion and gene expression. However, AI differed from IN memory CD8 T cells by their capacity to migrate to the lung parenchyma upon inflammation or infection, a process dependent on their expression of ITGA1/CD49a and ITGA4/CD49d integrins. Copyright © 2018 by The American Association of Immunologists, Inc.

Memory CD4 T cell subsets are kinetically heterogeneous and replenished from naive T cells at high levels.

PubMed

Gossel, Graeme; Hogan, Thea; Cownden, Daniel; Seddon, Benedict; Yates, Andrew J

2017-03-10

Characterising the longevity of immunological memory requires establishing the rules underlying the renewal and death of peripheral T cells. However, we lack knowledge of the population structure and how self-renewal and de novo influx contribute to the maintenance of memory compartments. Here, we characterise the kinetics and structure of murine CD4 T cell memory subsets by measuring the rates of influx of new cells and using detailed timecourses of DNA labelling that also distinguish the behaviour of recently divided and quiescent cells. We find that both effector and central memory CD4 T cells comprise subpopulations with highly divergent rates of turnover, and show that inflows of new cells sourced from the naive pool strongly impact estimates of memory cell lifetimes and division rates. We also demonstrate that the maintenance of CD4 T cell memory subsets in healthy mice is unexpectedly and strikingly reliant on this replenishment.

IFN-γ Induces the Erosion of Preexisting CD8 T Cell Memory during Infection with a Heterologous Intracellular Bacterium1

PubMed Central

Dudani, Renu; Murali-Krishna, Kaja; Krishnan, Lakshmi; Sad, Subash

2014-01-01

Memory T cells are critical for the control of intracellular pathogens and require few signals for maintenance; however, erosion of established preexisting memory CD8+ T cells has been shown to occur during infection with heterologous viral infections. We evaluated whether this also occurs during infection with various intracellular bacteria and what mechanisms may be involved. We demonstrate that erosion of established memory is also induced during infection of mice with various intracellular bacteria, such as Listeria monocytogenes, Salmonella typhimurium, and Mycobacterium bovis (bacillus Calmette-Guérin). The extent of erosion of established CD8+ T cell memory was dependent on the virulence of the heterologous pathogen, not persistence. Furthermore, when antibiotics were used to comprehensively eliminate the heterologous pathogen, the numbers of memory CD8+ T cells were not restored, indicating that erosion of preexisting memory CD8+ T cells was irreversible. Irrespective of the initial numbers of memory CD8+ T cells, challenge with the heterologous pathogen resulted in a similar extent of erosion of memory CD8+ T cells, suggesting that cellular competition was not responsible for erosion. After challenge with the heterologous pathogen, effector memory CD8+ T cells were rapidly eliminated. More importantly, erosion of preexisting memory CD8+ T cells was abrogated in the absence of IFN-γ. These studies help reveal the paradoxical role of IFN-γ. Although IFN-γ promotes the control of intracellular bacterial replication during primary infection, this comes at the expense of erosion of preexisting memory CD8+ T cells in the wake of infection with heterologous pathogens. PMID:18641306

Memory T cells in organ transplantation: progress and challenges

PubMed Central

Espinosa, Jaclyn R.; Samy, Kannan P.; Kirk, Allan D.

2017-01-01

Antigen-experienced T cells, also known as memory T cells, are functionally and phenotypically distinct from naive T cells. Their enhanced expression of adhesion molecules and reduced requirement for co-stimulation enables them to mount potent and rapid recall responses to subsequent antigen encounters. Memory T cells generated in response to prior antigen exposures can cross-react with other nonidentical, but similar, antigens. This heterologous cross-reactivity not only enhances protective immune responses, but also engenders de novo alloimmunity. This latter characteristic is increasingly recognized as a potential barrier to allograft acceptance that is worthy of immunotherapeutic intervention, and several approaches have been investigated. Calcineurin inhibition effectively controls memory T-cell responses to allografts, but this benefit comes at the expense of increased infectious morbidity. Lymphocyte depletion eliminates allospecific T cells but spares memory T cells to some extent, such that patients do not completely lose protective immunity. Co-stimulation blockade is associated with reduced adverse-effect profiles and improved graft function relative to calcineurin inhibition, but lacks efficacy in controlling memory T-cell responses. Targeting the adhesion molecules that are upregulated on memory T cells might offer additional means to control co-stimulation-blockade-resistant memory T-cell responses. PMID:26923209

[Ecological study on the mortality of residents in Manfredonia (Apulia Region, Southern Italy) from 1970 to 2013].

PubMed

Gianicolo, Emilio Antonio Luca; Mangia, Cristina; Cervino, Marco; Bruni, Antonella; De Marchi, Bruna; Biggeri, Annibale; Porcu, Rosa; Vigotti, Maria Angela

2016-01-01

OBIETTIVI: valutare lo stato di salute della popolazione residente nel comune di Manfredonia dal 1970 al 2013. DISEGNO: analisi descrittiva dell'andamento temporale della mortalità generale, per gruppi di cause, dal 1970 al 2013. SETTING E PARTECIPANTI: i dati di mortalità e le popolazioni residenti sono di fonte Istat. Sono state esaminate 55 cause di decesso. Le analisi sono disaggregate per sesso e periodo. PRINCIPALI MISURE DI OUTCOME: sono stati elaborati i rapporti standardizzati di mortalità (SMR%), con i rispettivi intervalli di confidenza al 90% (IC90%), e i tassi di mortalità standardizzati col metodo diretto (TSD ). RISULTATI: lo stato di salute misurato dal tasso di mortalità per tutte le cause migliora nel tempo: i TSD passano da 92 x10.000 negli anni 1970-1974 a 52 x10.000 nel biennio 2012-2013 negli uomini, da 70 x10.000 a 39 x10.000 nelle donne. Tuttavia, rispetto alla media regionale Manfredonia perde progressivamente il suo vantaggio, passando da -20% a -10% negli uomini, e da -20% a +1,5% nelle donne. Questo andamento è molto evidente per il complesso delle cause cardiovascolari, mentre i tumori maligni sono in generale nella media regionale. Nell'ultimo periodo disponibile per causa di decesso (2006-2011), la mortalità per infarto miocardico è stata più alta della media regionale (uomini: +35%; donne: +54%). I rapporti standardizzati di mortalità (SMR) mostrano tra gli uomini valori in crescita, in particolar modo rispetto al riferimento provinciale, con un eccesso a cominciare dal periodo 2006-2011 (22 decessi/anno e 19 attesi; SMR%: 117,2; IC90% 101,1-135,2; riferimento: provincia di Foggia). Anche tra le donne gli SMR% superano i riferimenti provinciali negli ultimi periodi esaminati (nel 2012-2013: 7 decessi/ anno e 4,2 attesi; SMR%: 116,4; IC90% 97,0-260,7; riferimento: provincia di Foggia). CONCLUSIONI: la mortalità a Manfredonia è diminuita in misura minore rispetto a quella osservata nei riferimenti provinciali e regionali. Il vantaggio che si osservava negli anni Sessanta si è, infatti, ridotto nel tempo, fino ad annullarsi negli ultimi anni. Dal 1970, Manfredonia ha progressivamente perso il vantaggio che aveva. Dagli anni Duemila, la mortalità per infarto del miocardio è in eccesso sulla media regionale e provinciale. Da casi documentati in letteratura si osserva che le popolazioni che sperimentano catastrofi di origine naturale o antropica possono fronteggiare un aumento di patologie cardiovascolari. La mortalità per tumore polmonare mostra un eccesso sulla media regionale, in particolare provinciale, a cominciare dal 2000, coerentemente con i tempi di latenza legati all'esposizione ad arsenico negli anni Settanta.

FG Width Scalability of the 3-D Vertical FG NAND Using the Sidewall Control Gate (SCG)

NASA Astrophysics Data System (ADS)

Seo, Moon-Sik; Endoh, Tetsuo

Recently, the 3-D vertical Floating Gate (FG) type NAND cell arrays with the Sidewall Control Gate (SCG), such as ESCG, DC-SF and S-SCG, are receiving attention to overcome the reliability issues of Charge Trap (CT) type device. Using this novel cell structure, highly reliable flash cell operations were successfully implemented without interference effect on the FG type cell. However, the 3-D vertical FG type cell has large cell size by about 60% for the cylindrical FG structure. In this point of view, we intensively investigate the scalability of the FG width of the 3-D vertical FG NAND cells. In case of the planar FG type NAND cell, the FG height cannot be scaled down due to the necessity of obtaining sufficient coupling ratio and high program speed. In contrast, for the 3-D vertical FG NAND with SCG, the FG is formed cylindrically, which is fully covered with surrounded CG, and very high CG coupling ratio can be achieved. As results, the scaling of FG width of the 3-D vertical FG NAND cell with S-SCG can be successfully demonstrated at 10nm regime, which is almost the same as the CT layer of recent BE-SONOS NAND.

miR-150 Regulates Memory CD8 T Cell Differentiation via c-Myb.

PubMed

Chen, Zeyu; Stelekati, Erietta; Kurachi, Makoto; Yu, Sixiang; Cai, Zhangying; Manne, Sasikanth; Khan, Omar; Yang, Xiaolu; Wherry, E John

2017-09-12

MicroRNAs play an important role in T cell responses. However, how microRNAs regulate CD8 T cell memory remains poorly defined. Here, we found that miR-150 negatively regulates CD8 T cell memory in vivo. Genetic deletion of miR-150 disrupted the balance between memory precursor and terminal effector CD8 T cells following acute viral infection. Moreover, miR-150-deficient memory CD8 T cells were more protective upon rechallenge. A key circuit whereby miR-150 repressed memory CD8 T cell development through the transcription factor c-Myb was identified. Without miR-150, c-Myb was upregulated and anti-apoptotic targets of c-Myb, such as Bcl-2 and Bcl-xL, were also increased, suggesting a miR-150-c-Myb survival circuit during memory CD8 T cell development. Indeed, overexpression of non-repressible c-Myb rescued the memory CD8 T cell defects caused by overexpression of miR-150. Overall, these results identify a key role for miR-150 in memory CD8 T cells through a c-Myb-controlled enhanced survival circuit. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Scarcity of autoreactive human blood IgA+ memory B cells

PubMed Central

Prigent, Julie; Lorin, Valérie; Kök, Ayrin; Hieu, Thierry; Bourgeau, Salomé

2016-01-01

Class‐switched memory B cells are key components of the “reactive” humoral immunity, which ensures a fast and massive secretion of high‐affinity antigen‐specific antibodies upon antigenic challenge. In humans, IgA class‐switched (IgA+) memory B cells and IgA antibodies are abundant in the blood. Although circulating IgA+ memory B cells and their corresponding secreted immunoglobulins likely possess major protective and/or regulatory immune roles, little is known about their specificity and function. Here, we show that IgA+ and IgG+ memory B‐cell antibodies cloned from the same healthy humans share common immunoglobulin gene features. IgA and IgG memory antibodies have comparable lack of reactivity to vaccines, common mucosa‐tropic viruses and commensal bacteria. However, the IgA+ memory B‐cell compartment contains fewer polyreactive clones and importantly, only rare self‐reactive clones compared to IgG+ memory B cells. Self‐reactivity of IgAs is acquired following B‐cell affinity maturation but not antibody class switching. Together, our data suggest the existence of different regulatory mechanisms for removing autoreactive clones from the IgG+ and IgA+ memory B‐cell repertoires, and/or different maturation pathways potentially reflecting the distinct nature and localization of the cognate antigens recognized by individual B‐cell populations. PMID:27469325

Secondary immunization generates clonally related antigen-specific plasma cells and memory B cells.

PubMed

Frölich, Daniela; Giesecke, Claudia; Mei, Henrik E; Reiter, Karin; Daridon, Capucine; Lipsky, Peter E; Dörner, Thomas

2010-09-01

Rechallenge with T cell-dependent Ags induces memory B cells to re-enter germinal centers (GCs) and undergo further expansion and differentiation into plasma cells (PCs) and secondary memory B cells. It is currently not known whether the expanded population of memory B cells and PCs generated in secondary GCs are clonally related, nor has the extent of proliferation and somatic hypermutation of their precursors been delineated. In this study, after secondary tetanus toxoid (TT) immunization, TT-specific PCs increased 17- to 80-fold on days 6-7, whereas TT-specific memory B cells peaked (delayed) on day 14 with a 2- to 22-fold increase. Molecular analyses of V(H)DJ(H) rearrangements of individual cells revealed no major differences of gene usage and CDR3 length between TT-specific PCs and memory B cells, and both contained extensive evidence of somatic hypermutation with a pattern consistent with GC reactions. This analysis identified clonally related TT-specific memory B cells and PCs. Within clusters of clonally related cells, sequences shared a number of mutations but also could contain additional base pair changes. The data indicate that although following secondary immunization PCs can derive from memory B cells without further somatic hypermutation, in some circumstances, likely within GC reactions, asymmetric mutation can occur. These results suggest that after the fate decision to differentiate into secondary memory B cells or PCs, some committed precursors continue to proliferate and mutate their V(H) genes.

Protecting and rescuing the effectors: roles of differentiation and survival in the control of memory T cell development

PubMed Central

Kurtulus, Sema; Tripathi, Pulak; Hildeman, David A.

2013-01-01

Vaccines, arguably the single most important intervention in improving human health, have exploited the phenomenon of immunological memory. The elicitation of memory T cells is often an essential part of successful long-lived protective immunity. Our understanding of T cell memory has been greatly aided by the development of TCR Tg mice and MHC tetrameric staining reagents that have allowed the precise tracking of antigen-specific T cell responses. Indeed, following acute infection or immunization, naïve T cells undergo a massive expansion culminating in the generation of a robust effector T cell population. This peak effector response is relatively short-lived and, while most effector T cells die by apoptosis, some remain and develop into memory cells. Although the molecular mechanisms underlying this cell fate decision remain incompletely defined, substantial progress has been made, particularly with regards to CD8+ T cells. For example, the effector CD8+ T cells generated during a response are heterogeneous, consisting of cells with more or less potential to develop into full-fledged memory cells. Development of CD8+ T cell memory is regulated by the transcriptional programs that control the differentiation and survival of effector T cells. While the type of antigenic stimulation and level of inflammation control effector CD8+ T cell differentiation, availability of cytokines and their ability to control expression and function of Bcl-2 family members governs their survival. These distinct differentiation and survival programs may allow for finer therapeutic intervention to control both the quality and quantity of CD8+ T cell memory. Effector to memory transition of CD4+ T cells is less well characterized than CD8+ T cells, emerging details will be discussed. This review will focus on the recent progress made in our understanding of the mechanisms underlying the development of T cell memory with an emphasis on factors controlling survival of effector T cells. PMID:23346085

TLR4 ligands lipopolysaccharide and monophosphoryl lipid a differentially regulate effector and memory CD8+ T Cell differentiation.

PubMed

Cui, Weiguo; Joshi, Nikhil S; Liu, Ying; Meng, Hailong; Kleinstein, Steven H; Kaech, Susan M

2014-05-01

Vaccines formulated with nonreplicating pathogens require adjuvants to help bolster immunogenicity. The role of adjuvants in Ab production has been well studied, but how they influence memory CD8(+) T cell differentiation remains poorly defined. In this study we implemented dendritic cell-mediated immunization to study the effects of commonly used adjuvants, TLR ligands, on effector and memory CD8(+) T cell differentiation in mice. Intriguingly, we found that the TLR4 ligand LPS was far more superior to other TLR ligands in generating memory CD8(+) T cells upon immunization. LPS boosted clonal expansion similar to the other adjuvants, but fewer of the activated CD8(+) T cells died during contraction, generating a larger pool of memory cells. Surprisingly, monophosphoryl lipid A (MPLA), another TLR4 ligand, enhanced clonal expansion of effector CD8(+) T cells, but it also promoted their terminal differentiation and contraction; thus, fewer memory CD8(+) T cells formed, and MPLA-primed animals were less protected against secondary infection compared with those primed with LPS. Furthermore, gene expression profiling revealed that LPS-primed effector cells displayed a stronger pro-memory gene expression signature, whereas the gene expression profile of MPLA-primed effector cells aligned closer with terminal effector CD8(+) T cells. Lastly, we demonstrated that the LPS-TLR4-derived "pro-memory" signals were MyD88, but not Toll/IL-1R domain-containing adapter inducing IFN-β, dependent. This study reveals the influential power of adjuvants on the quantity and quality of CD8(+) T cell memory, and that attention to adjuvant selection is crucial because boosting effector cell expansion may not always equate with more memory T cells or greater protection.

Engrams and Circuits Crucial for Systems Consolidation of a Memory

PubMed Central

Kitamura, Takashi; Ogawa, Sachie K.; Roy, Dheeraj S.; Okuyama, Teruhiro; Morrissey, Mark D.; Smith, Lillian M.; Redondo, Roger L.; Tonegawa, Susumu

2017-01-01

Episodic memories initially require rapid synaptic plasticity within the hippocampus for their formation and are gradually consolidated in neocortical networks for permanent storage. However, the engrams and circuits that support neocortical memory consolidation remain unknown. We found that neocortical prefrontal memory engram cells, critical for remote contextual fear memory, were rapidly generated during initial learning via inputs from both hippocampal-entorhinal cortex and basolateral amygdala. After their generation, the prefrontal engram cells, with support from hippocampal memory engram cells, became functionally mature with time. Whereas hippocampal engram cells gradually became silent with time, engram cells in the basolateral amygdala, which were necessary for fear memory, are maintained. Our data provide new insights into the functional reorganization of engrams and circuits underlying systems consolidation of memory. PMID:28386011

Generation of effector CD8+ T cells and their conversion to memory T cells

PubMed Central

Cui, Weiguo; Kaech, Susan M.

2015-01-01

Summary Immunological memory is a cardinal feature of adaptive immunity. We are now beginning to elucidate the mechanisms that govern the formation of memory T cells and their ability to acquire longevity, survive the effector-to-memory transition, and mature into multipotent, functional memory T cells that self-renew. Here, we discuss the recent findings in this area and highlight extrinsic and intrinsic factors that regulate the cellular fate of activated CD8+ T cells. PMID:20636815

Quiescence of Memory CD8(+) T Cells Is Mediated by Regulatory T Cells through Inhibitory Receptor CTLA-4.

PubMed

Kalia, Vandana; Penny, Laura Anne; Yuzefpolskiy, Yevgeniy; Baumann, Florian Martin; Sarkar, Surojit

2015-06-16

Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection yet exist in a functionally quiescent state. The paradigm is that memory T cells remain inactive due to lack of T cell receptor (TCR) stimuli. Here, we report that regulatory T (Treg) cells orchestrate memory T cell quiescence by suppressing effector and proliferation programs through inhibitory receptor, cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4). Loss of Treg cells resulted in activation of genome-wide transcriptional programs characteristic of effector T cells and drove transitioning as well as established memory CD8(+) T cells toward terminally differentiated KLRG-1(hi)IL-7Rα(lo)GzmB(hi) phenotype, with compromised metabolic fitness, longevity, polyfunctionality, and protective efficacy. CTLA-4 functionally replaced Treg cells in trans to rescue memory T cell defects and restore homeostasis. These studies present the CTLA-4-CD28-CD80/CD86 axis as a potential target to accelerate vaccine-induced immunity and improve T cell memory quality in current cancer immunotherapies proposing transient Treg cell ablation. Copyright © 2015 Elsevier Inc. All rights reserved.

Vaccine-elicited memory CD4+ T cell expansion is impaired in the lungs during tuberculosis.

PubMed

Carpenter, Stephen M; Yang, Jason D; Lee, Jinhee; Barreira-Silva, Palmira; Behar, Samuel M

2017-11-01

Immunological memory is the key biological process that makes vaccines possible. Although tuberculosis vaccines elicit protective immunity in animals, few provide durable protection. To understand why protection is transient, we evaluated the ability of memory CD4+ T cells to expand, differentiate, and control Mycobacterium tuberculosis. Both naïve and memory CD4+ T cells initially proliferated exponentially, and the accumulation of memory T cells in the lung correlated with early bacterial control. However, later during infection, memory CD4+ T cell proliferation was curtailed and no protection was observed. We show that memory CD4+ T cells are first activated in the LN and their recruitment to the lung attenuates bacterial growth. However, their interaction with Mtb-infected macrophages does not promote continued proliferation. We conclude that a lack of sustained expansion by memory-derived T cells in the lung limits the durability of their protection, linking their slower expansion with transient protection in vaccinated mice.

Retention of Ag-specific memory CD4+ T cells in the draining lymph node indicates lymphoid tissue resident memory populations.

PubMed

Marriott, Clare L; Dutton, Emma E; Tomura, Michio; Withers, David R

2017-05-01

Several different memory T-cell populations have now been described based upon surface receptor expression and migratory capabilities. Here we have assessed murine endogenous memory CD4 + T cells generated within a draining lymph node and their subsequent migration to other secondary lymphoid tissues. Having established a model response targeting a specific peripheral lymph node, we temporally labelled all the cells within draining lymph node using photoconversion. Tracking of photoconverted and non-photoconverted Ag-specific CD4 + T cells revealed the rapid establishment of a circulating memory population in all lymph nodes within days of immunisation. Strikingly, a resident memory CD4 + T cell population became established in the draining lymph node and persisted for several months in the absence of detectable migration to other lymphoid tissue. These cells most closely resembled effector memory T cells, usually associated with circulation through non-lymphoid tissue, but here, these cells were retained in the draining lymph node. These data indicate that lymphoid tissue resident memory CD4 + T-cell populations are generated in peripheral lymph nodes following immunisation. © 2017 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? Natural Killer Cells in Vaccination.

PubMed

Neely, Harold R; Mazo, Irina B; Gerlach, Carmen; von Andrian, Ulrich H

2017-12-18

Natural killer (NK) cells have historically been considered to be a part of the innate immune system, exerting a rapid response against pathogens and tumors in an antigen (Ag)-independent manner. However, over the past decade, evidence has accumulated suggesting that at least some NK cells display certain characteristics of adaptive immune cells. Indeed, NK cells can learn and remember encounters with a variety of Ags, including chemical haptens and viruses. Upon rechallenge, memory NK cells mount potent recall responses selectively to those Ags. This phenomenon, traditionally termed "immunological memory," has been reported in mice, nonhuman primates, and even humans and appears to be concentrated in discrete NK cell subsets. Because immunological memory protects against recurrent infections and is the central goal of active vaccination, it is crucial to define the mechanisms and consequences of NK cell memory. Here, we summarize the different kinds of memory responses that have been attributed to specific NK cell subsets and discuss the possibility to harness NK cell memory for vaccination purposes. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

A transcriptome-based model of central memory CD4 T cell death in HIV infection.

PubMed

Olvera-García, Gustavo; Aguilar-García, Tania; Gutiérrez-Jasso, Fany; Imaz-Rosshandler, Iván; Rangel-Escareño, Claudia; Orozco, Lorena; Aguilar-Delfín, Irma; Vázquez-Pérez, Joel A; Zúñiga, Joaquín; Pérez-Patrigeon, Santiago; Espinosa, Enrique

2016-11-22

Human central memory CD4 T cells are characterized by their capacity of proliferation and differentiation into effector memory CD4 T cells. Homeostasis of central memory CD4 T cells is considered a key factor sustaining the asymptomatic stage of Human Immunodeficiency Virus type 1 (HIV-1) infection, while progression to acquired immunodeficiency syndrome is imputed to central memory CD4 T cells homeostatic failure. We investigated if central memory CD4 T cells from patients with HIV-1 infection have a gene expression profile impeding proliferation and survival, despite their activated state. Using gene expression microarrays, we analyzed mRNA expression patterns in naive, central memory, and effector memory CD4 T cells from healthy controls, and naive and central memory CD4 T cells from patients with HIV-1 infection. Differentially expressed genes, defined by Log 2 Fold Change (FC) ≥ |0.5| and Log (odds) > 0, were used in pathway enrichment analyses. Central memory CD4 T cells from patients and controls showed comparable expression of differentiation-related genes, ruling out an effector-like differentiation of central memory CD4 T cells in HIV infection. However, 210 genes were differentially expressed in central memory CD4 T cells from patients compared with those from controls. Expression of 75 of these genes was validated by semi quantitative RT-PCR, and independently reproduced enrichment results from this gene expression signature. The results of functional enrichment analysis indicated movement to cell cycle phases G1 and S (increased CCNE1, MKI67, IL12RB2, ADAM9, decreased FGF9, etc.), but also arrest in G2/M (increased CHK1, RBBP8, KIF11, etc.). Unexpectedly, the results also suggested decreased apoptosis (increased CSTA, NFKBIA, decreased RNASEL, etc.). Results also suggested increased IL-1β, IFN-γ, TNF, and RANTES (CCR5) activity upstream of the central memory CD4 T cells signature, consistent with the demonstrated milieu in HIV infection. Our findings support a model where progressive loss of central memory CD4 T cells in chronic HIV-1 infection is driven by increased cell cycle entry followed by mitotic arrest, leading to a non-apoptotic death pathway without actual proliferation, possibly contributing to increased turnover.

Increased memory T cell populations in Pb-exposed children from an e-waste-recycling area.

PubMed

Cao, Junjun; Xu, Xijin; Zhang, Yu; Zeng, Zhijun; Hylkema, Machteld N; Huo, Xia

2018-03-01

Chronic exposure to heavy metals could affect cell-mediated immunity. The aim of this study was to explore the status of memory T cell development in preschool children from an e-waste recycling area. Blood lead (Pb) levels, peripheral T cell subpopulations, and serum levels of cytokines (IL-2/IL-7/IL-15), relevant to generation and homeostasis of memory T cells were evaluated in preschool children from Guiyu (e-waste-exposed group) and Haojiang (reference group). The correlations between blood Pb levels and percentages of memory T cell subpopulations were also evaluated. Guiyu children had higher blood Pb levels and increased percentages of CD4 + central memory T cells and CD8 + central memory T cells than in the Haojiang group. Moreover, blood Pb levels were positively associated with the percentages of CD4 + central memory T cells. In contrast, Pb exposure contributed marginally in the change of percentages of CD8 + central memory T cells in children. There was no significant difference in the serum cytokine levels between the e-waste-exposed and reference children. Taken together, preschool children from an e-waste recycling area suffer from relatively higher levels of Pb exposure, which might facilitate the development of CD4 + central memory T cells in these children. Copyright © 2017. Published by Elsevier B.V.

Stroma: the forgotten cells of innate immune memory.

PubMed

Crowley, Thomas; Buckley, Christopher D; Clark, Andrew R

2018-05-05

All organisms are constantly exposed to a variety of infectious and injurious stimuli. These induce inflammatory responses tailored to the threat posed. Whilst the innate immune system is the front line of response to each stimulant, it has been traditionally considered to lack memory, acting in a generic fashion until the adaptive immune arm can take over. This outmoded simplification of the roles of innate and acquired arms of the immune system has been challenged by evidence of myeloid cells altering their response to subsequent encounters based on earlier exposure. This concept of "innate immune memory" has been known for nearly a century, and is accepted amongst myeloid biologists. In recent years, other innate immune cells, such as natural killer cells, have been shown to display memory, suggesting innate immune memory is a trait common to several cell types. Over the last thirty years, evidence has slowly accumulated in favour of not only haematopoietic cells, but also stromal cells, being imbued with memory following inflammatory episodes. A recent publication showing this also to be true in epithelial cells suggests innate immune memory to be widespread, if underappreciated, in non-haematopoietic cells. In this review, we will examine the evidence supporting the existence of innate immune memory in stromal cells. We will also discuss the ramifications of memory in long-lived tissue-resident cells. Finally, we will pose questions we feel to be important in the understanding of these forgotten cells in the field of innate memory. This article is protected by copyright. All rights reserved. © 2018 British Society for Immunology.

CD73 expression identifies a subset of IgM+ antigen-experienced cells with memory attributes that is T cell and CD40 signalling dependent.

PubMed

D'Souza, Lucas; Gupta, Sneh Lata; Bal, Vineeta; Rath, Satyajit; George, Anna

2017-12-01

B-cell memory was long characterized as isotype-switched, somatically mutated and germinal centre (GC)-derived. However, it is now clear that the memory pool is a complex mixture that includes unswitched and unmutated cells. Further, expression of CD73, CD80 and CD273 has allowed the categorization of B-cell memory into multiple subsets, with combinatorial expression of the markers increasing with GC progression, isotype-switching and acquisition of somatic mutations. We have extended these findings to determine whether these markers can be used to identify IgM memory phenotypically as arising from T-dependent versus T-independent responses. We report that CD73 expression identifies a subset of antigen-experienced IgM + cells that share attributes of functional B-cell memory. This subset is reduced in the spleens of T-cell-deficient and CD40-deficient mice and in mixed marrow chimeras made with mutant and wild-type marrow, the proportion of CD73 + IgM memory is restored in the T-cell-deficient donor compartment but not in the CD40-deficient donor compartment, indicating that CD40 ligation is involved in its generation. We also report that CD40 signalling supports optimal expression of CD73 on splenic T cells and age-associated B cells (ABCs), but not on other immune cells such as neutrophils, marginal zone B cells, peritoneal cavity B-1 B cells and regulatory T and B cells. Our data indicate that in addition to promoting GC-associated memory generation during B-cell differentiation, CD40-signalling can influence the composition of the unswitched memory B-cell pool. They also raise the possibility that a fraction of ABCs may represent T-cell-dependent IgM memory. © 2017 John Wiley & Sons Ltd.

Enhanced anti-tumour immunity requires the interplay between resident and circulating memory CD8+ T cells

PubMed Central

Enamorado, Michel; Iborra, Salvador; Priego, Elena; Cueto, Francisco J.; Quintana, Juan A.; Martínez-Cano, Sarai; Mejías-Pérez, Ernesto; Esteban, Mariano; Melero, Ignacio; Hidalgo, Andrés; Sancho, David

2017-01-01

The goal of successful anti-tumoural immunity is the development of long-term protective immunity to prevent relapse. Infiltration of tumours with CD8+ T cells with a resident memory (Trm) phenotype correlates with improved survival. However, the interplay of circulating CD8+ T cells and Trm cells remains poorly explored in tumour immunity. Using different vaccination strategies that fine-tune the generation of Trm cells or circulating memory T cells, here we show that, while both subsets are sufficient for anti-tumour immunity, the presence of Trm cells improves anti-tumour efficacy. Transferred central memory T cells (Tcm) generate Trm cells following viral infection or tumour challenge. Anti-PD-1 treatment promotes infiltration of transferred Tcm cells within tumours, improving anti-tumour immunity. Moreover, Batf3-dependent dendritic cells are essential for reactivation of circulating memory anti-tumour response. Our findings show the plasticity, collaboration and requirements for reactivation of memory CD8+ T cells subsets needed for optimal tumour vaccination and immunotherapy. PMID:28714465

Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells

PubMed Central

Santich, Brian H.; Kim, Jin Young; Posada, Jacqueline G.; Ho, Jason; Buckner, Clarisa M.; Wang, Wei; Kardava, Lela; Garofalo, Mary; Marciano, Beatriz E.; Manischewitz, Jody; King, Lisa R.; Khurana, Surender; Chun, Tae-Wook; Golding, Hana; Fauci, Anthony S.; Malech, Harry L.

2012-01-01

CD27+ memory B cells are reduced in the blood of patients with chronic granulomatous disease (CGD) for reasons and consequences that remain unclear. Here we confirm not only decreased CD27+ but also IgG+ B cells in the blood of CGD patients compared with healthy donors (HDs). However, among IgG+ B cells, the ratio of CD27− to CD27+ was significantly higher in CGD patients compared with HDs. Similar to conventional memory B cells, CD27−IgG+ B cells of CGD patients expressed activation markers and had undergone somatic hypermutation, albeit at levels lower than their CD27+ counterparts. Functional analyses revealed slight reductions in frequencies of total IgG but not influenza-specific memory B-cell responses, as measured by Elispot in CGD patients compared with HDs. Serum IgG levels and influenza-specific antibodies were also normal in these CGD patients. Finally, we provide evidence that influenza-specific memory B cells can be present within the CD27−IgG+ B-cell compartment. Together, these findings show that, despite reduced circulating CD27+ memory B cells, CGD patients maintain an intact humoral immunologic memory, with potential contribution from CD27− B cells. PMID:23074274

Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells.

PubMed

Moir, Susan; De Ravin, Suk See; Santich, Brian H; Kim, Jin Young; Posada, Jacqueline G; Ho, Jason; Buckner, Clarisa M; Wang, Wei; Kardava, Lela; Garofalo, Mary; Marciano, Beatriz E; Manischewitz, Jody; King, Lisa R; Khurana, Surender; Chun, Tae-Wook; Golding, Hana; Fauci, Anthony S; Malech, Harry L

2012-12-06

CD27(+) memory B cells are reduced in the blood of patients with chronic granulomatous disease (CGD) for reasons and consequences that remain unclear. Here we confirm not only decreased CD27(+) but also IgG(+) B cells in the blood of CGD patients compared with healthy donors (HDs). However, among IgG(+) B cells, the ratio of CD27(-) to CD27(+) was significantly higher in CGD patients compared with HDs. Similar to conventional memory B cells, CD27(-)IgG(+) B cells of CGD patients expressed activation markers and had undergone somatic hypermutation, albeit at levels lower than their CD27(+) counterparts. Functional analyses revealed slight reductions in frequencies of total IgG but not influenza-specific memory B-cell responses, as measured by Elispot in CGD patients compared with HDs. Serum IgG levels and influenza-specific antibodies were also normal in these CGD patients. Finally, we provide evidence that influenza-specific memory B cells can be present within the CD27(-)IgG(+) B-cell compartment. Together, these findings show that, despite reduced circulating CD27(+) memory B cells, CGD patients maintain an intact humoral immunologic memory, with potential contribution from CD27(-) B cells.

Programmed Death 1 Regulates Memory Phenotype CD4 T Cell Accumulation, Inhibits Expansion of the Effector Memory Phenotype Subset and Modulates Production of Effector Cytokines

PubMed Central

Charlton, Joanna J.; Tsoukatou, Debbie; Mamalaki, Clio; Chatzidakis, Ioannis

2015-01-01

Memory phenotype CD4 T cells are found in normal mice and arise through response to environmental antigens or homeostatic mechanisms. The factors that regulate the homeostasis of memory phenotype CD4 cells are not clear. In the present study we demonstrate that there is a marked accumulation of memory phenotype CD4 cells, specifically of the effector memory (TEM) phenotype, in lymphoid organs and tissues of mice deficient for the negative co-stimulatory receptor programmed death 1 (PD-1). This can be correlated with decreased apoptosis but not with enhanced homeostatic turnover potential of these cells. PD-1 ablation increased the frequency of memory phenotype CD4 IFN-γ producers but decreased the respective frequency of IL-17A-producing cells. In particular, IFN-γ producers were more abundant but IL-17A producing cells were more scarce among PD-1 KO TEM-phenotype cells relative to WT. Transfer of peripheral naïve CD4 T cells suggested that accumulated PD-1 KO TEM-phenotype cells are of peripheral and not of thymic origin. This accumulation effect was mediated by CD4 cell-intrinsic mechanisms as shown by mixed bone marrow chimera experiments. Naïve PD-1 KO CD4 T cells gave rise to higher numbers of TEM-phenotype lymphopenia-induced proliferation memory cells. In conclusion, we provide evidence that PD-1 has an important role in determining the composition and functional aspects of memory phenotype CD4 T cell pool. PMID:25803808

Low interleukin-2 concentration favors generation of early memory T cells over effector phenotypes during chimeric antigen receptor T-cell expansion.

PubMed

Kaartinen, Tanja; Luostarinen, Annu; Maliniemi, Pilvi; Keto, Joni; Arvas, Mikko; Belt, Heini; Koponen, Jonna; Loskog, Angelica; Mustjoki, Satu; Porkka, Kimmo; Ylä-Herttuala, Seppo; Korhonen, Matti

2017-06-01

Adoptive T-cell therapy offers new options for cancer treatment. Clinical results suggest that T-cell persistence, depending on T-cell memory, improves efficacy. The use of interleukin (IL)-2 for in vitro T-cell expansion is not straightforward because it drives effector T-cell differentiation but does not promote the formation of T-cell memory. We have developed a cost-effective expansion protocol for chimeric antigen receptor (CAR) T cells with an early memory phenotype. Lymphocytes were transduced with third-generation lentiviral vectors and expanded using CD3/CD28 microbeads. The effects of altering the IL-2 supplementation (0-300 IU/mL) and length of expansion (10-20 days) on the phenotype of the T-cell products were analyzed. High IL-2 levels led to a decrease in overall generation of early memory T cells by both decreasing central memory T cells and augmenting effectors. T memory stem cells (T SCM , CD95 + CD45RO - CD45RA + CD27 + ) were present variably during T-cell expansion. However, their presence was not IL-2 dependent but was linked to expansion kinetics. CD19-CAR T cells generated in these conditions displayed in vitro antileukemic activity. In summary, production of CAR T cells without any cytokine supplementation yielded the highest proportion of early memory T cells, provided a 10-fold cell expansion and the cells were functionally potent. The number of early memory T cells in a T-cell preparation can be increased by simply reducing the amount of IL-2 and limiting the length of T-cell expansion, providing cells with potentially higher in vivo performance. These findings are significant for robust and cost-effective T-cell manufacturing. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Increased numbers of pre-existing memory CD8 T cells and decreased T-bet expression can restrain terminal differentiation of secondary effector and memory CD8 T cells1

PubMed Central

Joshi, Nikhil S.; Cui, Weiguo; Dominguez, Claudia; Chen, Jonathan H.; Hand, Timothy W.; Kaech, Susan M.

2011-01-01

Memory CD8 T cells acquire TEM properties following reinfection, and may reach terminally differentiated, senescent states (“Hayflick limit”) after multiple infections. The signals controlling this process are not well understood, but we found that the degree of 2o effector and memory CD8 T cell differentiation was intimately linked to the amount of T-bet expressed upon reactivation and pre-existing memory CD8 T cell number (i.e., 1o memory CD8 T cell precursor frequency) present during secondary infection. Compared to naïve cells, memory CD8 T cells were predisposed towards terminal effector (TE) cell differentiation because they could immediately respond to IL-12 and induce T-bet, even in the absence of antigen. TE cell formation following 2o or 3o infections was dependent on increased T-bet expression because T-bet+/− cells were resistant to these phenotypic changes. Larger numbers of pre-existing memory CD8 T cells limited the duration of 2o infection and the amount of IL-12 produced, and consequently, this reduced T-bet expression and the proportion of 2o TE CD8 T cells that formed. Together, these data show that, over repeated infections, memory CD8 T cell quality and proliferative fitness is not strictly determined by the number of serial encounters with antigen or cell divisions, but is a function of the CD8 T cell differentiation state, which is genetically controlled in a T-bet-dependent manner. This differentiation state can be modulated by pre-existing memory CD8 T cell number and the intensity of inflammation during reinfection. These results have important implications for vaccinations involving prime-boost strategies. PMID:21930973

CD4+CD25+ regulatory T cells suppress allograft rejection mediated by memory CD8+ T cells via a CD30-dependent mechanism.

PubMed

Dai, Zhenhua; Li, Qi; Wang, Yinong; Gao, Ge; Diggs, Lonnette S; Tellides, George; Lakkis, Fadi G

2004-01-01

CD4(+)CD25(+) regulatory T (Treg) cells suppress naive T cell responses, prevent autoimmunity, and delay allograft rejection. It is not known, however, whether Treg cells suppress allograft rejection mediated by memory T cells, as the latter mount faster and stronger immune responses than their naive counterparts. Here we show that antigen-induced, but not naive, Treg cells suppress allograft rejection mediated by memory CD8(+) T cells. Suppression was allospecific, as Treg cells induced by third-party antigens did not delay allograft rejection. In vivo and in vitro analyses revealed that the apoptosis of allospecific memory CD8(+) T cells is significantly increased in the presence of antigen-induced Treg cells, while their proliferation remains unaffected. Importantly, neither suppression of allograft rejection nor enhanced apoptosis of memory CD8(+) T cells was observed when Treg cells lacked CD30 or when CD30 ligand-CD30 interaction was blocked with anti-CD30 ligand Ab. This study therefore provides direct evidence that pathogenic memory T cells are amenable to suppression in an antigen-specific manner and identifies CD30 as a molecule that is critical for the regulation of memory T cell responses.

CD4+CD25+ regulatory T cells suppress allograft rejection mediated by memory CD8+ T cells via a CD30-dependent mechanism

PubMed Central

Dai, Zhenhua; Li, Qi; Wang, Yinong; Gao, Ge; Diggs, Lonnette S.; Tellides, George; Lakkis, Fadi G.

2004-01-01

CD4+CD25+ regulatory T (Treg) cells suppress naive T cell responses, prevent autoimmunity, and delay allograft rejection. It is not known, however, whether Treg cells suppress allograft rejection mediated by memory T cells, as the latter mount faster and stronger immune responses than their naive counterparts. Here we show that antigen-induced, but not naive, Treg cells suppress allograft rejection mediated by memory CD8+ T cells. Suppression was allospecific, as Treg cells induced by third-party antigens did not delay allograft rejection. In vivo and in vitro analyses revealed that the apoptosis of allospecific memory CD8+ T cells is significantly increased in the presence of antigen-induced Treg cells, while their proliferation remains unaffected. Importantly, neither suppression of allograft rejection nor enhanced apoptosis of memory CD8+ T cells was observed when Treg cells lacked CD30 or when CD30 ligand–CD30 interaction was blocked with anti–CD30 ligand Ab. This study therefore provides direct evidence that pathogenic memory T cells are amenable to suppression in an antigen-specific manner and identifies CD30 as a molecule that is critical for the regulation of memory T cell responses. PMID:14722622

Liver-primed memory T cells generated under noninflammatory conditions provide anti-infectious immunity.

PubMed

Böttcher, Jan P; Schanz, Oliver; Wohlleber, Dirk; Abdullah, Zeinab; Debey-Pascher, Svenja; Staratschek-Jox, Andrea; Höchst, Bastian; Hegenbarth, Silke; Grell, Jessica; Limmer, Andreas; Atreya, Imke; Neurath, Markus F; Busch, Dirk H; Schmitt, Edgar; van Endert, Peter; Kolanus, Waldemar; Kurts, Christian; Schultze, Joachim L; Diehl, Linda; Knolle, Percy A

2013-03-28

Development of CD8(+) T cell (CTL) immunity or tolerance is linked to the conditions during T cell priming. Dendritic cells (DCs) matured during inflammation generate effector/memory T cells, whereas immature DCs cause T cell deletion/anergy. We identify a third outcome of T cell priming in absence of inflammation enabled by cross-presenting liver sinusoidal endothelial cells. Such priming generated memory T cells that were spared from deletion by immature DCs. Similar to central memory T cells, liver-primed T cells differentiated into effector CTLs upon antigen re-encounter on matured DCs even after prolonged absence of antigen. Their reactivation required combinatorial signaling through the TCR, CD28, and IL-12R and controlled bacterial and viral infections. Gene expression profiling identified liver-primed T cells as a distinct Neuropilin-1(+) memory population. Generation of liver-primed memory T cells may prevent pathogens that avoid DC maturation by innate immune escape from also escaping adaptive immunity through attrition of the T cell repertoire. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Peripheral B cells latently infected with Epstein–Barr virus display molecular hallmarks of classical antigen-selected memory B cells

PubMed Central

Souza, Tatyana A.; Stollar, B. David; Sullivan, John L.; Luzuriaga, Katherine; Thorley-Lawson, David A.

2005-01-01

Epstein–Barr virus (EBV) establishes a lifelong persistent infection within peripheral blood B cells with the surface phenotype of memory cells. To date there is no proof that these cells have the genotype of true germinal-center-derived memory B cells. It is critical to understand the relative contribution of viral mimicry versus antigen signaling to the production of these cells because EBV encodes proteins that can affect the surface phenotype of infected cells and provide both T cell help and B cell receptor signals in the absence of cognate antigen. To address these questions we have developed a technique to identify single EBV-infected cells in the peripheral blood and examine their expressed Ig genes. The genes were all isotype-switched and somatically mutated. Furthermore, the mutations do not cause stop codons and display the pattern expected for antigen-selected memory cells based on their frequency, type, and location within the Ig gene. We conclude that latently infected peripheral blood B cells display the molecular hallmarks of classical antigen-selected memory B cells. Therefore, EBV does not disrupt the normal processing of latently infected cells into memory, and deviations from normal B cell biology are not tolerated in the infected cells. This article provides definitive evidence that EBV in the peripheral blood persists in true memory B cells. PMID:16330748

Sono- and photocatalytic activities of SnO2 nanoparticles for degradation of cationic and anionic dyes

NASA Astrophysics Data System (ADS)

Paramarta, Valentinus; Taufik, Ardiansyah; Munisa, Lusitra; Saleh, Rosari

2017-01-01

The current research work focuses on the catalytic activity of SnO2 nanoparticles (NPs) against degradation of both cationic dye (methylene blue) and anionic dye (Congo-red). SnO2 NPs were synthesized under the sol-gel method and were characterized by performing X-ray diffraction, Fourier Transform Infrared Spectroscopy (FT-IR), Transmission Electron Microscopy (TEM) Brunauer-Emmet-Teller (BET) surface area analysis and UV-Vis spectroscopy. The results demonstrate that SnO2 NPs has well crystalline structure with the crystallite size of 44 nm. The degradation of dyes was studied under ambient temperature using ultrasonicator and UV light, respectively. The sono- and photocatalytic activities of SnO2 NPs on dyes were analyzed by measuring the change in absorbance of dyes under UV-spectrophotometer. The degradation of the organic dyes has been calculated by monitoring the degradation in the concentration of the dyes before and after irradiation of ultrasonic and light, respectively. The influence of other parameters such as catalyst dosage, pH and scavenger have also been investigated. The catalytic activity is enhanced in the presence of ultrasonic irradiation. The degradation of both dyes follows pseudo-first order kinetics. The reusability tests have also been done to ensure the stability of the used catalysts. A reasonable mechanism of sono- and photocatalysis with SnO2 NPs has been proposed by correlating the active radical species involved with the physical properties of the as-synthesized samples.

Loss of memory B cells impairs maintenance of long-term serologic memory during HIV-1 infection.

PubMed

Titanji, Kehmia; De Milito, Angelo; Cagigi, Alberto; Thorstensson, Rigmor; Grützmeier, Sven; Atlas, Ann; Hejdeman, Bo; Kroon, Frank P; Lopalco, Lucia; Nilsson, Anna; Chiodi, Francesca

2006-09-01

Circulating memory B cells are severely reduced in the peripheral blood of HIV-1-infected patients. We investigated whether dysfunctional serologic memory to non-HIV antigens is related to disease progression by evaluating the frequency of memory B cells, plasma IgG, plasma levels of antibodies to measles, and Streptococcus pneumoniae, and enumerating measles-specific antibody-secreting cells in patients with primary, chronic, and long-term nonprogressive HIV-1 infection. We also evaluated the in vitro production of IgM and IgG antibodies against measles and S pneumoniae antigens following polyclonal activation of peripheral blood mononuclear cells (PBMCs) from patients. The percentage of memory B cells correlated with CD4+ T-cell counts in patients, thus representing a marker of disease progression. While patients with primary and chronic infection had severe defects in serologic memory, long-term nonprogressors had memory B-cell frequency and levels of antigen-specific antibodies comparable with controls. We also evaluated the effect of antiretroviral therapy on these serologic memory defects and found that antiretroviral therapy did not restore serologic memory in primary or in chronic infection. We suggest that HIV infection impairs maintenance of long-term serologic immunity to HIV-1-unrelated antigens and this defect is initiated early in infection. This may have important consequences for the response of HIV-infected patients to immunizations.

NFκB–Pim-1–Eomesodermin axis is critical for maintaining CD8 T-cell memory quality

PubMed Central

Knudson, Karin M.; Saxena, Vikas; Altman, Amnon; Daniels, Mark A.; Teixeiro, Emma

2017-01-01

T-cell memory is critical for long-term immunity. However, the factors involved in maintaining the persistence, function, and phenotype of the memory pool are undefined. Eomesodermin (Eomes) is required for the establishment of the memory pool. Here, we show that in T cells transitioning to memory, the expression of high levels of Eomes is not constitutive but rather requires a continuum of cell-intrinsic NFκB signaling. Failure to maintain NFκB signals after the peak of the response led to impaired Eomes expression and a defect in the maintenance of CD8 T-cell memory. Strikingly, we found that antigen receptor [T-cell receptor (TCR)] signaling regulates this process through expression of the NFκB-dependent kinase proviral integration site for Moloney murine leukemia virus-1 (PIM-1), which in turn regulates NFκB and Eomes. T cells defective in TCR-dependent NFκB signaling were impaired in late expression of Pim-1, Eomes, and CD8 memory. These defects were rescued when TCR-dependent NFκB signaling was restored. We also found that NFκB–Pim-1 signals were required at memory to maintain memory CD8 T-cell longevity, effector function, and Eomes expression. Hence, an NFκB–Pim-1–Eomes axis regulates Eomes levels to maintain memory fitness. PMID:28193872

A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis.

PubMed

Carpenter, Stephen M; Nunes-Alves, Cláudio; Booty, Matthew G; Way, Sing Sing; Behar, Samuel M

2016-01-01

T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRβ deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3β sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection.

A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis

PubMed Central

Carpenter, Stephen M.; Nunes-Alves, Cláudio; Booty, Matthew G.; Way, Sing Sing; Behar, Samuel M.

2016-01-01

T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRβ deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3β sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection. PMID:26745507

Diversity in T cell memory: An embarrassment of riches

PubMed Central

Jameson, Stephen C.; Masopust, David

2010-01-01

The adaptive immune response meets the needs of the organism to generate effector cells capable of controlling pathogens, but also leads to production of memory cells, which mediate more effective protection during rechallenge. In this review we focus on the generation, maintenance and function of memory T cells, with a special emphasis on the increasing evidence for great diversity among functional memory T cell subsets. PMID:20064446

Endogenous Memory CD8 T Cells Directly Mediate Cardiac Allograft Rejection

PubMed Central

Su, C. A.; Iida, S.; Abe, T.; Fairchild, R. L.

2014-01-01

Differences in levels of environmentally induced memory T cells that cross-react with donor MHC molecules are postulated to account for the efficacy of allograft tolerance inducing strategies in rodents versus their failure in nonhuman primates and human transplant patients. Strategies to study the impact of donor-reactive memory T cells on allografts in rodents have relied on the pre-transplant induction of memory T cells cross-reactive with donor allogeneic MHC molecules through recipient viral infection, priming directly with donor antigen, or adoptive transfer of donor-antigen primed memory T cells. Each approach accelerates allograft rejection and confers resistance to tolerance induction, but also biases the T cell repertoire to strong donor-reactivity. The ability of endogenous memory T cells within unprimed mice to directly reject an allograft is unknown. Here we show a direct association between increased duration of cold ischemic allograft storage and numbers and enhanced functions of early graft infiltrating endogenous CD8 memory T cells. These T cells directly mediate rejection of allografts subjected to prolonged ischemia and this rejection is resistant to costimulatory blockade. These findings recapitulate the clinically significant impact of endogenous memory T cells with donor reactivity in a mouse transplant model in the absence of prior recipient priming. PMID:24502272

Cell-autonomous CCL5 transcription by memory CD8 T cells is regulated by IL-4.

PubMed

Marçais, Antoine; Coupet, Charles-Antoine; Walzer, Thierry; Tomkowiak, Martine; Ghittoni, Raffaella; Marvel, Jacqueline

2006-10-01

Immunological memory is associated with the display of improved effector functions. The maintenance by CD8 memory cells of high levels of untranslated CCL5 mRNA allows these cells to immediately secrete this chemokine upon Ag stimulation. Untranslated mRNA storage is a newly described process supporting the immediate display of an effector function by memory lymphocytes. We have tested the capacity of different cytokines to regulate the memorization of CCL5 by memory CD8 T cells. We found that IL-4 treatment of murine CD8 T cells impairs immediate CCL5 secretion capacity by inhibiting CCL5 mRNA transcription through a STAT6-dependent pathway. The inhibition by IL-4 is reversible, as memory CD8 T cells reconstitute their CCL5 mRNA stores and reacquire their immediate CCL5 secretion capacity when IL-4 is withdrawn. This recovery is cell autonomous because it proceeds in culture medium in the absence of exogenous growth factors, suggesting that CCL5 expression by memory CD8 T cells is a default process. Overall, these results indicate that the expression of CCL5 is an intrinsic property acquired by memory CD8 T cells that is regulated by environmental factors.

Memory T cells maintain protracted protection against malaria.

PubMed

Krzych, Urszula; Zarling, Stasya; Pichugin, Alexander

2014-10-01

Immunologic memory is one of the cardinal features of antigen-specific immune responses, and the persistence of memory cells contributes to prophylactic immunizations against infectious agents. Adequately maintained memory T and B cell pools assure a fast, effective and specific response against re-infections. However, many aspects of immunologic memory are still poorly understood, particularly immunologic memory inducible by parasites, for example, Plasmodium spp., the causative agents of malaria. For example, memory responses to Plasmodium antigens amongst residents of malaria endemic areas appear to be either inadequately developed or maintained, because persons who survive episodes of childhood malaria remain vulnerable to intermittent malaria infections. By contrast, multiple exposures of humans and laboratory rodents to radiation-attenuated Plasmodium sporozoites (γ-spz) induce sterile and long-lasting protection against experimental sporozoite challenge. Multifactorial immune mechanisms maintain this protracted and sterile protection. While the presence of memory CD4 T cell subsets has been associated with lasting protection in humans exposed to multiple bites from Anopheles mosquitoes infected with attenuated Plasmodium falciparum, memory CD8 T cells maintain protection induced with Plasmodium yoelii and Plasmodium berghei γ-spz in murine models. In this review, we discuss our observations that show memory CD8 T cells specific for antigens expressed by P. berghei liver stage parasites as an indispensable component for the maintenance of protracted protective immunity against experimental malaria infection; moreover, the provision of an Ag-depot assures a quick recall of memory T cells as IFN-γ-producing effector CD8 T cells and IL-4- producing CD4 T cells that collaborate with B cells for an effective antibody response. Published by Elsevier B.V.

TLR4 ligands LPS and MPLA differentially regulate effector and memory CD8+ T cell differentiation

PubMed Central

Cui, Weiguo; Joshi, Nikhil S.; Liu, Ying; Meng, Hailong; Kleinstein, Steven H; Kaech, Susan M.

2014-01-01

Vaccines formulated with non-replicating pathogens require adjuvants to help bolster immunogenicity. The role of adjuvants in antibody production has been well studied, but how they influence memory CD8+ T cell differentiation remains poorly defined. Here we implemented dendritic cell (DC)-mediated immunization to study the effects of commonly used adjuvants, TLR ligands, on effector and memory CD8+ T cell differentiation in mice. Intriguingly, we found that the TLR4 ligand LPS was far more superior to other TLR ligands in generating memory CD8+ T cells upon immunization. LPS boosted clonal expansion similar to the other adjuvants, but fewer of the activated CD8+ T cells died during contraction, generating a larger pool of memory cells. Surprisingly, monophosphoryl lipid A (MPLA), another TLR4 ligand, enhanced clonal expansion of effector CD8+ T cells, but also promoted their terminal differentiation and contraction; thus, fewer memory CD8+ T cells formed and MPLA-primed animals were less protected against secondary infection compared to those primed with LPS. Furthermore, gene expression profiling revealed that LPS-primed effector cells displayed a stronger pro-memory gene expression signature, whereas the gene expression profile of MPLA-primed effector cells aligned closer with terminal effector CD8+ T cells. Lastly, we demonstrated that the LPS-TLR4-derived “pro-memory” signals were MyD88, but not Trif, dependent. This study reveals the influential power of adjuvants on the quantity and quality of CD8+ T cell memory, and that attention to adjuvant selection is crucial because boosting effector cell expansion may not always equate with more memory T cells or greater protection. PMID:24659688

A Genome-wide Regulatory Network Identifies Key Transcription Factors for Memory CD8+ T Cell Development

PubMed Central

Hu, Guangan; Chen, Jianzhu

2014-01-01

Memory CD8+ T cell development is defined by the expression of a specific set of memory signature genes (MSGs). Despite recent progress, many components of the transcriptional control of memory CD8+ T cell development are still unknown. To identify transcription factors (TFs) and their interactions in memory CD8+ T cell development, we construct a genome-wide regulatory network and apply it to identify key TFs that regulate MSGs. Most of the known TFs in memory CD8+ T cell development are rediscovered and about a dozen new TFs are also identified. Sox4, Bhlhe40, Bach2 and Runx2 are experimentally verified and Bach2 is further shown to promote both development and recall proliferation of memory CD8+ T cells through Prdm1 and Id3. Gene perturbation study identifies the mode of interactions among the TFs with Sox4 as a hub. The identified TFs and insights into their interactions should facilitate further dissection of molecular mechanisms underlying memory CD8+ T cell development. PMID:24335726

Memory-like Responses of Natural Killer Cells

PubMed Central

Cooper, Megan A.; Yokoyama, Wayne M.

2010-01-01

Summary Natural killer (NK) cells are lymphocytes with the capacity to produce cytokines and kill target cells upon activation. NK cells have long been categorized as members of the innate immune system and as such have been thought to follow the ‘rules’ of innate immunity, including the principle that they have no immunologic memory, a property thought to be strictly limited to adaptive immunity. However, recent studies have suggested that NK cells have the capacity to alter their behavior based on prior activation. This property is analogous to adaptive immune memory; however, some NK cell memory-like functions are not strictly antigen-dependent and can be demonstrated following cytokine stimulation. Here we discuss the recent evidence that NK cells can exhibit properties of immunologic memory, focusing on the ability of cytokines to non-specifically induce memory-like NK cells with enhanced responses to restimulation. PMID:20536571

Interregional synaptic maps among engram cells underlie memory formation.

PubMed

Choi, Jun-Hyeok; Sim, Su-Eon; Kim, Ji-Il; Choi, Dong Il; Oh, Jihae; Ye, Sanghyun; Lee, Jaehyun; Kim, TaeHyun; Ko, Hyoung-Gon; Lim, Chae-Seok; Kaang, Bong-Kiun

2018-04-27

Memory resides in engram cells distributed across the brain. However, the site-specific substrate within these engram cells remains theoretical, even though it is generally accepted that synaptic plasticity encodes memories. We developed the dual-eGRASP (green fluorescent protein reconstitution across synaptic partners) technique to examine synapses between engram cells to identify the specific neuronal site for memory storage. We found an increased number and size of spines on CA1 engram cells receiving input from CA3 engram cells. In contextual fear conditioning, this enhanced connectivity between engram cells encoded memory strength. CA3 engram to CA1 engram projections strongly occluded long-term potentiation. These results indicate that enhanced structural and functional connectivity between engram cells across two directly connected brain regions forms the synaptic correlate for memory formation. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Engrams and circuits crucial for systems consolidation of a memory.

PubMed

Kitamura, Takashi; Ogawa, Sachie K; Roy, Dheeraj S; Okuyama, Teruhiro; Morrissey, Mark D; Smith, Lillian M; Redondo, Roger L; Tonegawa, Susumu

2017-04-07

Episodic memories initially require rapid synaptic plasticity within the hippocampus for their formation and are gradually consolidated in neocortical networks for permanent storage. However, the engrams and circuits that support neocortical memory consolidation have thus far been unknown. We found that neocortical prefrontal memory engram cells, which are critical for remote contextual fear memory, were rapidly generated during initial learning through inputs from both the hippocampal-entorhinal cortex network and the basolateral amygdala. After their generation, the prefrontal engram cells, with support from hippocampal memory engram cells, became functionally mature with time. Whereas hippocampal engram cells gradually became silent with time, engram cells in the basolateral amygdala, which were necessary for fear memory, were maintained. Our data provide new insights into the functional reorganization of engrams and circuits underlying systems consolidation of memory. Copyright © 2017, American Association for the Advancement of Science.

Skin-resident CD4+ T cells protect against Leishmania major by recruiting and activating inflammatory monocytes

PubMed Central

Glennie, Nelson D.; Volk, Susan W.

2017-01-01

Tissue-resident memory T cells are required for establishing protective immunity against a variety of different pathogens, although the mechanisms mediating protection by CD4+ resident memory T cells are still being defined. In this study we addressed this issue with a population of protective skin-resident, IFNγ-producing CD4+ memory T cells generated following Leishmania major infection. We previously found that resident memory T cells recruit circulating effector T cells to enhance immunity. Here we show that resident memory CD4+ T cells mediate the delayed-hypersensitivity response observed in immune mice and provide protection without circulating T cells. This protection occurs rapidly after challenge, and requires the recruitment and activation of inflammatory monocytes, which limit parasites by production of both reactive oxygen species and nitric oxide. Overall, these data highlight a novel role for tissue-resident memory cells in recruiting and activating inflammatory monocytes, and underscore the central role that skin-resident T cells play in immunity to cutaneous leishmaniasis. PMID:28419151

γδ T cells exhibit multifunctional and protective memory in intestinal tissues

PubMed Central

Sheridan, Brian S.; Romagnoli, Pablo A.; Pham, Quynh-Mai; Fu, Han-Hsuan; Alonzo, Francis; Schubert, Wolf-Dieter; Freitag, Nancy E.; Lefrançois, Leo

2013-01-01

Summary The study of T cell memory and the target of vaccine design has focused on memory subsumed by T cells bearing the αβ T cell receptor. Alternatively, γδ T cells are thought to provide rapid immunity particularly at mucosal borders. Here we have shown that a distinct subset of mucosal γδ T cells mounts an immune response to oral Listeria monocytogenes (Lm) infection leading to the development of multifunctional memory T cells in the murine intestinal mucosa that is capable of simultaneously producing interferon-γ and interleukin-17A. Challenge infection with oral Lm, but not oral Salmonella or intravenous Lm, induced rapid expansion of memory γδ T cells suggesting contextual specificity to the priming pathogen. Importantly, memory γδ T cells were able to provide enhanced protection against infection. These findings illustrate a previously unrecognized role for γδ T cells with hallmarks of adaptive immunity in the intestinal mucosa. PMID:23890071

Ezh2 phosphorylation state determines its capacity to maintain CD8+ T memory precursors for antitumor immunity.

PubMed

He, Shan; Liu, Yongnian; Meng, Lijun; Sun, Hongxing; Wang, Ying; Ji, Yun; Purushe, Janaki; Chen, Pan; Li, Changhong; Madzo, Jozef; Issa, Jean-Pierre; Soboloff, Jonathan; Reshef, Ran; Moore, Bethany; Gattinoni, Luca; Zhang, Yi

2017-12-14

Memory T cells sustain effector T-cell production while self-renewing in reaction to persistent antigen; yet, excessive expansion reduces memory potential and impairs antitumor immunity. Epigenetic mechanisms are thought to be important for balancing effector and memory differentiation; however, the epigenetic regulator(s) underpinning this process remains unknown. Herein, we show that the histone methyltransferase Ezh2 controls CD8 + T memory precursor formation and antitumor activity. Ezh2 activates Id3 while silencing Id2, Prdm1 and Eomes, promoting the expansion of memory precursor cells and their differentiation into functional memory cells. Akt activation phosphorylates Ezh2 and decreases its control of these transcriptional programs, causing enhanced effector differentiation at the expense of T memory precursors. Engineering T cells with an Akt-insensitive Ezh2 mutant markedly improves their memory potential and capability of controlling tumor growth compared to transiently inhibiting Akt. These findings establish Akt-mediated phosphorylation of Ezh2 as a critical target to potentiate antitumor immunotherapeutic strategies.

Transcriptional Profiling of Antigen-Dependent Murine B Cell Differentiation and Memory Formation1

PubMed Central

Bhattacharya, Deepta; Cheah, Ming T.; Franco, Christopher B.; Hosen, Naoki; Pin, Christopher L.; Sha, William C.; Weissman, Irving L.

2015-01-01

Humoral immunity is characterized by the generation of Ab-secreting plasma cells and memory B cells that can more rapidly generate specific Abs upon Ag exposure than their naive counterparts. To determine the intrinsic differences that distinguish naive and memory B cells and to identify pathways that allow germinal center B cells to differentiate into memory B cells, we compared the transcriptional profiles of highly purified populations of these three cell types along with plasma cells isolated from mice immunized with a T-dependent Ag. The transcriptional profile of memory B cells is similar to that of naive B cells, yet displays several important differences, including increased expression of activation-induced deaminase and several antiapoptotic genes, chemotactic receptors, and costimulatory molecules. Retroviral expression of either Klf2 or Ski, two transcriptional regulators specifically enriched in memory B cells relative to their germinal center precursors, imparted a competitive advantage to Ag receptor and CD40-engaged B cells in vitro. These data suggest that humoral recall responses are more rapid than primary responses due to the expression of a unique transcriptional program by memory B cells that allows them to both be maintained at high frequencies and to detect and rapidly respond to antigenic re-exposure. PMID:17982071

FOXO1 opposition of CD8+ T cell effector programming confers early memory properties and phenotypic diversity.

PubMed

Delpoux, Arnaud; Lai, Chen-Yen; Hedrick, Stephen M; Doedens, Andrew L

2017-10-17

The factors and steps controlling postinfection CD8 + T cell terminal effector versus memory differentiation are incompletely understood. Whereas we found that naive TCF7 (alias "Tcf-1") expression is FOXO1 independent, early postinfection we report bimodal, FOXO1-dependent expression of the memory-essential transcription factor TCF7 in pathogen-specific CD8 + T cells. We determined the early postinfection TCF7 high population is marked by low TIM3 expression and bears memory signature hallmarks before the appearance of established memory precursor marker CD127 (IL-7R). These cells exhibit diminished TBET, GZMB, mTOR signaling, and cell cycle progression. Day 5 postinfection, TCF7 high cells express higher memory-associated BCL2 and EOMES, as well as increased accumulation potential and capacity to differentiate into memory phenotype cells. TCF7 retroviral transduction opposes GZMB expression and the formation of KLRG1 pos phenotype cells, demonstrating an active role for TCF7 in extinguishing the effector program and forestalling terminal differentiation. Past the peak of the cellular immune response, we report a gradient of FOXO1 and TCF7 expression, which functions to oppose TBET and orchestrate a continuum of effector-to-memory phenotypes.

Ablation of SLP-76 signaling after T cell priming generates memory CD4 T cells impaired in steady-state and cytokine-driven homeostasis.

PubMed

Bushar, Nicholas D; Corbo, Evann; Schmidt, Michelle; Maltzman, Jonathan S; Farber, Donna L

2010-01-12

The intracellular signaling mechanisms regulating the generation and long-term persistence of memory T cells in vivo remain unclear. In this study, we used mouse models with conditional deletion of the key T cell receptor (TCR)-coupled adaptor molecule SH2-domain-containing phosphoprotein of 76 kDa (SLP-76), to analyze signaling mechanisms for memory CD4 T cell generation, maintenance, and homeostasis. We found that ablation of SLP-76 expression after T cell priming did not inhibit generation of phenotypic effector or memory CD4 T cells; however, the resultant SLP-76-deficient memory CD4 T cells could not produce recall cytokines in response to TCR-mediated stimulation and showed decreased persistence in vivo. In addition, SLP-76-deficient memory CD4 T cells exhibited reduced steady-state homeostasis and were impaired in their ability to homeostatically expand in vivo in response to the gamma(c) cytokine IL-7, despite intact proximal signaling through the IL-7R-coupled JAK3/STAT5 pathway. Direct in vivo deletion of SLP-76 in polyclonal memory CD4 T cells likewise led to impaired steady-state homeostasis as well as impaired homeostatic responses to IL-7. Our findings demonstrate a dominant role for SLP-76-dependent TCR signals in regulating turnover and perpetuation of memory CD4 T cells and their responses to homeostatic cytokines, with implications for the selective survival of memory CD4 T cells following pathogen exposure, vaccination, and aging.

Dynamic phenotypic restructuring of the CD4 and CD8 T-cell subsets with age in healthy humans: a compartmental model analysis.

PubMed

Jackola, D R; Hallgren, H M

1998-11-16

In healthy humans, phenotypic restructuring occurs with age within the CD3+ T-lymphocyte complement. This is characterized by a non-linear decrease of the percentage of 'naive' (CD45RA+) cells and a corresponding non-linear increase of the percentage of 'memory' (CD45R0+) cells among both the CD4+ and CD8+ T-cell subsets. We devised a simple compartmental model to study the age-dependent kinetics of phenotypic restructuring. We also derived differential equations whose parameters determined yearly gains minus losses of the percentage and absolute numbers of circulating naive cells, yearly gains minus losses of the percentage and absolute numbers of circulating memory cells, and the yearly rate of conversion of naive to memory cells. Solutions of these evaluative differential equations demonstrate the following: (1) the memory cell complement 'resides' within its compartment for a longer time than the naive cell complement within its compartment for both CD4 and CD8 cells; (2) the average, annual 'turnover rate' is the same for CD4 and CD8 naive cells. In contrast, the average, annual 'turnover rate' for memory CD8 cells is 1.5 times that of memory CD4 cells; (3) the average, annual conversion rate of CD4 naive cells to memory cells is twice that of the CD8 conversion rate; (4) a transition in dynamic restructuring occurs during the third decade of life that is due to these differences in turnover and conversion rates, between and from naive to memory cells.

The contribution of epigenetic memory to immunologic memory.

PubMed

Zediak, Valerie P; Wherry, E John; Berger, Shelley L

2011-04-01

Memory T lymphocytes are distinct from antigen-inexperienced naïve T cells in that memory T cells can respond more rapidly when they re-encounter a pathogen. Work over the past decade has begun to define the epigenetic underpinnings of the transcriptional component of the memory T cell response. An emerging theme is the persistence of an active chromatin signature at relevant gene loci in resting memory T cells, even when those genes are transcriptionally inactive. This gives strength to the concept of gene poising, and has shown that memory T lymphocytes are an ideal model in which to further define various mechanisms of epigenetic poising. Copyright © 2011 Elsevier Ltd. All rights reserved.

Functional classification of memory CD8(+) T cells by CX3CR1 expression.

PubMed

Böttcher, Jan P; Beyer, Marc; Meissner, Felix; Abdullah, Zeinab; Sander, Jil; Höchst, Bastian; Eickhoff, Sarah; Rieckmann, Jan C; Russo, Caroline; Bauer, Tanja; Flecken, Tobias; Giesen, Dominik; Engel, Daniel; Jung, Steffen; Busch, Dirk H; Protzer, Ulrike; Thimme, Robert; Mann, Matthias; Kurts, Christian; Schultze, Joachim L; Kastenmüller, Wolfgang; Knolle, Percy A

2015-09-25

Localization of memory CD8(+) T cells to lymphoid or peripheral tissues is believed to correlate with proliferative capacity or effector function. Here we demonstrate that the fractalkine-receptor/CX3CR1 distinguishes memory CD8(+) T cells with cytotoxic effector function from those with proliferative capacity, independent of tissue-homing properties. CX3CR1-based transcriptome and proteome-profiling defines a core signature of memory CD8(+) T cells with effector function. We find CD62L(hi)CX3CR1(+) memory T cells that reside within lymph nodes. This population shows distinct migration patterns and positioning in proximity to pathogen entry sites. Virus-specific CX3CR1(+) memory CD8(+) T cells are scarce during chronic infection in humans and mice but increase when infection is controlled spontaneously or by therapeutic intervention. This CX3CR1-based functional classification will help to resolve the principles of protective CD8(+) T-cell memory.

Massive infection and loss of CD4+ T cells occurs in the intestinal tract of neonatal rhesus macaques in acute SIV infection.

PubMed

Wang, Xiaolei; Rasmussen, Terri; Pahar, Bapi; Poonia, Bhawna; Alvarez, Xavier; Lackner, Andrew A; Veazey, Ronald S

2007-02-01

Rapid, profound, and selective depletion of memory CD4+ T cells has now been confirmed to occur in simian immunodeficiency virus (SIV)-infected adult macaques and human immunodeficiency virus (HIV)-infected humans. Within days of infection, marked depletion of memory CD4+ T cells occurs primarily in mucosal tissues, the major reservoir for memory CD4+ T cells in adults. However, HIV infection in neonates often results in higher viral loads and rapid disease progression, despite the paucity of memory CD4+ T cells in the peripheral blood. Here, we examined the immunophenotype of CD4+ T cells in normal and SIV-infected neonatal macaques to determine the distribution of naive and memory T-cell subsets in tissues. We demonstrate that, similar to adults, neonates have abundant memory CD4+ T cells in the intestinal tract and spleen and that these are selectively infected and depleted in primary SIV infection. Within 12 days of SIV infection, activated (CD69+), central memory (CD95+CD28+) CD4+ T cells are marked and persistently depleted in the intestine and other tissues of neonates compared with controls. The results in dicate that "activated" central memory CD4+ T cells are the major target for early SIV infection and CD4+ T cell depletion in neonatal macaques.

Massive infection and loss of CD4+ T cells occurs in the intestinal tract of neonatal rhesus macaques in acute SIV infection

PubMed Central

Wang, Xiaolei; Rasmussen, Terri; Pahar, Bapi; Poonia, Bhawna; Alvarez, Xavier; Lackner, Andrew A.; Veazey, Ronald S.

2007-01-01

Rapid, profound, and selective depletion of memory CD4+ T cells has now been confirmed to occur in simian immunodeficiency virus (SIV)–infected adult macaques and human immunodeficiency virus (HIV)–infected humans. Within days of infection, marked depletion of memory CD4+ T cells occurs primarily in mucosal tissues, the major reservoir for memory CD4+ T cells in adults. However, HIV infection in neonates often results in higher viral loads and rapid disease progression, despite the paucity of memory CD4+ T cells in the peripheral blood. Here, we examined the immunophenotype of CD4+ T cells in normal and SIV-infected neonatal macaques to determine the distribution of naive and memory T-cell subsets in tissues. We demonstrate that, similar to adults, neonates have abundant memory CD4+ T cells in the intestinal tract and spleen and that these are selectively infected and depleted in primary SIV infection. Within 12 days of SIV infection, activated (CD69+), central memory (CD95+CD28+) CD4+ T cells are marked and persistently depleted in the intestine and other tissues of neonates compared with controls. The results in dicate that “activated” central memory CD4+ T cells are the major target for early SIV infection and CD4+ T cell depletion in neonatal macaques. PMID:17047153

Neutron imaging integrated circuit and method for detecting neutrons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nagarkar, Vivek V.; More, Mitali J.

The present disclosure provides a neutron imaging detector and a method for detecting neutrons. In one example, a method includes providing a neutron imaging detector including plurality of memory cells and a conversion layer on the memory cells, setting one or more of the memory cells to a first charge state, positioning the neutron imaging detector in a neutron environment for a predetermined time period, and reading a state change at one of the memory cells, and measuring a charge state change at one of the plurality of memory cells from the first charge state to a second charge statemore » less than the first charge state, where the charge state change indicates detection of neutrons at said one of the memory cells.« less

Memory B cells in Guillain-Barré syndrome.

PubMed

Wang, Qian; Xing, Chunye; Hao, Yanlei; Shi, Qiguang; Qi, Ziyou; Lv, Zhanyun; Song, Yan; Xu, Peng; Feng, Xungang; Zhang, Lili; Zhang, Yong; Wang, Yuzhong; Yuki, Nobuhiro

2017-04-15

IgG autoantibodies against gangliosides show the highest titers at the disease onset of axonal Guillain-Barré syndrome (GBS), in which there are no IgM anti-ganglioside antibodies. We hypothesized that memory B cells take part in the development of producing IgG autoantibodies. In this study, we analyzed the memory B cells in patients with GBS using flow cytometry. There was significantly higher percentage of memory B cells in patients with GBS than the healthy controls. The Spearman correlation analysis demonstrated that increased percentage of memory B cells was positively correlated with the clinical severity of the patients with GBS. Our study provides the evidences that memory B cells may be involved in mechanism of GBS. Copyright © 2017 Elsevier B.V. All rights reserved.

De novo alloreactive memory CD8+ T cells develop following allogeneic challenge when CNI immunosuppression is delayed.

PubMed

Hart-Matyas, M; Gareau, A J; Hirsch, G M; Lee, T D G

2015-01-01

Allospecific memory T cells are a recognized threat to the maintenance of solid-organ transplants. Limited information exists regarding the development of alloreactive memory T cells when post-transplant immunosuppression is present. The clinical practice of delaying calcineurin inhibitor (CNI) initiation post-transplant may permit the development of a de novo allospecific memory population. We investigated the development of de novo allospecific memory CD8+ T cells following the introduction of CNI immunosuppression in a murine model using allogeneic cell priming. Recipient mice alloprimed with splenocytes from fully mismatched donors received cyclosporine (CyA), initiated at 0, 2, 6, or 10days post-prime. Splenocytes from recipients were analyzed by flow cytometry or enzyme-linked immunosorbent assay for evidence of memory cell formation. Memory and effector CD8+ T cell development was prevented when CyA was initiated at 0day or 2days post-prime (p<0.001), but not 6days post-prime. Following a boost challenge, these memory CD8+ T cells were capable of producing a similarly sized population of secondary effectors as recipients not treated with CyA (p>0.05). Delaying CyA up to 6days or later post-prime permits the development of functional de novo allospecific memory CD8+ T cells. The development of this potentially detrimental T cell population in patients could be prevented by starting CNI immunosuppression early post-transplant. Copyright © 2014 Elsevier B.V. All rights reserved.

CLONAL MEMORY

PubMed Central

McMichael, A. J.; Williamson, A. R.

1974-01-01

A single clone of B cells producing anti-DNP antibody recognizable by the isoelectric-focusing spectrum has been used, in a double transfer system, to study clonal memory. Trasnsferable B memory develops between 4 and 7 days after the first transfer with antigen. B-memory cells thus proliferate before or concomitantly with antibody-forming cells. PMID:4545165

Telomerase Is Involved in IL-7-Mediated Differential Survival of Naive and Memory CD4+ T Cells1

PubMed Central

Yang, Yinhua; An, Jie; Weng, Nan-ping

2008-01-01

IL-7 plays an essential role in T cell maintenance and survival. The survival effect of IL-7 is thought to be mediated through regulation of Bcl2 family proteins. After a comparative analysis of IL-7-induced growth and cell death of human naive and memory CD4+ T cells, we observed that more memory CD4+ T cells underwent cell division and proceeded to apoptosis than naive cells in response to IL-7. However, IL-7-induced expressions of Bcl2 family members (Bcl2, Bcl-xL, Bax, and Bad) were similar between naive and memory cells. Instead, we found that IL-7 induced higher levels of telomerase activity in naive cells than in memory cells, and the levels of IL-7-induced telomerase activity had a significant inverse correlation with cell death in CD4+ T cells. Furthermore, we showed that reducing expression of telomerase reverse transcriptase and telomerase activity significantly increased cell death of IL-7-cultured CD4+ T cells. Together, these findings demonstrate that telomerase is involved in IL-7-mediated differential survival of naive and memory CD4+ T cells. PMID:18322183

Work zone intrusion alarm effectiveness.

DOT National Transportation Integrated Search

2010-09-01

16. Abstract : The New Jersey Department of Transportation (NJDOT) commissioned a study to evaluate how : effective a work zone safety device known as the SonoBlaster! Work Zone Intrusion Alarm would be : in protecting maintenance workers fro...

Friends not foes: CTLA-4 blockade and mTOR inhibition cooperate during CD8+ T cell priming to promote memory formation and metabolic readiness.

PubMed

Pedicord, Virginia A; Cross, Justin R; Montalvo-Ortiz, Welby; Miller, Martin L; Allison, James P

2015-03-01

During primary Ag encounter, T cells receive numerous positive and negative signals that control their proliferation, function, and differentiation, but how these signals are integrated to modulate T cell memory has not been fully characterized. In these studies, we demonstrate that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mammalian target of rapamycin inhibition, during in vivo T cell priming leads to both an increase in the frequency of memory CD8(+) T cells and improved memory responses to tumors and bacterial challenges. This enhanced efficacy corresponds to increased early expansion and memory precursor differentiation of CD8(+) T cells and increased mitochondrial biogenesis and spare respiratory capacity in memory CD8(+) T cells in mice treated with anti-CTLA-4 and rapamycin during immunization. Collectively, these results reveal that mammalian target of rapamycin inhibition cooperates with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and proliferation, and an optimal metabolic program for CD8(+) T cell memory. Copyright © 2015 by The American Association of Immunologists, Inc.

Flexible and twistable non-volatile memory cell array with all-organic one diode-one resistor architecture.

PubMed

Ji, Yongsung; Zeigler, David F; Lee, Dong Su; Choi, Hyejung; Jen, Alex K-Y; Ko, Heung Cho; Kim, Tae-Wook

2013-01-01

Flexible organic memory devices are one of the integral components for future flexible organic electronics. However, high-density all-organic memory cell arrays on malleable substrates without cross-talk have not been demonstrated because of difficulties in their fabrication and relatively poor performances to date. Here we demonstrate the first flexible all-organic 64-bit memory cell array possessing one diode-one resistor architectures. Our all-organic one diode-one resistor cell exhibits excellent rewritable switching characteristics, even during and after harsh physical stresses. The write-read-erase-read output sequence of the cells perfectly correspond to the external pulse signal regardless of substrate deformation. The one diode-one resistor cell array is clearly addressed at the specified cells and encoded letters based on the standard ASCII character code. Our study on integrated organic memory cell arrays suggests that the all-organic one diode-one resistor cell architecture is suitable for high-density flexible organic memory applications in the future.

Humoral Immune Reconstitution Kinetics after Allogeneic Hematopoietic Stem Cell Transplantation in Children: A Maturation Block of IgM Memory B Cells May Lead to Impaired Antibody Immune Reconstitution.

PubMed

Abdel-Azim, Hisham; Elshoury, Amro; Mahadeo, Kris M; Parkman, Robertson; Kapoor, Neena

2017-09-01

Although T cell immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been well studied, long-term B cell immune reconstitution remains less characterized. We evaluated humoral immune reconstitution among 71 pediatric allo-HSCT recipients. Although tetanus toxoid antibody levels were normal at 1 year after allo-HSCT, antipolysaccharide carbohydrate antibodies remained persistently low for up to 5 years. While naive B cell counts normalized by 6 months, IgM memory B cell deficiency persisted for up to 2 years (P = .01); switched memory B cell deficiency normalized by 1 year after allo-HSCT. CD4 + T cell immune reconstitution correlated with that of switched memory B cells as early as 6 months after allo-HSCT (r = .55, P = .002) but did not correlate with IgM memory B cells at any time point after allo-HSCT. Taken together, this suggests that allo-HSCT recipients have impaired antibody immune reconstitution, mainly due to IgM memory B cell maturation block, compared with more prompt T cell-dependent switched memory cell immune reconstitution. We further explored other factors that might affect humoral immune reconstitution. The use of total body irradiation was associated with lower naive B cells counts at 6 months after HSCT (P = .04) and lower IgM (P = .008) and switched (P = .003) memory B cells up to 2 years. Allo-HSCT recipients with extensive chronic graft-versus-host disease had lower IgM memory B cell counts (P = .03) up to 2 years after allo-HSCT. The use of cord blood was associated with better naive (P = .01), IgM (P = .0005), and switched memory (P = .006) B cells immune reconstitution. These findings may inform future prophylaxis and treatment strategies regarding risk of overwhelming infection, graft-versus-host disease, and post-allogeneic HSCT revaccination. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Immune memory: the basics and how to trigger an efficient long-term immune memory.

PubMed

Beverley, P C L

2010-01-01

Immunological memory consists of expanded clones of T and B lymphocytes that show an increased rate of cell division and shortened telomeres compared with naïve cells. However, exhaustion of clones is delayed by kinetic heterogeneity within clones and altered survival and up-regulation of telomerase. Prolonged maintenance of protective B-cell immunity is T-cell dependent and requires a balance between plasma cells and memory B cells. Protective T-cell immunity also requires correct quality of T cells and that they are located appropriately. Copyright 2009 Elsevier Ltd. All rights reserved.

In Vitro-Generated Tc17 Cells Present a Memory Phenotype and Serve As a Reservoir of Tc1 Cells In Vivo

PubMed Central

Flores-Santibáñez, Felipe; Cuadra, Bárbara; Fernández, Dominique; Rosemblatt, Mariana V.; Núñez, Sarah; Cruz, Pablo; Gálvez-Cancino, Felipe; Cárdenas, J. César; Lladser, Alvaro; Rosemblatt, Mario; Bono, María Rosa; Sauma, Daniela

2018-01-01

Memory CD8+ T cells are ideal candidates for cancer immunotherapy because they can mediate long-term protection against tumors. However, the therapeutic potential of different in vitro-generated CD8+ T cell effector subsets to persist and become memory cells has not been fully characterized. Type 1 CD8+ T (Tc1) cells produce interferon-γ and are endowed with high cytotoxic capacity, whereas IL-17-producing CD8+ T (Tc17) cells are less cytotoxic but display enhanced self-renewal capacity. We sought to evaluate the functional properties of in vitro-generated Tc17 cells and elucidate their potential to become long lasting memory cells. Our results show that in vitro-generated Tc17 cells display a greater in vivo persistence and expansion in response to secondary antigen stimulation compared to Tc1 cells. When transferred into recipient mice, Tc17 cells persist in secondary lymphoid organs, present a recirculation behavior consistent with central memory T cells, and can shift to a Tc1 phenotype. Accordingly, Tc17 cells are endowed with a higher mitochondrial spare respiratory capacity than Tc1 cells and express higher levels of memory-related molecules than Tc1 cells. Together, these results demonstrate that in vitro-generated Tc17 cells acquire a central memory program and provide a lasting reservoir of Tc1 cells in vivo, thus supporting the use of Tc17 lymphocytes in the design of novel and more effective therapies. PMID:29472932

CXCR4 is critical for CD8+ memory T cell homeostatic self-renewal but not rechallenge self-renewal1

PubMed Central

Chaix, Julie; Nish, Simone A.; Lin, Wen-Hsuan W.; Rothman, Nyanza J.; Ding, Lei; Wherry, E. John; Reiner, Steven L.

2014-01-01

Central memory (CM) CD8+ T cells “remember” prior encounters because they maintain themselves through cell division in the absence of ongoing challenge (homeostatic self-renewal) as well as reproduce the central memory fate while manufacturing effector cells during secondary antigen encounters (rechallenge self-renewal). We tested the consequence of conditional deletion of the bone marrow (BM) homing receptor CXCR4 on antiviral T cell responses. CXCR4-deficient CD8+ T cells have impaired memory cell maintenance due to defective homeostatic proliferation. Upon rechallenge, however, CXCR4-deficient T cells can re-expand and renew the central memory pool while producing secondary effector cells. The critical BM-derived signals essential for CD8+ T cell homeostatic self-renewal appear to be dispensable to yield self-renewing, functionally asymmetric cell fates during rechallenge. PMID:24973450

CD4+CD62L+ Central Memory T Cells Can Be Converted to Foxp3+ T Cells

PubMed Central

Zhang, Xiaolong; Chang Li, Xian; Xiao, Xiang; Sun, Rui; Tian, Zhigang; Wei, Haiming

2013-01-01

The peripheral Foxp3+ Treg pool consists of naturally arising Treg (nTreg) and adaptive Treg cells (iTreg). It is well known that naive CD4+ T cells can be readily converted to Foxp3+ iTreg in vitro, and memory CD4+ T cells are resistant to conversion. In this study, we investigated the induction of Foxp3+ T cells from various CD4+ T-cell subsets in human peripheral blood. Though naive CD4+ T cells were readily converted to Foxp3+ T cells with TGF-β and IL-2 treatment in vitro, such Foxp3+ T cells did not express the memory marker CD45RO as do Foxp3+ T cells induced in the peripheral blood of Hepatitis B Virus (HBV) patients. Interestingly, a subset of human memory CD4+ T cells, defined as CD62L+ central memory T cells, could be induced by TGF-β to differentiate into Foxp3+ T cells. It is well known that Foxp3+ T cells derived from human CD4+CD25- T cells in vitro are lack suppressive functions. Our data about the suppressive functions of CD4+CD62L+ central memory T cell-derived Foxp3+ T cells support this conception, and an epigenetic analysis of these cells showed a similar methylation pattern in the FOXP3 Treg-specific demethylated region as the naive CD4+ T cell-derived Foxp3+ T cells. But further research showed that mouse CD4+ central memory T cells also could be induced to differentiate into Foxp3+ T cells, such Foxp3+ T cells could suppress the proliferation of effector T cells. Thus, our study identified CD4+CD62L+ central memory T cells as a novel potential source of iTreg. PMID:24155942

Hippocampal awake replay in fear memory retrieval

PubMed Central

Wu, Chun-Ting; Haggerty, Daniel; Kemere, Caleb; Ji, Daoyun

2017-01-01

Hippocampal place cells are key to episodic memories. How these cells participate in memory retrieval remains unclear. Here, after rats acquired a fear memory by receiving mild foot-shocks at a shock zone of a track, we analyzed place cells when the animals were placed back to the track and displayed an apparent memory retrieval behavior: avoidance of the shock zone. We found that place cells representing the shock zone were reactivated, despite the fact that the animals did not enter the shock zone. This reactivation occurred in ripple-associated awake replay of place cell sequences encoding the paths from the animal’s current positions to the shock zone, but not in place cell sequences within individual cycles of theta oscillation. The result reveals a specific place cell pattern underlying the inhibitory avoidance behavior and provides strong evidence for the involvement of awake replay in fear memory retrieval. PMID:28218916

Origin and Function of Circulating Plasmablasts during Acute Viral Infections.

PubMed

Fink, Katja

2012-01-01

Activated B cells proliferate and differentiate into antibody-producing cells, long-lived plasma cells, and memory B cells after immunization or infection. Repeated encounter of the same antigen triggers the rapid re-activation of pre-existing specific memory B cells, which then potentially enter new germinal center reactions and differentiate into short-lived plasmablasts or remain in the system as memory B cells. Short-lived class-switched IgG and IgA plasmablasts appear in the circulation transiently and the frequency of these cells can be remarkably high. The specificities and affinities of single plasmablasts in humans have been reported for several viral infections, so far most extensively for influenza and HIV. In general, the immunoglobulin variable regions of plasmablasts are highly mutated and diverse, suggesting that plasmablasts are derived from memory B cells, yet it is unclear which memory B cell subsets are activated and whether activated memory B cells adapt or mature before differentiation. This review summarizes what is known about the phenotype and the origin of human plasmablasts in the context of viral infections and whether these cells can be predictors of long-lived immunity.

Bcl-2 Allows Effector and Memory CD8+ T Cells To Tolerate Higher Expression of Bim

PubMed Central

Kurtulus, Sema; Tripathi, Pulak; Moreno-Fernandez, Maria E.; Sholl, Allyson; Katz, Jonathan D.; Grimes, H. Leighton; Hildeman, David A.

2014-01-01

As acute infections resolve, most effector CD8+ T cells die, whereas some persist and become memory T cells. Recent work showed that subsets of effector CD8+ T cells, identified by reciprocal expression of killer cell lectin-like receptor G1 (KLRG1) and CD127, have different lifespans. Similar to previous reports, we found that effector CD8+ T cells reported to have a longer lifespan (i.e., KLRG1lowCD127high) have increased levels of Bcl-2 compared with their shorter-lived KLRG1highCD127low counterparts. Surprisingly, we found that these effector KLRG1lowCD127high CD8+ T cells also had increased levels of Bim compared with KLRG1highCD127low cells. Similar effects were observed in memory cells, in which CD8+ central memory T cells expressed higher levels of Bim and Bcl-2 than did CD8+ effector memory T cells. Using both pharmacologic and genetic approaches, we found that survival of both subsets of effector and memory CD8+ T cells required Bcl-2 to combat the proapoptotic activity of Bim. Interestingly, inhibition or absence of Bcl-2 led to significantly decreased expression of Bim in surviving effector and memory T cells. In addition, manipulation of Bcl-2 levels by IL-7 or IL-15 also affected expression of Bim in effector CD8+ T cells. Finally, we found that Bim levels were significantly increased in effector CD8+ T cells lacking Bax and Bak. Together, these data indicate that cells having the highest levels of Bim are selected against during contraction of the response and that Bcl-2 determines the level of Bim that effector and memory T cells can tolerate. PMID:21451108

Cytokine-Induced Memory-Like Differentiation Enhances Unlicensed Natural Killer Cell Antileukemia and FcγRIIIa-Triggered Responses.

PubMed

Wagner, Julia A; Berrien-Elliott, Melissa M; Rosario, Maximillian; Leong, Jeffrey W; Jewell, Brea A; Schappe, Timothy; Abdel-Latif, Sara; Fehniger, Todd A

2017-03-01

Cytokine-induced memory-like natural killer (NK) cells differentiate after short-term preactivation with IL-12, IL-15, and IL-18 and display enhanced effector function in response to cytokines or tumor targets for weeks after the initial preactivation. Conventional NK cell function depends on a licensing signal, classically delivered by an inhibitory receptor engaging its cognate MHC class I ligand. How licensing status integrates with cytokine-induced memory-like NK cell responses is unknown. We investigated this interaction using killer cell immunoglobulin-like receptor- and HLA-genotyped primary human NK cells. Memory-like differentiation resulted in enhanced IFN-γ production triggered by leukemia targets or FcγRIIIa ligation within licensed NK cells, which exhibited the highest functionality of the NK cell subsets interrogated. IFN-γ production by unlicensed memory-like NK cells was also enhanced to a level comparable with that of licensed control NK cells. Mechanistically, differences in responses to FcγRIIIa-based triggering were not explained by alterations in key signaling intermediates, indicating that the underlying biology of memory-like NK cells is distinct from that of adaptive NK cells in human cytomegalovirus-positive individuals. Additionally, memory-like NK cells responded robustly to cytokine receptor restimulation with no impact of licensing status. These results demonstrate that both licensed and unlicensed memory-like NK cell populations have enhanced functionality, which may be translated to improve leukemia immunotherapy. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Neem leaf glycoprotein promotes dual generation of central and effector memory CD8(+) T cells against sarcoma antigen vaccine to induce protective anti-tumor immunity.

PubMed

Ghosh, Sarbari; Sarkar, Madhurima; Ghosh, Tithi; Guha, Ipsita; Bhuniya, Avishek; Saha, Akata; Dasgupta, Shayani; Barik, Subhasis; Bose, Anamika; Baral, Rathindranath

2016-03-01

We have previously shown that Neem Leaf Glycoprotein (NLGP) mediates sustained tumor protection by activating host immune response. Now we report that adjuvant help from NLGP predominantly generates CD44(+)CD62L(high)CCR7(high) central memory (TCM; in lymph node) and CD44(+)CD62L(low)CCR7(low) effector memory (TEM; in spleen) CD8(+) T cells of Swiss mice after vaccination with sarcoma antigen (SarAg). Generated TCM and TEM participated either to replenish memory cell pool for sustained disease free states or in rapid tumor eradication respectively. TCM generated after SarAg+NLGP vaccination underwent significant proliferation and IL-2 secretion following SarAg re-stimulation. Furthermore, SarAg+NLGP vaccination helps in greater survival of the memory precursor effector cells at the peak of the effector response and their maintenance as mature memory cells, in comparison to single modality treatment. Such response is corroborated with the reduced phosphorylation of FOXO in the cytosol and increased KLF2 in the nucleus associated with enhanced CD62L, CCR7 expression of lymph node-resident CD8(+) T cells. However, spleen-resident CD8(+) T memory cells show superior efficacy for immediate memory-to-effector cell conversion. The data support in all aspects that SarAg+NLGP demonstrate superiority than SarAg vaccination alone that benefits the host by rapid effector functions whenever required, whereas, central-memory cells are thought to replenish the memory cell pool for ultimate sustained disease free survival till 60 days following post-vaccination tumor inoculation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Generation of memory B cells and their reactivation.

PubMed

Inoue, Takeshi; Moran, Imogen; Shinnakasu, Ryo; Phan, Tri Giang; Kurosaki, Tomohiro

2018-05-01

The successful establishment of humoral memory response depends on at least two layers of defense. Pre-existing protective antibodies secreted by long-lived plasma cells act as a first line of defense against reinfection ("constitutive humoral memory"). Previously, a second line of defense in which pathogen-experienced memory B cells are rapidly reactivated to produce antibodies ("reactive humoral memory"), was considered as simply a back-up system for the first line (particularly for re-infection with homologous viruses). However, in the case of re-infection with similar but different strains of viruses, or in response to viral escape mutants, the reactive humoral memory plays a crucial role. Here, we review recent progress in our understanding of how memory B cells are generated in the pre-GC stage and during the GC reaction, and how these memory B cells are robustly reactivated with the help of memory Tfh cells to generate the secondary antibody response. In addition, we discuss how these advances may be relevant to the quest for a vaccine that can induce broadly reactive antibodies against influenza and HIV. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Induction of CD4 T cell memory by local cellular collectivity.

PubMed

Polonsky, Michal; Rimer, Jacob; Kern-Perets, Amos; Zaretsky, Irina; Miller, Stav; Bornstein, Chamutal; David, Eyal; Kopelman, Naama Meira; Stelzer, Gil; Porat, Ziv; Chain, Benjamin; Friedman, Nir

2018-06-15

Cell differentiation is directed by signals driving progenitors into specialized cell types. This process can involve collective decision-making, when differentiating cells determine their lineage choice by interacting with each other. We used live-cell imaging in microwell arrays to study collective processes affecting differentiation of naïve CD4 + T cells into memory precursors. We found that differentiation of precursor memory T cells sharply increases above a threshold number of locally interacting cells. These homotypic interactions involve the cytokines interleukin-2 (IL-2) and IL-6, which affect memory differentiation orthogonal to their effect on proliferation and survival. Mathematical modeling suggests that the differentiation rate is continuously modulated by the instantaneous number of locally interacting cells. This cellular collectivity can prioritize allocation of immune memory to stronger responses. Copyright © 2018, American Association for the Advancement of Science.

Requirement for CD4 T Cell Help in Generating Functional CD8 T Cell Memory

NASA Astrophysics Data System (ADS)

Shedlock, Devon J.; Shen, Hao

2003-04-01

Although primary CD8 responses to acute infections are independent of CD4 help, it is unknown whether a similar situation applies to secondary responses. We show that depletion of CD4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses by memory CD8 cells to reinfection. Memory CD8 cells generated in CD4+/+ mice responded normally when transferred into CD4-/- hosts, whereas memory CD8 cells generated in CD4-/- mice mounted defective recall responses in CD4+/+ adoptive hosts. These results demonstrate a previously undescribed role for CD4 help in the development of functional CD8 memory.

Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation

PubMed Central

Shinoda, Kenta; Hirahara, Kiyoshi; Iinuma, Tomohisa; Ichikawa, Tomomi; Suzuki, Akane S.; Sugaya, Kaoru; Tumes, Damon J.; Yamamoto, Heizaburo; Hara, Takahiro; Tani-ichi, Shizue; Ikuta, Koichi; Okamoto, Yoshitaka; Nakayama, Toshinori

2016-01-01

Memory CD4+ T helper (Th) cells are central to long-term protection against pathogens, but they can also be pathogenic and drive chronic inflammatory disorders. How these pathogenic memory Th cells are maintained, particularly at sites of local inflammation, remains unclear. We found that ectopic lymphoid-like structures called inducible bronchus-associated lymphoid tissue (iBALT) are formed during chronic allergic inflammation in the lung, and that memory-type pathogenic Th2 (Tpath2) cells capable of driving allergic inflammation are maintained within the iBALT structures. The maintenance of memory Th2 cells within iBALT is supported by Thy1+IL-7–producing lymphatic endothelial cells (LECs). The Thy1+IL-7–producing LECs express IL-33 and T-cell–attracting chemokines CCL21 and CCL19. Moreover, ectopic lymphoid structures consisting of memory CD4+ T cells and IL-7+IL-33+ LECs were found in nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, Thy1+IL-7–producing LECs control chronic allergic airway inflammation by providing a survival niche for memory-type Tpath2 cells. PMID:27140620

Comprehensive Approach for Identifying the T Cell Subset Origin of CD3 and CD28 Antibody-Activated Chimeric Antigen Receptor-Modified T Cells.

PubMed

Schmueck-Henneresse, Michael; Omer, Bilal; Shum, Thomas; Tashiro, Haruko; Mamonkin, Maksim; Lapteva, Natalia; Sharma, Sandhya; Rollins, Lisa; Dotti, Gianpietro; Reinke, Petra; Volk, Hans-Dieter; Rooney, Cliona M

2017-07-01

The outcome of therapy with chimeric Ag receptor (CAR)-modified T cells is strongly influenced by the subset origin of the infused T cells. However, because polyclonally activated T cells acquire a largely CD45RO + CCR7 - effector memory phenotype after expansion, regardless of subset origin, it is impossible to know which subsets contribute to the final T cell product. To determine the contribution of naive T cell, memory stem T cell, central memory T cell, effector memory T cell, and terminally differentiated effector T cell populations to the CD3 and CD28-activated CAR-modified T cells that we use for therapy, we followed the fate and function of individually sorted CAR-modified T cell subsets after activation with CD3 and CD28 Abs (CD3/28), transduction and culture alone, or after reconstitution into the relevant subset-depleted population. We show that all subsets are sensitive to CAR transduction, and each developed a distinct T cell functional profile during culture. Naive-derived T cells showed the greatest rate of proliferation but had more limited effector functions and reduced killing compared with memory-derived populations. When cultured in the presence of memory T cells, naive-derived T cells show increased differentiation, reduced effector cytokine production, and a reduced reproliferative response to CAR stimulation. CD3/28-activated T cells expanded in IL-7 and IL-15 produced greater expansion of memory stem T cells and central memory T cell-derived T cells compared with IL-2. Our strategy provides a powerful tool to elucidate the characteristics of CAR-modified T cells, regardless of the protocol used for expansion, reveals the functional properties of each expanded T cell subset, and paves the way for a more detailed evaluation of the effects of manufacturing changes on the subset contribution to in vitro-expanded T cells. Copyright © 2017 by The American Association of Immunologists, Inc.

Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease.

PubMed

Roy, Dheeraj S; Arons, Autumn; Mitchell, Teryn I; Pignatelli, Michele; Ryan, Tomás J; Tonegawa, Susumu

2016-03-24

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.

Diet-induced obesity does not impact the generation and maintenance of primary memory CD8 T cells.

PubMed

Khan, Shaniya H; Hemann, Emily A; Legge, Kevin L; Norian, Lyse A; Badovinac, Vladimir P

2014-12-15

The extent to which obesity compromises the differentiation and maintenance of protective memory CD8 T cell responses and renders obese individuals susceptible to infection remains unknown. In this study, we show that diet-induced obesity did not impact the maintenance of pre-existing memory CD8 T cells, including acquisition of a long-term memory phenotype (i.e., CD27(hi), CD62L(hi), KLRG1(lo)) and function (i.e., cytokine production, secondary expansion, and memory CD8 T cell-mediated protection). Additionally, obesity did not influence the differentiation and maintenance of newly evoked memory CD8 T cell responses in inbred and outbred hosts generated in response to different types of systemic (LCMV, L. monocytogenes) and/or localized (influenza virus) infections. Interestingly, the rate of naive-to-memory CD8 T cell differentiation after a peptide-coated dendritic cell immunization was similar in lean and obese hosts, suggesting that obesity-associated inflammation, unlike pathogen- or adjuvant-induced inflammation, did not influence the development of endogenous memory CD8 T cell responses. Therefore, our studies reveal that the obese environment does not influence the development or maintenance of memory CD8 T cell responses that are either primed before or after obesity is established, a surprising notion with important implications for future studies aiming to elucidate the role obesity plays in host susceptibility to infections. Copyright © 2014 by The American Association of Immunologists, Inc.

Tolerance induction of IgG+ memory B cells by T cell-independent type II antigens.

PubMed

Haniuda, Kei; Nojima, Takuya; Ohyama, Kyosuke; Kitamura, Daisuke

2011-05-15

Memory B cells generated during a T cell-dependent immune response rapidly respond to a secondary immunization by producing abundant IgG Abs that bind cognate Ag with high affinity. It is currently unclear whether this heightened recall response by memory B cells is due to augmented IgG-BCR signaling, which has only been demonstrated in the context of naive transgenic B cells. To address this question, we examined whether memory B cells can respond in vivo to Ags that stimulate only through BCR, namely T cell-independent type II (TI-II) Ags. In this study, we show that the TI-II Ag (4-hydroxy-3-nitrophenyl) acetyl (NP)-Ficoll cannot elicit the recall response in mice first immunized with the T cell-dependent Ag NP-chicken γ-globulin. Moreover, the NP-Ficoll challenge in vivo as well as in vitro significantly inhibits a subsequent recall response to NP-chicken γ-globulin in a B cell-intrinsic manner. This NP-Ficoll-mediated tolerance is caused by the preferential elimination of IgG(+) memory B cells binding to NP with high affinity. These data indicate that BCR cross-linking with a TI-II Ag does not activate IgG(+) memory B cells, but rather tolerizes them, identifying a terminal checkpoint of memory B cell differentiation that may prevent autoimmunity.

Memory CD8+ T Cells Protect Dendritic Cells from CTL Killing1

PubMed Central

Watchmaker, Payal B.; Urban, Julie A.; Berk, Erik; Nakamura, Yutaro; Mailliard, Robbie B.; Watkins, Simon C.; van Ham, S. Marieke; Kalinski, Pawel

2010-01-01

CD8+ T cells have been shown to be capable of either suppressing or promoting immune responses. To reconcile these contrasting regulatory functions, we compared the ability of human effector and memory CD8+ T cells to regulate survival and functions of dendritic cells (DC). We report that, in sharp contrast to the effector cells (CTLs) that kill DCs in a granzyme B- and perforin-dependent mechanism, memory CD8+ T cells enhance the ability of DCs to produce IL-12 and to induce functional Th1 and CTL responses in naive CD4+ and CD8+ T cell populations. Moreover, memory CD8+ T cells that release the DC-activating factor TNF-α before the release of cytotoxic granules induce DC expression of an endogenous granzyme B inhibitor PI-9 and protect DCs from CTL killing with similar efficacy as CD4+ Th cells. The currently identified DC-protective function of memory CD8+ T cells helps to explain the phenomenon of CD8+ T cell memory, reduced dependence of recall responses on CD4+ T cell help, and the importance of delayed administration of booster doses of vaccines for the optimal outcome of immunization. PMID:18322193

CD4+ virtual memory: Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity.

PubMed

Marusina, Alina I; Ono, Yoko; Merleev, Alexander A; Shimoda, Michiko; Ogawa, Hiromi; Wang, Elizabeth A; Kondo, Kayo; Olney, Laura; Luxardi, Guillaume; Miyamura, Yoshinori; Yilma, Tilahun D; Villalobos, Itzel Bustos; Bergstrom, Jennifer W; Kronenberg, Daniel G; Soulika, Athena M; Adamopoulos, Iannis E; Maverakis, Emanual

2017-02-01

It is widely accepted that central and effector memory CD4 + T cells originate from naïve T cells after they have encountered their cognate antigen in the setting of appropriate co-stimulation. However, if this were true the diversity of T cell receptor (TCR) sequences within the naïve T cell compartment should be far greater than that of the memory T cell compartment, which is not supported by TCR sequencing data. Here we demonstrate that aged mice with far fewer naïve T cells, respond to the model antigen, hen eggwhite lysozyme (HEL), by utilizing the same TCR sequence as their younger counterparts. CD4 + T cell repertoire analysis of highly purified T cell populations from naive animals revealed that the HEL-specific clones displayed effector and central "memory" cell surface phenotypes even prior to having encountered their cognate antigen. Furthermore, HEL-inexperienced CD4 + T cells were found to reside within the naïve, regulatory, central memory, and effector memory T cell populations at similar frequencies and the majority of the CD4 + T cells within the regulatory and memory populations were unexpanded. These findings support a new paradigm for CD4 + T cell maturation in which a specific clone can undergo a differentiation process to exhibit a "memory" or regulatory phenotype without having undergone a clonal expansion event. It also demonstrates that a foreign-specific T cell is just as likely to reside within the regulatory T cell compartment as it would the naïve compartment, arguing against the specificity of the regulatory T cell compartment being skewed towards self-reactive T cell clones. Finally, we demonstrate that the same set of foreign and autoreactive CD4 + T cell clones are repetitively generated throughout adulthood. The latter observation argues against T cell-depleting strategies or autologous stem cell transplantation as therapies for autoimmunity-as the immune system has the ability to regenerate pathogenic clones. Published by Elsevier Ltd.

Immune signatures of protective spleen memory CD8 T cells.

PubMed

Brinza, Lilia; Djebali, Sophia; Tomkowiak, Martine; Mafille, Julien; Loiseau, Céline; Jouve, Pierre-Emmanuel; de Bernard, Simon; Buffat, Laurent; Lina, Bruno; Ottmann, Michèle; Rosa-Calatrava, Manuel; Schicklin, Stéphane; Bonnefoy, Nathalie; Lauvau, Grégoire; Grau, Morgan; Wencker, Mélanie; Arpin, Christophe; Walzer, Thierry; Leverrier, Yann; Marvel, Jacqueline

2016-11-24

Memory CD8 T lymphocyte populations are remarkably heterogeneous and differ in their ability to protect the host. In order to identify the whole range of qualities uniquely associated with protective memory cells we compared the gene expression signatures of two qualities of memory CD8 T cells sharing the same antigenic-specificity: protective (Influenza-induced, Flu-TM) and non-protective (peptide-induced, TIM) spleen memory CD8 T cells. Although Flu-TM and TIM express classical phenotypic memory markers and are polyfunctional, only Flu-TM protects against a lethal viral challenge. Protective memory CD8 T cells express a unique set of genes involved in migration and survival that correlate with their unique capacity to rapidly migrate within the infected lung parenchyma in response to influenza infection. We also enlighten a new set of poised genes expressed by protective cells that is strongly enriched in cytokines and chemokines such as Ccl1, Ccl9 and Gm-csf. CCL1 and GM-CSF genes are also poised in human memory CD8 T cells. These immune signatures are also induced by two other pathogens (vaccinia virus and Listeria monocytogenes). The immune signatures associated with immune protection were identified on circulating cells, i.e. those that are easily accessible for immuno-monitoring and could help predict vaccines efficacy.

Characterization of a CD44/CD122int memory CD8 T cell subset generated under sterile inflammatory conditions.

PubMed

Mbitikon-Kobo, Florentin-Martial; Vocanson, Marc; Michallet, Marie-Cécile; Tomkowiak, Martine; Cottalorda, Anne; Angelov, Georgi S; Coupet, Charles-Antoine; Djebali, Sophia; Marçais, Antoine; Dubois, Bertrand; Bonnefoy-Bérard, Nathalie; Nicolas, Jean-François; Arpin, Christophe; Marvel, Jacqueline

2009-03-15

Most memory CD8 T cell subsets that have been hitherto defined are generated in response to infectious pathogens. In this study, we have characterized the CD8 T cells that survive priming conditions, devoid of pathogen-derived danger signals. In both a TCR-transgenic model and a model of contact hypersensitivity, we show that the priming of naive CD8 T cells under sterile inflammatory conditions generates memory. The corresponding memory CD8 T cells can be identified by their intermediate expression levels of CD44 and CD122. We also show that CD44/122(int) memory CD8 T cells spontaneously develop in wild type mice and that they display intermediate levels of several other memory traits including functional (IFN-gamma secretion capacity, CCL5 messenger stores), phenotypic, and molecular (T-bet and eomesodermin expression levels) features. We finally show that they correspond to an early differentiation stage and can further differentiate in CD44/122(high) memory T cells. Altogether, our results identify a new memory CD8 T cell subset that is generated under sterile inflammatory conditions and involved in the recall contact hypersensitivity reactions that are responsible for allergic contact dermatitis.

Kinetic Inductance Memory Cell and Architecture for Superconducting Computers

NASA Astrophysics Data System (ADS)

Chen, George J.

Josephson memory devices typically use a superconducting loop containing one or more Josephson junctions to store information. The magnetic inductance of the loop in conjunction with the Josephson junctions provides multiple states to store data. This thesis shows that replacing the magnetic inductor in a memory cell with a kinetic inductor can lead to a smaller cell size. However, magnetic control of the cells is lost. Thus, a current-injection based architecture for a memory array has been designed to work around this problem. The isolation between memory cells that magnetic control provides is provided through resistors in this new architecture. However, these resistors allow leakage current to flow which ultimately limits the size of the array due to power considerations. A kinetic inductance memory array will be limited to 4K bits with a read access time of 320 ps for a 1 um linewidth technology. If a power decoder could be developed, the memory architecture could serve as the blueprint for a fast (<1 ns), large scale (>1 Mbit) superconducting memory array.

White Adipose Tissue Is a Reservoir for Memory T Cells and Promotes Protective Memory Responses to Infection.

PubMed

Han, Seong-Ji; Glatman Zaretsky, Arielle; Andrade-Oliveira, Vinicius; Collins, Nicholas; Dzutsev, Amiran; Shaik, Jahangheer; Morais da Fonseca, Denise; Harrison, Oliver J; Tamoutounour, Samira; Byrd, Allyson L; Smelkinson, Margery; Bouladoux, Nicolas; Bliska, James B; Brenchley, Jason M; Brodsky, Igor E; Belkaid, Yasmine

2017-12-19

White adipose tissue bridges body organs and plays a fundamental role in host metabolism. To what extent adipose tissue also contributes to immune surveillance and long-term protective defense remains largely unknown. Here, we have shown that at steady state, white adipose tissue contained abundant memory lymphocyte populations. After infection, white adipose tissue accumulated large numbers of pathogen-specific memory T cells, including tissue-resident cells. Memory T cells in white adipose tissue expressed a distinct metabolic profile, and white adipose tissue from previously infected mice was sufficient to protect uninfected mice from lethal pathogen challenge. Induction of recall responses within white adipose tissue was associated with the collapse of lipid metabolism in favor of antimicrobial responses. Our results suggest that white adipose tissue represents a memory T cell reservoir that provides potent and rapid effector memory responses, positioning this compartment as a potential major contributor to immunological memory. Published by Elsevier Inc.

Enhanced clonal burst size corrects an otherwise defective memory response by CD8+ recent thymic emigrants

PubMed Central

Deets, Katherine A.; Berkley, Amy M.; Bergsbaken, Tessa; Fink, Pamela J.

2016-01-01

The youngest peripheral T cells (recent thymic emigrants or RTEs) are functionally distinct from naïve T cells that have completed post-thymic maturation. We now assess the RTE memory response, and find that RTEs produced less granzyme B than their mature counterparts during infection, but proliferated more and therefore generated equivalent target killing in vivo. After infection, RTE numbers contracted less dramatically than those of mature T cells, but RTEs were delayed in their transition to central memory, displaying impaired expression of CD62L, IL-2, Eomesodermin, and CXCR4, which resulted in impaired bone marrow localization. RTE-derived and mature memory cells expanded equivalently during rechallenge, indicating the robust proliferative capacity of RTEs was maintained independently of central memory phenotype. Thus, the diminished effector function and delayed central memory differentiation of RTE-derived memory cells are counterbalanced by their increased proliferative capacity, driving the efficacy of the RTE response to that of mature T cells. PMID:26873989

Cutting Edge: Enhanced Clonal Burst Size Corrects an Otherwise Defective Memory Response by CD8+ Recent Thymic Emigrants.

PubMed

Deets, Katherine A; Berkley, Amy M; Bergsbaken, Tessa; Fink, Pamela J

2016-03-15

The youngest peripheral T cells (recent thymic emigrants [RTEs]) are functionally distinct from naive T cells that have completed postthymic maturation. We assessed the RTE memory response and found that RTEs produced less granzyme B than their mature counterparts during infection but proliferated more and, therefore, generated equivalent target killing in vivo. Postinfection, RTE numbers contracted less dramatically than those of mature T cells, but RTEs were delayed in their transition to central memory, displaying impaired expression of CD62L, IL-2, Eomesodermin, and CXCR4, which resulted in impaired bone marrow localization. RTE-derived and mature memory cells expanded equivalently during rechallenge, indicating that the robust proliferative capacity of RTEs was maintained independently of central memory phenotype. Thus, the diminished effector function and delayed central memory differentiation of RTE-derived memory cells are counterbalanced by their increased proliferative capacity, driving the efficacy of the RTE response to that of mature T cells. Copyright © 2016 by The American Association of Immunologists, Inc.

Associative memory cells and their working principle in the brain

PubMed Central

Wang, Jin-Hui; Cui, Shan

2018-01-01

The acquisition, integration and storage of exogenous associated signals are termed as associative learning and memory. The consequences and processes of associative thinking and logical reasoning based on these stored exogenous signals can be memorized as endogenous signals, which are essential for decision making, intention, and planning. Associative memory cells recruited in these primary and secondary associative memories are presumably the foundation for the brain to fulfill cognition events and emotional reactions in life, though the plasticity of synaptic connectivity and neuronal activity has been believed to be involved in learning and memory. Current reports indicate that associative memory cells are recruited by their mutual synapse innervations among co-activated brain regions to fulfill the integration, storage and retrieval of associated signals. The activation of these associative memory cells initiates information recall in the mind, and the successful activation of their downstream neurons endorses memory presentations through behaviors and emotion reactions. In this review, we aim to draw a comprehensive diagram for associative memory cells, working principle and modulation, as well as propose their roles in cognition, emotion and behaviors. PMID:29487741

In Vitro Measles Virus Infection of Human Lymphocyte Subsets Demonstrates High Susceptibility and Permissiveness of both Naive and Memory B Cells.

PubMed

Laksono, Brigitta M; Grosserichter-Wagener, Christina; de Vries, Rory D; Langeveld, Simone A G; Brem, Maarten D; van Dongen, Jacques J M; Katsikis, Peter D; Koopmans, Marion P G; van Zelm, Menno C; de Swart, Rik L

2018-04-15

Measles is characterized by a transient immune suppression, leading to an increased risk of opportunistic infections. Measles virus (MV) infection of immune cells is mediated by the cellular receptor CD150, expressed by subsets of lymphocytes, dendritic cells, macrophages, and thymocytes. Previous studies showed that human and nonhuman primate memory T cells express higher levels of CD150 than naive cells and are more susceptible to MV infection. However, limited information is available about the CD150 expression and relative susceptibility to MV infection of B-cell subsets. In this study, we assessed the susceptibility and permissiveness of naive and memory T- and B-cell subsets from human peripheral blood or tonsils to in vitro MV infection. Our study demonstrates that naive and memory B cells express CD150, but at lower frequencies than memory T cells. Nevertheless, both naive and memory B cells proved to be highly permissive to MV infection. Furthermore, we assessed the susceptibility and permissiveness of various functionally distinct T and B cells, such as helper T (T H ) cell subsets and IgG- and IgA-positive memory B cells, in peripheral blood and tonsils. We demonstrated that T H 1T H 17 cells and plasma and germinal center B cells were the subsets most susceptible and permissive to MV infection. Our study suggests that both naive and memory B cells, along with several other antigen-experienced lymphocytes, are important target cells of MV infection. Depletion of these cells potentially contributes to the pathogenesis of measles immune suppression. IMPORTANCE Measles is associated with immune suppression and is often complicated by bacterial pneumonia, otitis media, or gastroenteritis. Measles virus infects antigen-presenting cells and T and B cells, and depletion of these cells may contribute to lymphopenia and immune suppression. Measles has been associated with follicular exhaustion in lymphoid tissues in humans and nonhuman primates, emphasizing the importance of MV infection of B cells in vivo However, information on the relative susceptibility of B-cell subsets is scarce. Here, we compared the susceptibility and permissiveness to in vitro MV infection of human naive and memory T- and B-cell subsets isolated from peripheral blood or tonsils. Our results demonstrate that both naive and memory B cells are more permissive to MV infection than T cells. The highest infection levels were detected in plasma cells and germinal center B cells, suggesting that infection and depletion of these populations contribute to reduced host resistance. Copyright © 2018 Laksono et al.

In Vitro Measles Virus Infection of Human Lymphocyte Subsets Demonstrates High Susceptibility and Permissiveness of both Naive and Memory B Cells

PubMed Central

Laksono, Brigitta M.; Grosserichter-Wagener, Christina; de Vries, Rory D.; Langeveld, Simone A. G.; Brem, Maarten D.; van Dongen, Jacques J. M.; Koopmans, Marion P. G.

2018-01-01

ABSTRACT Measles is characterized by a transient immune suppression, leading to an increased risk of opportunistic infections. Measles virus (MV) infection of immune cells is mediated by the cellular receptor CD150, expressed by subsets of lymphocytes, dendritic cells, macrophages, and thymocytes. Previous studies showed that human and nonhuman primate memory T cells express higher levels of CD150 than naive cells and are more susceptible to MV infection. However, limited information is available about the CD150 expression and relative susceptibility to MV infection of B-cell subsets. In this study, we assessed the susceptibility and permissiveness of naive and memory T- and B-cell subsets from human peripheral blood or tonsils to in vitro MV infection. Our study demonstrates that naive and memory B cells express CD150, but at lower frequencies than memory T cells. Nevertheless, both naive and memory B cells proved to be highly permissive to MV infection. Furthermore, we assessed the susceptibility and permissiveness of various functionally distinct T and B cells, such as helper T (TH) cell subsets and IgG- and IgA-positive memory B cells, in peripheral blood and tonsils. We demonstrated that TH1TH17 cells and plasma and germinal center B cells were the subsets most susceptible and permissive to MV infection. Our study suggests that both naive and memory B cells, along with several other antigen-experienced lymphocytes, are important target cells of MV infection. Depletion of these cells potentially contributes to the pathogenesis of measles immune suppression. IMPORTANCE Measles is associated with immune suppression and is often complicated by bacterial pneumonia, otitis media, or gastroenteritis. Measles virus infects antigen-presenting cells and T and B cells, and depletion of these cells may contribute to lymphopenia and immune suppression. Measles has been associated with follicular exhaustion in lymphoid tissues in humans and nonhuman primates, emphasizing the importance of MV infection of B cells in vivo. However, information on the relative susceptibility of B-cell subsets is scarce. Here, we compared the susceptibility and permissiveness to in vitro MV infection of human naive and memory T- and B-cell subsets isolated from peripheral blood or tonsils. Our results demonstrate that both naive and memory B cells are more permissive to MV infection than T cells. The highest infection levels were detected in plasma cells and germinal center B cells, suggesting that infection and depletion of these populations contribute to reduced host resistance. PMID:29437964

Preparation of zeolite nanorods by corona discharge plasma for degradation of phenazopyridine by heterogeneous sono-Fenton-like process.

PubMed

Khataee, Alireza; Rad, Tannaz Sadeghi; Vahid, Behrouz; Khorram, Sirous

2016-11-01

The plasma-modified clinoptilolite (PMC) nanorods were prepared from natural clinoptilolite (NC) utilizing environmentally-friendly corona discharge plasma. The PMC and NC were characterized by XRD, FT-IR, SEM, EDX, XPS and BET, which confirmed the nanocatalyst formation. The catalytic performance of the PMC in the heterogeneous sono-Fenton-like process was greater than the NC for treatment of phenazopyridine (PhP). The desired amounts were obtained for experimental parameters including initial pH (5), PMC dosage (2g/L), K2S2O8 concentration (2mmol/L), ultrasonic power (300W) and PhP concentration (10mg/L). Reactive oxygen species scavengers decreased the removal efficiency of the PhP. The treatment process followed pseudo-first order kinetic and seven degradation intermediates were identified by the GC-MS technique. Copyright © 2016 Elsevier B.V. All rights reserved.

DFT studies on the multi-channel reaction of CH3S+NO2

NASA Astrophysics Data System (ADS)

Tang, Yi-Zhen; Sun, Hao; Pan, Ya-Ru; Pan, Xiu-Mei; Wang, Rong-Shun

The mechanisms for the reaction of CH3S with NO2 are investigated at the QCISD(T)/6-311++G(d,p)//B3LYP/6-311++G(d,p) on both single and triple potential energy surfaces (PESs). The geometries, vibrational frequencies, and zero-point energy (ZPE) correction of all stationary points involved in the title reaction are calculated at the B3LYP/6-311++G(d,p) level. More accurate energies are obtained at the QCISD(T)/6-311++G(d,p). The results show that 5 intermediates and 14 transition states are found. The reaction is more predominant on the single PES, while it is negligible on the triple PES. Without any barrier height for the whole process, the main channel of the reaction is to form CH3SONO and then dissociate to CH3SO+NO.

The Role of Ultrasound on Advanced Oxidation Processes.

PubMed

Babu, Sundaram Ganesh; Ashokkumar, Muthupandian; Neppolian, Bernaurdshaw

2016-10-01

This chapter describes the use of ultrasound in remediation of wastewater contaminated with organic pollutants in the absence and presence of other advanced oxidation processes (AOPs) such as sonolysis, sono-ozone process, sonophotocatalysis, sonoFenton systems and sonophoto-Fenton methods in detail. All these methods are explained with the suitable literature illustrations. In most of the cases, hybrid AOPs (combination of ultrasound with one or more AOPs) resulted in superior efficacy to that of individual AOP. The advantageous effects such as additive and synergistic effects obtained by operating the hybrid AOPs are highlighted with appropriate examples. It is worth to mention here that the utilization of ultrasound is not only restricted in preparation of modern active catalysts but also extensively used for the wastewater treatment. Interestingly, ultrasound coupled AOPs are operationally simple, efficient, and environmentally benign, and can be readily applied for large scale industrial processes which make them economically viable.

Human Infant Memory B Cell and CD4+ T Cell Responses to HibMenCY-TT Glyco-Conjugate Vaccine

PubMed Central

Fuery, Angela; Richmond, Peter C.; Currie, Andrew J.

2015-01-01

Carrier-specific T cell and polysaccharide-specific B cell memory responses are not well characterised in infants following glyco-conjugate vaccination. We aimed to determine if the number of Meningococcal (Men) C- and Y- specific memory B cells and; number and quality of Tetanus Toxoid (TT) carrier-specific memory CD4+ T cells are associated with polysaccharide-specific IgG post HibMenCY-TT vaccination. Healthy infants received HibMenCY-TT vaccine at 2, 4 and 6 months with a booster at 12 months. Peripheral blood mononuclear cells were isolated and polysaccharide-specific memory B cells enumerated using ELISpot. TT-specific memory CD4+ T cells were detected and phenotyped based on CD154 expression and intracellular TNF-α, IL-2 and IFN-γ expression following stimulation. Functional polysaccharide-specific IgG titres were measured using the serum bactericidal activity (SBA) assay. Polysaccharide-specific Men C- but not Men Y- specific memory B cell frequencies pre-boost (12 months) were significantly associated with post-boost (13 months) SBA titres. Regression analysis showed no association between memory B cell frequencies post-priming (at 6 or 7 months) and SBA at 12 months or 13 months. TT-specific CD4+ T cells were detected at frequencies between 0.001 and 0.112 as a percentage of CD3+ T cells, but their numbers were not associated with SBA titres. There were significant negative associations between SBA titres at M13 and cytokine expression at M7 and M12. Conclusion: Induction of persistent polysaccharide-specific memory B cells prior to boosting is an important determinant of secondary IgG responses in infants. However, polysaccharide-specific functional IgG responses appear to be independent of the number and quality of circulating carrier-specific CD4+ T cells after priming. PMID:26191794

Different Dynamics for IgG and IgA Memory B Cells in Adolescents following a Meningococcal Serogroup C Tetanus Toxoid Conjugate Booster Vaccination Nine Years after Priming: A Role for Priming Age?

PubMed Central

Stoof, Susanne P.; Buisman, Anne-Marie; van Rooijen, Debbie M.; Boonacker, Rianne; van der Klis, Fiona R. M.; Sanders, Elisabeth A. M.; Berbers, Guy A. M.

2015-01-01

Background Antibody levels wane rapidly after Meningococcal serogroup C conjugate (MenCC) vaccination in young children, rendering the need for an adolescent booster dose. It is not clear whether circulating memory B cells are associated with persistence of MenC-specific antibody levels. Methods Measurement of MenC-specific IgG and IgA memory B cells and levels of serum and salivary MenC-specific IgG and IgA in healthy 10-, 12- and 15-year-olds prior to and one month and one year after a MenCC booster vaccination. All participants had received a primary MenCC vaccination nine years earlier. Results The number of circulating MenC-specific IgG memory B cells prior to booster was low and not predictive for MenC-specific IgG responses in serum or saliva post-booster, whereas the number of MenC-specific IgA memory B cells pre-booster positively correlated with MenC-specific IgA levels in saliva post-booster (R = 0.5, P<0.05). The booster induced a clear increase in the number of MenC-specific IgG and IgA memory B cells. The number of MenC-PS-specific IgG memory B cells at 1 month post-booster was highest in the 12-year-olds. The number of MenC-specific memory B cells at one month post-booster showed no correlation with the rate of MenC-specific antibody decay throughout the first year post-booster. Conclusions Circulating MenC-specific IgA memory B cells correlate with IgA responses in saliva, whereas circulating MenC-specific IgG memory B cells are not predictive for MenC-specific IgG responses in serum or saliva. Our results are suggestive for age-dependent differences in pre-existing memory against MenC. PMID:26458006

Different Dynamics for IgG and IgA Memory B Cells in Adolescents following a Meningococcal Serogroup C Tetanus Toxoid Conjugate Booster Vaccination Nine Years after Priming: A Role for Priming Age?

PubMed

Stoof, Susanne P; Buisman, Anne-Marie; van Rooijen, Debbie M; Boonacker, Rianne; van der Klis, Fiona R M; Sanders, Elisabeth A M; Berbers, Guy A M

2015-01-01

Antibody levels wane rapidly after Meningococcal serogroup C conjugate (MenCC) vaccination in young children, rendering the need for an adolescent booster dose. It is not clear whether circulating memory B cells are associated with persistence of MenC-specific antibody levels. Measurement of MenC-specific IgG and IgA memory B cells and levels of serum and salivary MenC-specific IgG and IgA in healthy 10-, 12- and 15-year-olds prior to and one month and one year after a MenCC booster vaccination. All participants had received a primary MenCC vaccination nine years earlier. The number of circulating MenC-specific IgG memory B cells prior to booster was low and not predictive for MenC-specific IgG responses in serum or saliva post-booster, whereas the number of MenC-specific IgA memory B cells pre-booster positively correlated with MenC-specific IgA levels in saliva post-booster (R = 0.5, P<0.05). The booster induced a clear increase in the number of MenC-specific IgG and IgA memory B cells. The number of MenC-PS-specific IgG memory B cells at 1 month post-booster was highest in the 12-year-olds. The number of MenC-specific memory B cells at one month post-booster showed no correlation with the rate of MenC-specific antibody decay throughout the first year post-booster. Circulating MenC-specific IgA memory B cells correlate with IgA responses in saliva, whereas circulating MenC-specific IgG memory B cells are not predictive for MenC-specific IgG responses in serum or saliva. Our results are suggestive for age-dependent differences in pre-existing memory against MenC.

Histone acetylation is associated with differential gene expression in the rapid and robust memory CD8+ T-cell response

PubMed Central

Fann, Monchou; Godlove, Jason M.; Catalfamo, Marta; Wood, William H.; Chrest, Francis J.; Chun, Nicholas; Granger, Larry; Wersto, Robert; Madara, Karen; Becker, Kevin; Henkart, Pierre A.; Weng, Nan-ping

2006-01-01

To understand the molecular basis for the rapid and robust memory T-cell responses, we examined gene expression and chromatin modification by histone H3 lysine 9 (H3K9) acetylation in resting and activated human naive and memory CD8+ T cells. We found that, although overall gene expression patterns were similar, a number of genes are differentially expressed in either memory or naive cells in their resting and activated states. To further elucidate the basis for differential gene expression, we assessed the role of histone H3K9 acetylation in differential gene expression. Strikingly, higher H3K9 acetylation levels were detected in resting memory cells, prior to their activation, for those genes that were differentially expressed following activation, indicating that hyperacetylation of histone H3K9 may play a role in selective and rapid gene expression of memory CD8+ T cells. Consistent with this model, we showed that inducing high levels of H3K9 acetylation resulted in an increased expression in naive cells of those genes that are normally expressed differentially in memory cells. Together, these findings suggest that differential gene expression mediated at least in part by histone H3K9 hyperacetylation may be responsible for the rapid and robust memory CD8+ T-cell response. PMID:16868257

Primary Sjögren's syndrome is characterized by distinct phenotypic and transcriptional profiles of IgD+ unswitched memory B cells.

PubMed

Roberts, Mustimbo E P; Kaminski, Denise; Jenks, Scott A; Maguire, Craig; Ching, Kathryn; Burbelo, Peter D; Iadarola, Michael J; Rosenberg, Alexander; Coca, Andreea; Anolik, Jennifer; Sanz, Iñaki

2014-09-01

The significance of distinct B cell abnormalities in primary Sjögren's syndrome (SS) remains to be established. We undertook this study to analyze the phenotype and messenger RNA (mRNA) transcript profiles of B cell subsets in patients with primary SS and to compare them with those in sicca syndrome patients and healthy controls. CD19+ B cells from 26 patients with primary SS, 27 sicca syndrome patients, and 22 healthy controls were analyzed by flow cytometry. Gene expression profiles of purified B cell subsets (from 3-5 subjects per group per test) were analyzed using Affymetrix gene arrays. Patients with primary SS had lower frequencies of CD27+IgD- switched memory B cells and CD27+IgD+ unswitched memory B cells compared with healthy controls. Unswitched memory B cell frequencies were also lower in sicca syndrome patients and correlated inversely with serologic hyperactivity in both disease states. Further, unswitched memory B cells in primary SS had lower expression of CD1c and CD21. Gene expression analysis of CD27+ memory B cells separated patients with primary SS from healthy controls and identified a subgroup of sicca syndrome patients with a primary SS-like transcript profile. Moreover, unswitched memory B cell gene expression analysis identified 187 genes differentially expressed between patients with primary SS and healthy controls. A decrease in unswitched memory B cells with serologic hyperactivity is characteristic of both established primary SS and a subgroup of sicca syndrome, which suggests the value of these B cells both as biomarkers of future disease progression and for understanding disease pathogenesis. Overall, the mRNA transcript analysis of unswitched memory B cells suggests that their activation in primary SS takes place through innate immune pathways in the context of attenuated antigen-mediated adaptive signaling. Thus, our findings provide important insight into the mechanisms and potential consequences of decreased unswitched memory B cells in primary SS. Copyright © 2014 by the American College of Rheumatology.

Persistence of memory B-cell and T-cell responses to the quadrivalent HPV vaccine in HIV-infected children.

PubMed

Weinberg, Adriana; Huang, Sharon; Moscicki, Anna-Barbara; Saah, Afred; Levin, Myron J

2018-04-24

To determine the magnitude and persistence of quadrivalent human papillomavirus (HPV)16 and HPV18 B-cell and T-cell memory after three or four doses of quadrivalent HPV vaccine (QHPV) in HIV-infected children. Seventy-four HIV-infected children immunized with four doses and 23 with three doses of QHPV had HPV16 and HPV18 IgG B-cell and IFNγ and IL2 T-cell ELISPOT performed at 2, 3.5 and 4-5 years after the last dose. HPV16 and HPV18 T-cell responses were similar in both treatment groups, with higher responses to HPV16 vs. HPV18. These HPV T-cell responses correlated with HIV disease characteristics at the study visits. Global T-cell function declined over time as measured by nonspecific mitogenic stimulation. B-cell memory was similar across treatment groups and HPV genotypes. There was a decline in HPV-specific B-cell memory over time that reached statistical significance for HPV16 in the four-dose group. B-cell and T-cell memory did not significantly differ after either three or four doses of QHPV in HIV-infected children. The clinical consequences of decreasing global T-cell function and HPV B-cell memory over time in HIV-infected children requires further investigation.

Real-time tracking of cell cycle progression during CD8+ effector and memory T-cell differentiation

PubMed Central

Kinjyo, Ichiko; Qin, Jim; Tan, Sioh-Yang; Wellard, Cameron J.; Mrass, Paulus; Ritchie, William; Doi, Atsushi; Cavanagh, Lois L.; Tomura, Michio; Sakaue-Sawano, Asako; Kanagawa, Osami; Miyawaki, Atsushi; Hodgkin, Philip D.; Weninger, Wolfgang

2015-01-01

The precise pathways of memory T-cell differentiation are incompletely understood. Here we exploit transgenic mice expressing fluorescent cell cycle indicators to longitudinally track the division dynamics of individual CD8+ T cells. During influenza virus infection in vivo, naive T cells enter a CD62Lintermediate state of fast proliferation, which continues for at least nine generations. At the peak of the anti-viral immune response, a subpopulation of these cells markedly reduces their cycling speed and acquires a CD62Lhi central memory cell phenotype. Construction of T-cell family division trees in vitro reveals two patterns of proliferation dynamics. While cells initially divide rapidly with moderate stochastic variations of cycling times after each generation, a slow-cycling subpopulation displaying a CD62Lhi memory phenotype appears after eight divisions. Phenotype and cell cycle duration are inherited by the progeny of slow cyclers. We propose that memory precursors cell-intrinsically modulate their proliferative activity to diversify differentiation pathways. PMID:25709008

Real-time tracking of cell cycle progression during CD8+ effector and memory T-cell differentiation.

PubMed

Kinjyo, Ichiko; Qin, Jim; Tan, Sioh-Yang; Wellard, Cameron J; Mrass, Paulus; Ritchie, William; Doi, Atsushi; Cavanagh, Lois L; Tomura, Michio; Sakaue-Sawano, Asako; Kanagawa, Osami; Miyawaki, Atsushi; Hodgkin, Philip D; Weninger, Wolfgang

2015-02-24

The precise pathways of memory T-cell differentiation are incompletely understood. Here we exploit transgenic mice expressing fluorescent cell cycle indicators to longitudinally track the division dynamics of individual CD8(+) T cells. During influenza virus infection in vivo, naive T cells enter a CD62L(intermediate) state of fast proliferation, which continues for at least nine generations. At the peak of the anti-viral immune response, a subpopulation of these cells markedly reduces their cycling speed and acquires a CD62L(hi) central memory cell phenotype. Construction of T-cell family division trees in vitro reveals two patterns of proliferation dynamics. While cells initially divide rapidly with moderate stochastic variations of cycling times after each generation, a slow-cycling subpopulation displaying a CD62L(hi) memory phenotype appears after eight divisions. Phenotype and cell cycle duration are inherited by the progeny of slow cyclers. We propose that memory precursors cell-intrinsically modulate their proliferative activity to diversify differentiation pathways.

Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates.

PubMed

Poirier, Nicolas; Chevalier, Melanie; Mary, Caroline; Hervouet, Jeremy; Minault, David; Baker, Paul; Ville, Simon; Le Bas-Bernardet, Stephanie; Dilek, Nahzli; Belarif, Lyssia; Cassagnau, Elisabeth; Scobie, Linda; Blancho, Gilles; Vanhove, Bernard

2016-01-01

Novel therapies that specifically target activation and expansion of pathogenic immune cell subsets responsible for autoimmune attacks are needed to confer long-term remission. Pathogenic cells in autoimmunity include memory T lymphocytes that are long-lived and present rapid recall effector functions with reduced activation requirements. Whereas the CD28 costimulation pathway predominantly controls priming of naive T cells and hence generation of adaptive memory cells, the roles of CD28 costimulation on established memory T lymphocytes and the recall of memory responses remain controversial. In contrast to CD80/86 antagonists (CTLA4-Ig), selective CD28 antagonists blunt T cell costimulation while sparing CTLA-4 and PD-L1-dependent coinhibitory signals. Using a new selective CD28 antagonist, we showed that Ag-specific reactivation of human memory T lymphocytes was prevented. Selective CD28 blockade controlled both cellular and humoral memory recall in nonhuman primates and induced long-term Ag-specific unresponsiveness in a memory T cell-mediated inflammatory skin model. No modification of memory T lymphocytes subsets or numbers was observed in the periphery, and importantly no significant reactivation of quiescent viruses was noticed. These findings indicate that pathogenic memory T cell responses are controlled by both CD28 and CTLA-4/PD-L1 cosignals in vivo and that selectively targeting CD28 would help to promote remission of autoimmune diseases and control chronic inflammation. Copyright © 2015 by The American Association of Immunologists, Inc.

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity.

PubMed

Nakayama, Yumi; Kosek, Jolanta; Capone, Lori; Hur, Eun Mi; Schafer, Peter H; Ringheim, Garth E

2017-10-01

BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27 + memory and memory-like CD27 - IgD - double-negative (DN) B cells, but not CD27 - IgD + naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27 + memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines. Copyright © 2017 by The American Association of Immunologists, Inc.

The Respiratory Environment Diverts the Development of Antiviral Memory CD8 T Cells.

PubMed

Shane, Hillary L; Reagin, Katie L; Klonowski, Kimberly D

2018-06-01

Our understanding of memory CD8 + T cells has been largely derived from acute, systemic infection models. However, memory CD8 + T cells generated from mucosal infection exhibit unique properties and, following respiratory infection, are not maintained in the lung long term. To better understand how infection route modifies memory differentiation, we compared murine CD8 + T cell responses to a vesicular stomatitis virus (VSV) challenge generated intranasally (i.n.) or i.v. The i.n. infection resulted in greater peak expansion of VSV-specific CD8 + T cells. However, this numerical advantage was rapidly lost during the contraction phase of the immune response, resulting in memory CD8 + T cell numerical deficiencies when compared with i.v. infection. Interestingly, the antiviral CD8 + T cells generated in response to i.n. VSV exhibited a biased and sustained proportion of early effector cells (CD127 lo KLRG1 lo ) akin to the developmental program favored after i.n. influenza infection, suggesting that respiratory infection broadly favors an incomplete memory differentiation program. Correspondingly, i.n. VSV infection resulted in lower CD122 expression and eomesodermin levels by VSV-specific CD8 + T cells, further indicative of an inferior transition to bona fide memory. These results may be due to distinct (CD103 + CD11b + ) dendritic cell subsets in the i.n. versus i.v. T cell priming environments, which express molecules that regulate T cell signaling and the balance between tolerance and immunity. Therefore, we propose that distinct immunization routes modulate both the quality and quantity of antiviral effector and memory CD8 + T cells in response to an identical pathogen and should be considered in CD8 + T cell-based vaccine design. Copyright © 2018 by The American Association of Immunologists, Inc.

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

PubMed Central

Nakayama, Yumi; Kosek, Jolanta; Capone, Lori; Schafer, Peter H.

2017-01-01

BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines. PMID:28848067

B-cell activation with CD40L or CpG measures the function of B-cell subsets and identifies specific defects in immunodeficient patients.

PubMed

Marasco, Emiliano; Farroni, Chiara; Cascioli, Simona; Marcellini, Valentina; Scarsella, Marco; Giorda, Ezio; Piano Mortari, Eva; Leonardi, Lucia; Scarselli, Alessia; Valentini, Diletta; Cancrini, Caterina; Duse, Marzia; Grimsholm, Ola; Carsetti, Rita

2017-01-01

Around 65% of primary immunodeficiencies are antibody deficiencies. Functional tests are useful tools to study B-cell functions in vitro. However, no accepted guidelines for performing and evaluating functional tests have been issued yet. Here, we report our experience on the study of B-cell functions in infancy and throughout childhood. We show that T-independent stimulation with CpG measures proliferation and differentiation potential of memory B cells. Switched memory B cells respond better than IgM memory B cells. On the other hand, CD40L, a T-dependent stimulus, does not induce plasma cell differentiation, but causes proliferation of naïve and memory B cells. During childhood, the production of plasmablasts in response to CpG increases with age mirroring the development of memory B cells. The response to CD40L does not change with age. In patients with selective IgA deficiency (SIgAD), we observed that switched memory B cells are reduced due to the absence of IgA memory B cells. In agreement, IgA plasma cells are not generated in response to CpG. Unexpectedly, B cells from SIgAD patients show a reduced proliferative response to CD40L. Our results demonstrate that functional tests are an important tool to assess the functions of the humoral immune system. © 2016 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Novel Metal-Ferroelectric-Semiconductor Field-Effect Transistor Memory Cell Design

NASA Technical Reports Server (NTRS)

Phillips, Thomas A.; Bailey, Mark; Ho, Fat Duen

2004-01-01

The use of a Metal-Ferroelectric-Semiconductor Field-Effect Transistor (MFSFET) in a resistive-load SRAM memory cell has been investigated A typical two-transistor resistive-load SRAM memory cell architecture is modified by replacing one of the NMOS transistors with an n-channel MFSFET. The gate of the MFSFET is connected to a polling voltage pulse instead of the other NMOS transistor drain. The polling voltage pulses are of sufficient magnitude to saturate the ferroelectric gate material and force the MFSFET into a particular logic state. The memory cell circuit is further modified by the addition of a PMOS transistor and a load resistor in order to improve the retention characteristics of the memory cell. The retention characteristics of both the "1" and "0" logic states are simulated. The simulations show that the MFSFET memory cell design can maintain both the "1" and "0" logic states for a long period of time.

Telomere length dynamics in human memory T cells specific for viruses causing acute or latent infections

PubMed Central

2013-01-01

Background Declining telomere length (TL) is associated with T cell senescence. While TL in naïve and memory T cells declines with increasing age, there is limited data on TL dynamics in virus-specific memory CD4+ T cells in healthy adults. We combined BrdU-labeling of virus-stimulated T cells followed with flow cytometry-fluorescent in situ hybridization for TL determination. We analyzed TL in T cells specific for several virus infections: non-recurring acute (vaccinia virus, VACV), recurring-acute (influenza A virus, IAV), and reactivating viruses (varicella-zoster virus, VZV, and cytomegalovirus, CMV) in 10 healthy subjects. Additionally, five subjects provided multiple blood samples separated by up to 10 years. Results VACV- and CMV-specific T cells had longer average TL than IAV-specific CD4+ T cells. Although most virus-specific cells were CD45RA-, we observed a minor population of BrdU+ CD45RA+ T cells characterized by long telomeres. Longitudinal analysis demonstrated a slow decline in average TL in virus-specific T cells. However, in one subject, VZV reactivation led to an increase in average TL in VZV-specific memory T cells, suggesting a conversion of longer TL cells from the naïve T cell repertoire. Conclusions TLs in memory CD4+ T cells in otherwise healthy adults are heterogeneous and follow distinct virus-specific kinetics. These findings suggests that the distribution of TL and the creation and maintenance of long TL memory T cells could be important for the persistence of long-lived T cell memory. PMID:23971624

Telomere length dynamics in human memory T cells specific for viruses causing acute or latent infections.

PubMed

O'Bryan, Joel M; Woda, Marcia; Co, Mary; Mathew, Anuja; Rothman, Alan L

2013-08-26

Declining telomere length (TL) is associated with T cell senescence. While TL in naïve and memory T cells declines with increasing age, there is limited data on TL dynamics in virus-specific memory CD4+ T cells in healthy adults. We combined BrdU-labeling of virus-stimulated T cells followed with flow cytometry-fluorescent in situ hybridization for TL determination. We analyzed TL in T cells specific for several virus infections: non-recurring acute (vaccinia virus, VACV), recurring-acute (influenza A virus, IAV), and reactivating viruses (varicella-zoster virus, VZV, and cytomegalovirus, CMV) in 10 healthy subjects. Additionally, five subjects provided multiple blood samples separated by up to 10 years. VACV- and CMV-specific T cells had longer average TL than IAV-specific CD4+ T cells. Although most virus-specific cells were CD45RA-, we observed a minor population of BrdU+ CD45RA+ T cells characterized by long telomeres. Longitudinal analysis demonstrated a slow decline in average TL in virus-specific T cells. However, in one subject, VZV reactivation led to an increase in average TL in VZV-specific memory T cells, suggesting a conversion of longer TL cells from the naïve T cell repertoire. TLs in memory CD4+ T cells in otherwise healthy adults are heterogeneous and follow distinct virus-specific kinetics. These findings suggests that the distribution of TL and the creation and maintenance of long TL memory T cells could be important for the persistence of long-lived T cell memory.

Simian immunodeficiency virus infection induces severe loss of intestinal central memory T cells which impairs CD4+ T-cell restoration during antiretroviral therapy.

PubMed

Verhoeven, D; Sankaran, S; Dandekar, S

2007-08-01

Simian immunodeficiency virus (SIV) infection leads to severe loss of intestinal CD4(+) T cells and, as compared to peripheral blood, restoration of these cells is slow during antiretroviral therapy (ART). Mechanisms for this delay have not been examined in context of which specific CD4(+) memory subsets or lost and fail to regenerate during ART. Fifteen rhesus macaques were infected with SIV, five of which received ART (FTC/PMPA) for 30 weeks. Viral loads were measured by real-time PCR. Flow cytometric analysis determined changes in T-cell subsets and their proliferative state. Changes in proliferative CD4(+) memory subsets during infection accelerated their depletion. This reduced the central memory CD4(+) T-cell pool and contributed to slow CD4(+) T-cell restoration during ART. There was a lack of restoration of the CD4(+) central memory and effector memory T-cell subsets in gut-associated lymphoid tissue during ART, which may contribute to the altered intestinal T-cell homeostasis in SIV infection.

Autoreactive Memory CD4+ T Lymphocytes that mediate Chronic Uveitis Reside in the Bone Marrow through STAT3-dependent Mechanisms

PubMed Central

Oh, Hyun-Mee; Yu, Cheng-Rong; Lee, YongJun; Chan, Chi-Chao; Maminishkis, Arvydas; Egwuagu, Charles E.

2011-01-01

Organ-specific autoimmune diseases are usually characterized by repeated cycles of remission and recurrent inflammation. However, where the autoreactive memory T-cells reside in-between episodes of recurrent inflammation is largely unknown. In this study, we have established a mouse model of chronic uveitis characterized by progressive photoreceptor-cell loss, retinal-degeneration, focal retinitis, retinal vasculitis, multifocal-choroiditis and choroidal neovascularization, providing for the first time a useful model for studying long-term pathological consequences of chronic inflammation of the neuroretina. We show that several months after inception of acute uveitis that autoreactive memory T-cells specific to retinal autoantigen, IRBP, relocated to bone marrow (BM). The IRBP-specific memory T-cells (IL-7RαHiLy6CHiCD4+) resided in BM in resting state but upon re-stimulation converted to IL-17-/IFN-γ-expressing effectors (IL-7RαLowLy6CLowCD4+) that mediated uveitis. We further show that T-cells from STAT3-deficient (CD4-STAT3KO) mice are defective in α4β1 and osteopontin expression; defects that correlated with inability of IRBP-specific memory CD4-STAT3KO T-cells to traffic into BM. We adoptively transferred uveitis to naïve mice using BM cells from WT mice with chronic uveitis but not BM cells from CD4-STAT3KO, providing direct evidence that memory T-cells that mediate uveitis reside in BM and that STAT3-dependent mechanism may be required for migration into and retention of memory T-cells in BM. Identifying BM as survival-niche for T-cells that cause uveitis, suggests that BM stromal cells that provide survival signals to autoreactive memory T-cells and STAT3-dependent mechanisms that mediate their relocation into BM, are attractive therapeutic targets that can be exploited to selectively deplete memory T-cells that drive chronic inflammation. PMID:21832158

Sinoporphyrin sodium triggered sono-photodynamic effects on breast cancer both in vitro and in vivo.

PubMed

Liu, Yichen; Wang, Pan; Liu, Quanhong; Wang, Xiaobing

2016-07-01

Sono-photodynamic therapy (SPDT) is a promising anti-cancer strategy. Briefly, SPDT combines ultrasound and light to activate sensitizers that produce mechanical, sonochemical and photochemical activities. Sinoporphyrin sodium (DVDMS) is a newly identified sensitizer that shows great potential in both sonodynamic therapy (SDT) and photodynamic therapy (PDT). In this study, we primarily evaluated the combined effects of SDT and PDT by using DVDMS on breast cancer both in vitro and in vivo. In vitro, DVDMS-SPDT elicits much serious cytotoxicity compared with either SDT or PDT alone by MTT and colony formation assays. 2',7'-Dichlorodihydrofluo-rescein-diacetate (DCFH-DA) and dihydroethidium (DHE) staining revealed that intracellular reactive oxygen species (ROS) were significantly increased in groups given combined therapy. Terephthalic acid (TA) method and FD500-uptake assay reflected that cavitational effects and cell membrane permeability changes after ultrasound irradiation were also involved in the enhancement of combination therapy. In vivo, DVDMS-SPDT markedly inhibits the tumor volume and tumor weight growth. Hematoxylin-eosin staining and immunohistochemistry analysis show DVDMS-SPDT greatly suppressed tumor proliferation. Further, DVDMS-SPDT significantly inhibits tumor lung metastasis in the highly metastatic 4T1 mouse xenograft model, which is consistent well with the in vitro findings evaluated by transwell assay. Moreover, DVDMS-SPDT did not produces obvious effect on body weight and major organs in 4T1 xenograft model. The results suggest that by combination SDT and PDT, the sensitizer DVDMS would produce much better therapeutic effects, and DVDMS-SPDT may be a potential strategy against highly metastatic breast cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

Heterogeneous sono-Fenton-like process using martite nanocatalyst prepared by high energy planetary ball milling for treatment of a textile dye.

PubMed

Dindarsafa, Mahsa; Khataee, Alireza; Kaymak, Baris; Vahid, Behrouz; Karimi, Atefeh; Rahmani, Amir

2017-01-01

High energy planetary ball milling was applied to prepare sono-Fenton nanocatalyst from natural martite (NM). The NM samples were milled for 2-6h at the speed of 320rpm for production of various ball milled martite (BMM) samples. The catalytic performance of the BMMs was greater than the NM for treatment of Acid Blue 92 (AB92) in heterogeneous sono-Fenton-like process. The NM and the BMM samples were characterized by XRD, FT-IR, SEM, EDX and BET analyses. The particle size distribution of the 6h-milled martite (BMM 3 ) was in the range of 10-90nm, which had the highest surface area compared to the other samples. Then, the impact of main operational parameters was investigated on the process. Complete removal of the dye was obtained at the desired conditions including initial pH 7, 2.5g/L BMM 3 dosage, 10mg/L AB92 concentration, and 150W ultrasonic power after 30min of treatment. The treatment process followed pseudo-first order kinetic. Environmentally-friendly modification of the NM, low leached iron amount and repeated application at milder pH were the significant benefits of the BMM 3 . The GC-MS was successfully used to identify the generated intermediates. Eventually, an artificial neural network (ANN) was applied to predict the AB92 removal efficiency based upon the experimental data with a proper correlation coefficient (R 2 =0.9836). Copyright © 2016 Elsevier B.V. All rights reserved.

Arsenic removal with composite iron matrix filters in Bangladesh: a field and laboratory study.

PubMed

Neumann, Anke; Kaegi, Ralf; Voegelin, Andreas; Hussam, Abul; Munir, Abul K M; Hug, Stephan J

2013-05-07

The main arsenic mitigation measures in Bangladesh, well-switching and deep tube wells, have reduced As exposure, but water treatment is important where As-free water is not available. Zero-valent iron (ZVI) based SONO household filters, developed in Bangladesh, remove As by corrosion of locally available inexpensive surplus iron and sand filtration in two buckets. We investigated As removal in SONO filters in the field and laboratory, covering a range of typical groundwater concentrations (in mg/L) of As (0.14-0.96), Fe (0-17), P (0-4.4), Ca (45-162), and Mn (0-2.8). Depending on influent Fe(II) concentrations, 20-80% As was removed in the top sand layer, but As removal to safe levels occurred in the ZVI-layer of the first bucket. Residual As, Fe, and Mn were removed after re-aeration in the sand of the second bucket. New and over 8-year-old filters removed As to <50 μg/L and mostly to <10 μg/L and Mn to <0.2 mg/L. Vertical concentration profiles revealed formation of Fe(II) by corrosion of Fe(0) with O2 and incorporation of As into forming amorphous Fe phases in the composite iron matrix (CIM) of newer filters and predominantly magnetite in older filters. As mass balances indicated that users filtered less than reported volumes of water, pointing to the need for more educational efforts. All tested SONO filters provided safe drinking water without replacement for up to over 8 years of use.

Investigation on the inertial cavitation threshold and shell properties of commercialized ultrasound contrast agent microbubbles.

PubMed

Guo, Xiasheng; Li, Qian; Zhang, Zhe; Zhang, Dong; Tu, Juan

2013-08-01

The inertial cavitation (IC) activity of ultrasound contrast agents (UCAs) plays an important role in the development and improvement of ultrasound diagnostic and therapeutic applications. However, various diagnostic and therapeutic applications have different requirements for IC characteristics. Here through IC dose quantifications based on passive cavitation detection, IC thresholds were measured for two commercialized UCAs, albumin-shelled KangRun(®) and lipid-shelled SonoVue(®) microbubbles, at varied UCA volume concentrations (viz., 0.125 and 0.25 vol. %) and acoustic pulse lengths (viz., 5, 10, 20, 50, and 100 cycles). Shell elastic and viscous coefficients of UCAs were estimated by fitting measured acoustic attenuation spectra with Sarkar's model. The influences of sonication condition (viz., acoustic pulse length) and UCA shell properties on IC threshold were discussed based on numerical simulations. Both experimental measurements and numerical simulations indicate that IC thresholds of UCAs decrease with increasing UCA volume concentration and acoustic pulse length. The shell interfacial tension and dilatational viscosity estimated for SonoVue (0.7 ± 0.11 N/m, 6.5 ± 1.01 × 10(-8) kg/s) are smaller than those of KangRun (1.05 ± 0.18 N/m, 1.66 ± 0.38 × 10(-7) kg/s); this might result in lower IC threshold for SonoVue. The current results will be helpful for selecting and utilizing commercialized UCAs for specific clinical applications, while minimizing undesired IC-induced bioeffects.

Shaping the CD4+ memory immune response against tuberculosis: the role of antigen persistence, location and multi-functionality.

PubMed

Ancelet, Lindsay; Kirman, Joanna

2012-02-01

Abstract Effective vaccination against intracellular pathogens, such as tuberculosis (TB), relies on the generation and maintenance of CD4 memory T cells. An incomplete understanding of the memory immune response has hindered the rational design of a new, more effective TB vaccine. This review discusses how the persistence of antigen, the location of memory cells, and their multifunctional ability shape the CD4 memory T cell response against TB.

Peripheral CD4+ naïve/memory ratio is an independent predictor of survival in non-small cell lung cancer

PubMed Central

Yang, Peng; Ma, Junhong; Yang, Xin; Li, Wei

2017-01-01

Background To investigate the clinical significance of naïve T cells, memory T cells, CD45RA+CD45RO+ T cells, and naïve/memory ratio in non-small cell lung cancer (NSCLC) patients. Methods Pretreatment peripheral blood samples from 76 NSCLC patients and 28 age- and sex-matched healthy volunteers were collected and tested for immune cells by flow cytometry. We compared the expression of these immune cells between patients and healthy controls and evaluated their predictive roles for survival in NSCLC by cox proportional hazards model. Results Decreased naïve CD4+ T cells, naïve CD8+ T cells, CD4+ naïve/memory ratios and CD4+CD45RA+CD45RO+ T cells, and increased memory CD4+ T cells, were observed in 76 NSCLC patients compared to healthy volunteers. Univariate analysis revealed that elevated CD4+ naïve/memory ratio correlated with prolonged progression-free survival (P=0.013). Multivariate analysis confirmed its predictive role with a hazard ratio of 0.35 (95% confidence interval, 0.19-0.75, P=0.012). Conclusions Peripheral CD4+ naïve/memory ratio can be used as a predictive biomarker in NSCLC patients and used to optimize personalized treatment strategies. PMID:29137371

A new model for CD8+ T cell memory inflation based upon a recombinant adenoviral vector1

PubMed Central

Bolinger, Beatrice; Sims, Stuart; O’Hara, Geraldine; de Lara, Catherine; Tchilian, Elma; Firner, Sonja; Engeler, Daniel; Ludewig, Burkhard; Klenerman, Paul

2013-01-01

CD8+ T cell memory inflation, first described in murine cytomegalovirus (MCMV) infection, is characterized by the accumulation of high-frequency, functional antigen-specific CD8+ T cell pools with an effector-memory phenotype and enrichment in peripheral organs. Although persistence of antigen is considered essential, the rules underpinning memory inflation are still unclear. The MCMV model is, however, complicated by the virus’s low-level persistence, and stochastic reactivation. We developed a new model of memory inflation based upon a βgal-recombinant adenovirus vector (Ad-LacZ). After i.v. administration in C57BL/6 mice we observe marked memory inflation in the βgal96 epitope, while a second epitope, βgal497, undergoes classical memory formation. The inflationary T cell responses show kinetics, distribution, phenotype and functions similar to those seen in MCMV and are reproduced using alternative routes of administration. Memory inflation in this model is dependent on MHC Class II. As in MCMV, only the inflating epitope showed immunoproteasome-independence. These data define a new model for memory inflation, which is fully replication-independent, internally controlled and reproduces the key immunologic features of the CD8+ T cell response. This model provides insight into the mechanisms responsible for memory inflation, and since it is based on a vaccine vector, also is relevant to novel T cell-inducing vaccines in humans. PMID:23509359

Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease

PubMed Central

Roy, Dheeraj S.; Arons, Autumn; Mitchell, Teryn I.; Pignatelli, Michele; Ryan, Tomás J.; Tonegawa, Susumu

2016-01-01

Summary Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions1. Memory decline in early stages of Alzheimer’s is mostly limited to episodic memory, for which the hippocampus (HPC) plays a crucial role2. However, it has been uncertain whether the observed amnesia in early stages of Alzheimer’s is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early Alzheimer’s, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are utilized, revealing a retrieval, rather than a storage impairment. Prior to amyloid plaque deposition, the amnesia in these mice is age-dependent3–5, which correlates with a progressive reduction of spine density of hippocampal dentate gyrus (DG) engram cells. We show that optogenetic induction of long-term potentiation (LTP) at perforant path (PP) synapses of DG engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of DG engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in early stages of Alzheimer’s disease. PMID:26982728

IL-15 signaling promotes adoptive effector T-cell survival and memory formation in irradiation-induced lymphopenia.

PubMed

Xu, Aizhang; Bhanumathy, Kalpana Kalyanasundaram; Wu, Jie; Ye, Zhenmin; Freywald, Andrew; Leary, Scot C; Li, Rongxiu; Xiang, Jim

2016-01-01

Lymphopenia promotes naïve T-cell homeostatic proliferation and adoptive effector T-cell survival and memory formation. IL-7 plays a critical role in homeostatic proliferation, survival and memory formation of naïve T-cells in lymphopenia, and its underlying molecular mechanism has also been well studied. However, the mechanism for adoptively transferred effector T-cell survival and memory formation is not fully understood. Here, we transferred in vitro-activated transgenic OT-I CD8(+) effector T-cells into irradiation (600 rads)-induced lymphopenic C57BL/6, IL-7 knockout (KO) and IL-15 KO mice, and investigated the survival and memory formation of transferred T-cells in lymphopenia. We demonstrate that transferred T-cells prolong their survival and enhance their memory in lymphopenic mice, in a manner that depends on IL-15 signaling, but not IL-7. We determine that in vitro stimulation of naïve or effector T-cells with IL-7 and IL-15 reduces IL-7Rα, and increases and/or maintains IL-15Rβ expression, respectively. Consistent with these findings, the expression of IL-7Rα and IL-15Rβ is down- and up-regulated, respectively, in vivo on transferred T-cells in an early phase post T-cell transfer in lymphopenia. We further show that in vitro IL-15 restimulation-induced memory T-cells (compared to IL-2 restimulation-induced effector T-cells) and in vivo transferred T-cells in irradiated IL-15-sufficient C57BL/6 mice (compared to IL-15-deficient IL-15 KO mice) have increased mitochondrial content, but less NADH and lower mitochondrial potential (ΔΨm), and demonstrate greater phosphorylation of signal transducers and activators of transcription-5 (STAT5) and Unc-51-like kinase-1 (ULK1), and higher expression of B-cell leukemia/lymphoma-2 (Bcl2) and memory-, autophagy- and mitochondrial biogenesis-related molecules. Irradiation-induced lymphopenia promotes effector T-cell survival via IL-15 signaling the STAT5/Bcl2 pathway, enhances T-cell memory formation via IL-15 activation of the forkhead-box family of transcription factor (FOXO)/eomesodermin (Eomes) memory and ULK1/autophagy-related gene-7 (ATG7) autophagy pathways, and via IL-15 activation of the mitochondrial remodeling. Our data thus identify some important targets to consider when designing potent adoptive T-cell immunotherapies of cancer.

Production of IL-10 by CD4+ regulatory T cells during the resolution of infection promotes the maturation of memory CD8+ T cells

PubMed Central

Laidlaw, Brian J; Cui, Weiguo; Amezquita, Robert A; Gray, Simon M; Guan, Tianxia; Lu, Yisi; Kobayashi, Yasushi; Flavell, Richard A; Kleinstein, Steven H; Craft, Joe; Kaech, Susan M

2016-01-01

Memory CD8+ T cells are critical for host defense upon reexposure to intracellular pathogens. We found that interleukin 10 (IL-10) derived from CD4+ regulatory T cells (Treg cells) was necessary for the maturation of memory CD8+ T cells following acute infection with lymphocytic choriomeningitis virus (LCMV). Treg cell–derived IL-10 was most important during the resolution phase, calming inflammation and the activation state of dendritic cells. Adoptive transfer of IL-10-sufficient Treg cells during the resolution phase ‘restored’ the maturation of memory CD8+ T cells in IL-10-deficient mice. Our data indicate that Treg cell–derived IL-10 is needed to insulate CD8+ T cells from inflammatory signals, and reveal that the resolution phase of infection is a critical period that influences the quality and function of developing memory CD8+ T cells. PMID:26147684

A short CD3/CD28 costimulation combined with IL-21 enhance the generation of human memory stem T cells for adoptive immunotherapy.

PubMed

Alvarez-Fernández, C; Escribà-Garcia, L; Vidal, S; Sierra, J; Briones, J

2016-07-19

Immunotherapy based on the adoptive transfer of gene modified T cells is an emerging approach for the induction of tumor-specific immune responses. Memory stem T cells, due to their enhanced antitumor and self-renewal capacity, have become potential candidate for adoptive T cell therapy of cancer. Methods to generate memory stem T cells ex vivo rely on CD3/CD28 costimulation and the use of cytokines such as IL-7 and IL-15 during the entire culture period. However, a strong costimulation may induce differentiation of memory stem T cells to effector memory T cells. Here we show that manipulation of the length of the costimulation and addition of IL-21 enhance the ex vivo expansion of memory stem T cells. Purified naïve T cells from healthy donors were cultured in the presence of anti-CD3/CD28 coated beads, IL-7, IL-15 and/or IL-21 (25 ng/ml). T cells phenotype from the different memory and effector subpopulations were analyzed by multiparametric flow cytometry. A short anti-CD3/CD28 costimulation of naïve T cells, combined with IL-7 and IL-15 significantly increased the frequencies of CD4(+) and CD8(+) memory stem T cells ex vivo, compared to a prolonged costimulation (34.6 ± 4.4 % vs 15.6 ± 4.24 % in CD4(+); p = 0.008, and 20.5 ± 4.00 % vs 7.7 ± 2.53 % in CD8(+); p = 0.02). Moreover, the addition of IL-21 to this condition further enhanced the enrichment and expansion of CD4(+) and CD8(+) memory stem T cells with an increase in the absolute numbers (0.7 × 10(6) ± 0.1 vs 0.26 × 10(6) ± 0.1 cells for CD4(+); p = 0.002 and 1.1 × 10(6) ± 0.1 vs 0.27 × 10(6) ± 0.1 cells for CD8(+); p = 0.0002; short + IL-21 vs long). These new in vitro conditions increase the frequencies and expansion of memory stem T cells and may have relevant clinical implications for the generation of this memory T cell subset for adoptive cell therapy of patients with cancer.

Memory T cells and vaccines.

PubMed

Esser, Mark T; Marchese, Rocio D; Kierstead, Lisa S; Tussey, Lynda G; Wang, Fubao; Chirmule, Narendra; Washabaugh, Michael W

2003-01-17

T lymphocytes play a central role in the generation of a protective immune response in many microbial infections. After immunization, dendritic cells take up microbial antigens and traffic to draining lymph nodes where they present processed antigens to naïve T cells. These naïve T cells are stimulated to proliferate and differentiate into effector and memory T cells. Activated, effector and memory T cells provide B cell help in the lymph nodes and traffic to sites of infection where they secrete anti-microbial cytokines and kill infected cells. At least two types of memory cells have been defined in humans based on their functional and migratory properties. T central-memory (T(CM)) cells are found predominantly in lymphoid organs and can not be immediately activated, whereas T effector-memory (T(EM)) cells are found predominantly in peripheral tissue and sites of inflammation and exhibit rapid effector function. Most currently licensed vaccines induce antibody responses capable of mediating long-term protection against lytic viruses such as influenza and small pox. In contrast, vaccines against chronic pathogens that require cell-mediated immune responses to control, such as malaria, Mycobacterium tuberculosis (TB), human immunodeficiency virus (HIV) and hepatitis C virus (HCV), are currently not available or are ineffective. Understanding the mechanisms by which long-lived cellular immune responses are generated following vaccination should facilitate the development of safe and effective vaccines against these emerging diseases. Here, we review the current literature with respect to memory T cells and their implications to vaccine development.

Differential influence of hippocampal subfields to memory formation: insights from patients with temporal lobe epilepsy.

PubMed

Coras, Roland; Pauli, Elisabeth; Li, Jinmei; Schwarz, Michael; Rössler, Karl; Buchfelder, Michael; Hamer, Hajo; Stefan, Hermann; Blumcke, Ingmar

2014-07-01

To clarify the anatomical organization of human memory remains a major challenge in clinical neuroscience. Experimental data suggest dentate gyrus granule cells play a major role in memory acquisition, i.e. pattern separation and rapid pattern completion, whereas hippocampal CA1 neurons are implicated in place memory and autobiographical memory retrieval. Patients with temporal lobe epilepsy present with a broad spectrum of memory impairment, which can be assessed during clinical examination. Although long seizure histories may contribute to a pathophysiological reorganization of functional connectivity, surgical resection of the epileptic hippocampus offers a unique possibility to anatomically study the differential contribution of hippocampal subfields to compromised learning and memory in humans. Herein, we tested the hypothesis of hippocampal subfield specialization in a series of 100 consecutive patients with temporal lobe epilepsy submitted to epilepsy surgery. Memory profiles were obtained from intracarotid amobarbital testing and non-invasive verbal memory assessment before surgery, and correlated with histopathologically quantified cell loss pattern in hippocampal subfields obtained from the same patients using the new international consensus classification for hippocampal sclerosis proposed by the International League against Epilepsy (HS ILAE). Interestingly, patients with CA1 predominant cell loss (HS ILAE Type 2; n = 13) did not show declarative memory impairment and were indistinguishable from patients without any hippocampal cell loss (n = 19). In contrast, 63 patients with neuronal loss affecting all hippocampal subfields including CA1, CA4 and dentate gyrus (HS ILAE Type 1), or predominant cell loss in CA4 and partially affecting also CA3 and dentate gyrus (HS ILAE Type 3, n = 5) showed significantly reduced declarative memory capacities (intracarotid amobarbital testing: P < 0.001; verbal memory: P < 0.05). Our results suggested an alternative model of how memory processing can be organized amongst hippocampal subfields, and that CA1 pyramidal cells are less critically involved in declarative human memory acquisition compared to dentate gyrus granule cells or CA4/CA3 pyramidal cells. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

gp49B-mediated negative regulation of antibody production by memory and marginal zone B cells.

PubMed

Fukao, Saori; Haniuda, Kei; Nojima, Takuya; Takai, Toshiyuki; Kitamura, Daisuke

2014-07-15

The rapid Ab responses observed after primary and secondary immunizations are mainly derived from marginal zone (MZ) and memory B cells, respectively, but it is largely unknown how these responses are negatively regulated. Several inhibitory receptors have been identified and their roles have been studied, but mainly on follicular B cells and much less so on MZ B, and never on memory B cells. gp49B is an Ig superfamily member that contains two ITIMs in its cytoplasmic tail, and it has been shown to negatively regulate mast cell, macrophage, and NK cell responses. In this study, we demonstrate that gp49B is preferentially expressed on memory and MZ B cells. We show that gp49B(-/-) mice produce more IgM after a primary immunization and more IgM and IgG1 after a secondary immunization than gp49B(+/+) mice in T cell-dependent immune responses. Memory and MZ B cells from gp49B(-/-) mice also produce more Abs upon in vitro stimulation with CD40 than those from gp49B(+/+) mice. The in vitro IgM production by MZ B cells from gp49B(+/+), but not gp49B(-/-), mice is suppressed by interaction with a putative gp49B ligand, the integrin αvβ3 heterodimer. In addition, gp49B(-/-) mice exhibited exaggerated IgE production in the memory recall response. These results suggest that plasma cell development from memory and MZ B cells, as well as subsequent Ab production, are suppressed via gp49B. In memory B cells, this suppression also prevents excessive IgE production, thus curtailing allergic diseases. Copyright © 2014 by The American Association of Immunologists, Inc.

CD4+ T-Cell-Independent Secondary Immune Responses to Pneumocystis Pneumonia

PubMed Central

de la Rua, Nicholas M.; Samuelson, Derrick R.; Charles, Tysheena P.; Welsh, David A.; Shellito, Judd E.

2016-01-01

Pneumocystis pneumonia is a major cause of morbidity and mortality among immunocompromised patients, especially in the context of HIV/AIDS. In the murine model of Pneumocystis pneumonia, CD4+ T-cells are required for clearance of a primary infection of Pneumocystis, but not the memory recall response. We hypothesized that the memory recall response in the absence of CD4+ T-cells is mediated by a robust memory humoral response, CD8+ T-cells, and IgG-mediated phagocytosis by alveolar macrophages. To investigate the role of CD8+ T-cells and alveolar macrophages in the immune memory response to Pneumocystis, mice previously challenged with Pneumocystis were depleted of CD8+ T-cells or alveolar macrophages prior to re-infection. Mice depleted of CD4+ T-cells prior to secondary challenge cleared Pneumocystis infection within 48 h identical to immunocompetent mice during a secondary memory recall response. However, loss of CD8+ T-cells or macrophages prior to the memory recall response significantly impaired Pneumocystis clearance. Specifically, mice depleted of CD8+ T-cells or alveolar macrophages had significantly higher fungal burden in the lungs. Furthermore, loss of alveolar macrophages significantly skewed the lung CD8+ T-cell response toward a terminally differentiated effector memory population and increased the percentage of IFN-γ+ CD8+ T-cells. Finally, Pneumocystis-infected animals produced significantly more bone marrow plasma cells and Pneumocystis-specific IgG significantly increased macrophage-mediated killing of Pneumocystis in vitro. These data suggest that secondary immune memory responses to Pneumocystis are mediated, in part, by CD8+ T-cells, alveolar macrophages, and the production of Pneumocystis-specific IgG. PMID:27242785

Kinetics and clonality of immunological memory in humans.

PubMed

Beverley, Peter C L

2004-10-01

T-cell immunological memory consists largely of clones of proliferating lymphocytes maintained by antigenic stimulation and the survival and proliferative effects of cytokines. The duration of survival of memory clones in humans is determine by the Hayflick limit on the number of cell divisions, the rate of cycling of memory cells and factors that control erosion of telomeres, including mechanisms that control telomerase.

Fucosyltransferase Induction during Influenza Virus Infection Is Required for the Generation of Functional Memory CD4+ T Cells

PubMed Central

Carrette, Florent; Henriquez, Monique L.; Fujita, Yu

2018-01-01

T cells mediating influenza viral control are instructed in lymphoid and nonlymphoid tissues to differentiate into memory T cells that confer protective immunity. The mechanisms by which influenza virus–specific memory CD4+ T cells arise have been attributed to changes in transcription factors, cytokines and cytokine receptors, and metabolic programming. The molecules involved in these biosynthetic pathways, including proteins and lipids, are modified to varying degrees of glycosylation, fucosylation, sialation, and sulfation, which can alter their function. It is currently unknown how the glycome enzymatic machinery regulates CD4+ T cell effector and memory differentiation. In a murine model of influenza virus infection, we found that fucosyltransferase enzymatic activity was induced in effector and memory CD4+ T cells. Using CD4+ T cells deficient in the Fut4/7 enzymes that are expressed only in hematopoietic cells, we found decreased frequencies of effector cells with reduced expression of T-bet and NKG2A/C/E in the lungs during primary infection. Furthermore, Fut4/7−/− effector CD4+ T cells had reduced survival with no difference in proliferation or capacity for effector function. Although Fut4/7−/− CD4+ T cells seeded the memory pool after primary infection, they failed to form tissue-resident cells, were dysfunctional, and were unable to re-expand after secondary infection. Our findings highlight an important regulatory axis mediated by cell-intrinsic fucosyltransferase activity in CD4+ T cell effectors that ensure the development of functional memory CD4+ T cells. PMID:29491007

Tracing Donor-MHC Class II Reactive B cells in Mouse Cardiac Transplantation: Delayed CTLA4-Ig Treatment Prevents Memory Alloreactive B-Cell Generation.

PubMed

Yang, Jinghui; Chen, Jianjun; Young, James S; Wang, Qiang; Yin, Dengping; Sciammas, Roger; Chong, Anita S

2016-08-01

The dual role of B cells as drivers and suppressors of the immune responses have underscored the need to trace the fate of B cells recognizing donor major histocompatibility complex class I and class II after allograft transplantation. In this study, we used donor class II tetramers to trace the fate of I-E-specific B cells after immunization with BALB/c spleen cells or cardiac transplantation, in naive or sensitized C57BL/6 recipients. We combined this approach with genetic lineage tracing of memory B cells in activation-induced cytidine deaminase regulated Cre transgenic mice crossed to the ROSA26-enhanced yellow fluorescent protein reporter mice to track endogenous I-E-specific memory B cell generation. Immunization with BALB/c splenocytes or heart transplantation induced an expansion and differentiation of I-E-specific B cells into germinal center B cells, whereas BALB/c heart transplantation into sensitized recipients induced the preferential differentiation into antibody-secreting cells. A 10.8-fold increase in the frequency of I-E-specific memory B cells was observed by day 42 postimmunization. Treatment with CTLA4-Ig starting on day 0 or day 7 postimmunization abrogated I-E-specific memory B cell generation and sensitized humoral responses, but not if treatment commenced on day 14. The majority of donor-specific memory B cells are generated between days 7 and 14 postimmunization, thus revealing a flexible timeframe whereby delayed CTLA4-Ig administration can inhibit sensitization and the generation of memory graft-reactive B cells.

Application of long-term cultured interferon-gamma enzyme-linked immunospot assay for assessing effector and memory T cell responses in cattle

USDA-ARS?s Scientific Manuscript database

Effector and memory T cells are generated through developmental programing of naïve cells following antigen recognition. If the infection is controlled, up to 95% of the T cells generated during the expansion phase are eliminated (i.e., contraction phase) and memory T cells remain, sometimes for a l...

Th1-like Plasmodium-Specific Memory CD4+ T Cells Support Humoral Immunity.

PubMed

Zander, Ryan A; Vijay, Rahul; Pack, Angela D; Guthmiller, Jenna J; Graham, Amy C; Lindner, Scott E; Vaughan, Ashley M; Kappe, Stefan H I; Butler, Noah S

2017-11-14

Effector T cells exhibiting features of either T helper 1 (Th1) or T follicular helper (Tfh) populations are essential to control experimental Plasmodium infection and are believed to be critical for resistance to clinical malaria. To determine whether Plasmodium-specific Th1- and Tfh-like effector cells generate memory populations that contribute to protection, we developed transgenic parasites that enable high-resolution study of anti-malarial memory CD4 T cells in experimental models. We found that populations of both Th1- and Tfh-like Plasmodium-specific memory CD4 T cells persist. Unexpectedly, Th1-like memory cells exhibit phenotypic and functional features of Tfh cells during recall and provide potent B cell help and protection following transfer, characteristics that are enhanced following ligation of the T cell co-stimulatory receptor OX40. Our findings delineate critical functional attributes of Plasmodium-specific memory CD4 T cells and identify a host-specific factor that can be targeted to improve resolution of acute malaria and provide durable, long-term protection against Plasmodium parasite re-exposure. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Cytokine activation induces human memory-like NK cells.

PubMed

Romee, Rizwan; Schneider, Stephanie E; Leong, Jeffrey W; Chase, Julie M; Keppel, Catherine R; Sullivan, Ryan P; Cooper, Megan A; Fehniger, Todd A

2012-12-06

Natural killer (NK) cells are lymphocytes that play an important role in the immune response to infection and malignancy. Recent studies in mice have shown that stimulation of NK cells with cytokines or in the context of a viral infection results in memory-like properties. We hypothesized that human NK cells exhibit such memory-like properties with an enhanced recall response after cytokine preactivation. In the present study, we show that human NK cells preactivated briefly with cytokine combinations including IL-12, IL-15, and IL-18 followed by a 7- to 21-day rest have enhanced IFN-γ production after restimulation with IL-12 + IL-15, IL-12 + IL-18, or K562 leukemia cells. This memory-like phenotype was retained in proliferating NK cells. In CD56(dim) NK cells, the memory-like IFN-γ response was correlated with the expression of CD94, NKG2A, NKG2C, and CD69 and a lack of CD57 and KIR. Therefore, human NK cells have functional memory-like properties after cytokine activation, which provides a novel rationale for integrating preactivation with combinations of IL-12, IL-15, and IL-18 into NK cell immunotherapy strategies.

Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions.

PubMed

Seifert, Marc; Przekopowitz, Martina; Taudien, Sarah; Lollies, Anna; Ronge, Viola; Drees, Britta; Lindemann, Monika; Hillen, Uwe; Engler, Harald; Singer, Bernhard B; Küppers, Ralf

2015-02-10

The generation and functions of human peripheral blood (PB) IgM(+)IgD(+)CD27(+) B lymphocytes with somatically mutated IgV genes are controversially discussed. We determined their differential gene expression to naive B cells and to IgM-only and IgG(+) memory B cells. This analysis revealed a high similarity of IgM(+)(IgD(+))CD27(+) and IgG(+) memory B cells but also pointed at distinct functional capacities of both subsets. In vitro analyses revealed a tendency of activated IgM(+)IgD(+)CD27(+) B cells to migrate to B-cell follicles and undergo germinal center (GC) B-cell differentiation, whereas activated IgG(+) memory B cells preferentially showed a plasma cell (PC) fate. This observation was supported by reverse regulation of B-cell lymphoma 6 and PR domain containing 1 and differential BTB and CNC homology 1, basic leucine zipper transcription factor 2 expression. Moreover, IgM(+)IgD(+)CD27(+) B lymphocytes preferentially responded to neutrophil-derived cytokines. Costimulation with catecholamines, carcinoembryonic antigen cell adhesion molecule 8 (CEACAM8), and IFN-γ caused differentiation of IgM(+)IgD(+)CD27(+) B cells into PCs, induced class switching to IgG2, and was reproducible in cocultures with neutrophils. In conclusion, this study substantiates memory B-cell characteristics of human IgM(+)IgD(+)CD27(+) B cells in that they share typical memory B-cell transcription patterns with IgG(+) post-GC B cells and show a faster and more vigorous restimulation potential, a hallmark of immune memory. Moreover, this work reveals a functional plasticity of human IgM memory B cells by showing their propensity to undergo secondary GC reactions upon reactivation, but also by their special role in early inflammation via interaction with immunomodulatory neutrophils.

The overall pathological status of the left hippocampus determines preoperative verbal memory performance in left mesial temporal lobe epilepsy.

PubMed

Witt, Juri-Alexander; Coras, Roland; Schramm, Johannes; Becker, Albert J; Elger, Christian E; Blümcke, Ingmar; Helmstaedter, Christoph

2014-04-01

Studies on hippocampal cell loss in epilepsy have produced diverging evidence as to which subfields are specifically related to memory. This may be due to rather small and often heterogeneous samples, or to different memory measures. Therefore, the current study examined hippocampal cell densities and memory in a large sample of patients with solely mesial temporal lobe epilepsy (mTLE), employing measures with proven sensitivity to mesiotemporal pathology. In 104 patients who had undergone epilepsy surgery for mTLE, we evaluated the role of segmental hippocampal cell loss and its underlying factor structure with regard to presurgical verbal and figural memory while controlling for side-of-surgery and hemispheric dominance. First of all, patients showed material-specific memory impairment concordant with the lateralization of epilepsy. Factor analysis of segmental cell loss revealed a single factor reflecting the overall integrity of the hippocampus. The overall pathological status of the left hippocampus correlated with verbal memory parameters (r = 0.33-0.34, P < 0.05), especially when controlling for atypical hemispheric dominance (r = 0.50-0.57, P < 0.01), and explained up to 33% of the observed variance. Further analyses revealed no superior role of a single subfield or cell loss pattern for memory performance. No systematic relations between neuronal cell densities of the right hippocampus and memory function were found, nor did left or right hippocampal pathology explain figural memory parameters. The results suggest that the overall pathological status of the left hippocampus - rather than a specific subfield pathology - is predictive for verbal memory in mTLE. The finding that figural memory parameters, although sensitive to right mTLE, were not related to neuronal cell densities of the right hippocampus, puts the left/right hippocampus verbal/nonverbal memory dichotomy into perspective. Copyright © 2013 Wiley Periodicals, Inc.

Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis

PubMed Central

Perdomo, Carolina; Zedler, Ulrike; Kühl, Anja A.; Lozza, Laura; Saikali, Philippe; Sander, Leif E.; Vogelzang, Alexis; Kupz, Andreas

2016-01-01

ABSTRACT Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (TRM) cells have been implicated in protective immune responses against viral infections, but the role of TRM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and TRM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4+ T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8+ T cells displayed prototypical TRM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies. PMID:27879332

Distinct Effects of Saracatinib on Memory CD8+ T-cell Differentiation

PubMed Central

Takai, Shinji; Sabzevari, Helen; Farsaci, Benedetto; Schlom, Jeffrey; Greiner, John W.

2012-01-01

Immunologic memory involving CD8+ T-cells is a hallmark of an adaptive antigen-specific immune response and comprises a critical component of protective immunity. Designing approaches that enhance long-term T-cell memory would, for the most part, fortify vaccines and enhance host protection against infectious diseases and, perhaps, cancer immunotherapy. A better understanding of the cellular programs involved in the antigen-specific T-cell response has led to new approaches that target the magnitude and quality of the memory T-cell response. Here we show that T-cells from T-cell receptor transgenic mice for the nucleoprotein of influenza virus NP68 exhibit the distinct phases priming, expansion, contraction, memory - of an antigen-specific T-cell response when exposed in vitro to the cognate peptide. Saracatinib, a specific inhibitor of Src family kinases, administered at low doses during the expansion or contraction phases, increased CD62Lhigh/CD44high central memory CD8+ T-cells and IFN-γ production, while suppressing immunity when added during the priming phase. These effects by saracatinib were not accompanied by the expected decline of Src family kinases, but were accompanied by Akt-mTOR suppression and/or mediated via another pathway. Increased central memory cells by saracatinib were recapitulated in mice using a poxvirus-based influenza vaccine, thus underscoring the importance of dose and timing of the inhibitor in the context of memory T-cell differentiation. Finally, vaccine plus saracatinib treatment showed better protection against tumor challenge. The immune-potentiating effects on CD8+ T-cells by a low dose of saracatinib might afford better protection from pathogen or cancer when combined with vaccine. PMID:22450814

Intravaginal infection with herpes simplex virus type-2 (HSV-2) generates a functional effector memory T cell population that persists in the murine genital tract.

PubMed

Tang, Vera A; Rosenthal, Kenneth L

2010-12-01

Although the female genital tract is the main portal of entry for sexually transmitted infections in women, we still have limited understanding of the generation, maintenance and characteristics of memory T cells in the local tissue. Here, we utilized a mouse model of intravaginal HSV-2 infection and tetramers against the immunodominant HSV glycoprotein B epitope recognized by CD8+ T cells to examine the generation, maintenance and characteristics of anti-HSV memory T cells in the genital tract following acute infection. Our results show that the highest percentage of HSVgB-specific CD8+ T cells was found in the genital tract compared to the spleen or iliac lymphnode. Indeed, although the actual number of CD8+ T cells contracted following viral clearance, approximately one quarter of the CD8+ population that remained in the genital tissue was HSVgB-specific. Memory gB-tetramer+CD8 T cells in the genital tract were positive for CD127 and KLRG1 and negative for CD62L and CCR7, thus confirming that HSV-specific CD8 cells were effector memory T cells that lack the capacity for homing to lymphoid tissues. Functionally, both memory CD8+ and CD4+ HSV-specific populations in the genital tract produced IFNγ when stimulated in vitro and CD4+ cells also produced TNFα. Genital HSVgB-specific memory T cells expressed tissue-homing integrins CD103 (αE integrin) and CD49a (VLA-1 or α1 integrin). Our findings suggest that HSV-specific memory T cells are retained in the genital tract, poised to act as an early line of defense against future virus encounter. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Tumor-Targeting Anti-CD20 Antibodies Mediate In Vitro Expansion of Memory Natural Killer Cells: Impact of CD16 Affinity Ligation Conditions and In Vivo Priming.

PubMed

Capuano, Cristina; Battella, Simone; Pighi, Chiara; Franchitti, Lavinia; Turriziani, Ombretta; Morrone, Stefania; Santoni, Angela; Galandrini, Ricciarda; Palmieri, Gabriella

2018-01-01

Natural killer (NK) cells represent a pivotal player of innate anti-tumor immune responses. The impact of environmental factors in shaping the representativity of different NK cell subsets is increasingly appreciated. Human cytomegalovirus (HCMV) infection profoundly affects NK cell compartment, as documented by the presence of a CD94/NKG2C + FcεRIγ - long-lived "memory" NK cell subset, endowed with enhanced CD16-dependent functional capabilities, in a fraction of HCMV-seropositive subjects. However, the requirements for memory NK cell pool establishment/maintenance and activation have not been fully characterized yet. Here, we describe the capability of anti-CD20 tumor-targeting therapeutic monoclonal antibodies (mAbs) to drive the selective in vitro expansion of memory NK cells and we show the impact of donor' HCMV serostatus and CD16 affinity ligation conditions on this event. In vitro expanded memory NK cells maintain the phenotypic and functional signature of their freshly isolated counterpart; furthermore, our data demonstrate that CD16 affinity ligation conditions differently affect memory NK cell proliferation and functional activation, as rituximab-mediated low-affinity ligation represents a superior proliferative stimulus, while high-affinity aggregation mediated by glycoengineered obinutuzumab results in improved multifunctional responses. Our work also expands the molecular and functional characterization of memory NK cells, and investigates the possible impact of CD16 functional allelic variants on their in vivo and in vitro expansions. These results reveal new insights in Ab-driven memory NK cell responses in a therapeutic setting and may ultimately inspire new NK cell-based intervention strategies against cancer, in which the enhanced responsiveness to mAb-bound target could significantly impact therapeutic efficacy.

A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory.

PubMed

Siegel, Andrea M; Heimall, Jennifer; Freeman, Alexandra F; Hsu, Amy P; Brittain, Erica; Brenchley, Jason M; Douek, Daniel C; Fahle, Gary H; Cohen, Jeffrey I; Holland, Steven M; Milner, Joshua D

2011-11-23

STAT3 transcription factor signaling in specific T helper cell differentiation has been well described, although the broader roles for STAT3 in lymphocyte memory are less clear. Patients with autosomal-dominant hyper-IgE syndrome (AD-HIES) carry dominant-negative STAT3 mutations and are susceptible to a variety of bacterial and fungal infections. We found that AD-HIES patients have a cell-intrinsic defect in the number of central memory CD4(+) and CD8(+) T cells compared to healthy controls. Naive T cells from AD-HIES patients had lower expression of memory-related transcription factors BCL6 and SOCS3, a primary proliferation defect, and they failed to acquire central memory-like surface phenotypes in vitro. AD-HIES patients showed a decreased ability to control varicella zoster virus (VZV) and Epstein-Barr virus (EBV) latency, and T cell memory to both of these viruses was compromised. These data point to a specific role for STAT3 in human central memory T cell formation and in control of certain chronic viruses. Copyright © 2011 Elsevier Inc. All rights reserved.

Single-Cell Memory Regulates a Neural Circuit for Sensory Behavior.

PubMed

Kobayashi, Kyogo; Nakano, Shunji; Amano, Mutsuki; Tsuboi, Daisuke; Nishioka, Tomoki; Ikeda, Shingo; Yokoyama, Genta; Kaibuchi, Kozo; Mori, Ikue

2016-01-05

Unveiling the molecular and cellular mechanisms underlying memory has been a challenge for the past few decades. Although synaptic plasticity is proven to be essential for memory formation, the significance of "single-cell memory" still remains elusive. Here, we exploited a primary culture system for the analysis of C. elegans neurons and show that a single thermosensory neuron has an ability to form, retain, and reset a temperature memory. Genetic and proteomic analyses found that the expression of the single-cell memory exhibits inter-individual variability, which is controlled by the evolutionarily conserved CaMKI/IV and Raf pathway. The variable responses of a sensory neuron influenced the neural activity of downstream interneurons, suggesting that modulation of the sensory neurons ultimately determines the behavioral output in C. elegans. Our results provide proof of single-cell memory and suggest that the individual differences in neural responses at the single-cell level can confer individuality. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Association between memory B-cells and clinical and immunological features of primary Sjögren's syndrome and Sicca patients.

PubMed

Barcelos, Filipe; Martins, Catarina; Papoila, Ana; Geraldes, Carlos; Cardigos, Joana; Nunes, Glória; Lopes, Teresa; Alves, Nuno; Vaz-Patto, José; Branco, Jaime; Borrego, Luís-Miguel

2018-06-01

B-cells play a pivotal role in primary Sjögren's syndrome (pSS) pathogenesis. We aim to (1) evaluate the distribution of B-lymphocyte subpopulations in pSS and Sicca patients, (2) establish cut-off points that discriminate pSS from controls, (3) evaluate the association between memory B-cells and phenotypic features in pSS. We included 57 pSS patients, 68 Sicca and 24 healthy controls. Circulating B-cells were characterized by flow cytometry as naïve and memory subsets and classified from Bm1 to Bm5. Compared to controls, pSS patients had lower percentages (29.5 vs 44.4%) and absolute numbers (47 vs 106 cells/µl) of memory B-cells. Through ROC curves, a cut-off of ≤ 58 total memory B-cells/µl yielded a specificity of 0.88 and a sensitivity of 0.60 for pSS, and was met by 59.6% of pSS patients, 38.8% of Sicca and 12.5% of controls. A cut-off of < 23.5 Switched-memory B-cells/µl yielded a specificity of 0.88 and a sensitivity of 0.54 and was met by 54.4% of pSS patients, 37.3% of Sicca and 12.5% of controls. In pSS, lower total memory B-cells count was associated with longer disease duration (14.3 vs 8.1 years, p = 0.006) and more active disease profile, as evaluated by the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) (3.1 vs 1.4, p = 0.043). Decreased numbers of memory B-cells clearly discriminated pSS from controls and can also have prognostic value. It remains to be clarified whether Sicca patients with decreased memory B-cells represent pSS and if B-cell profiling could help in the diagnosis of pSS.

Long-term antibody memory induced by synthetic peptide vaccination is protective against Streptococcus pyogenes infection and is independent of memory T-cell help

PubMed Central

Pandey, Manisha; Wykes, Michelle N; Hartas, Jon; Good, Michael F; Batzloff, Michael R

2013-01-01

Streptococcus pyogenes (group A streptococcus; GAS) is a leading human pathogen associated with a diverse array of mucosal and systemic infections. Vaccination with J8, a conserved region synthetic peptide derived from the M-protein of GAS and containing only 12 amino acids from GAS, when conjugated to DT, has been shown to protect mice against a lethal GAS challenge. Protection has been previously shown to be antibody-mediated. J8 does not contain a dominant GAS-specific T-cell epitope. The current study examined long-term antibody memory and dissected the role of B and T-cells. Our results demonstrated that vaccination generates specific memory B-cells and long-lasting antibody responses. The memory B-cell response can be activated following boost with antigen or limiting numbers of whole bacteria. We further show that these memory responses protect against systemic infection with GAS. T-cell help is required for activation of memory B-cells but can be provided by naïve T-cells responding directly to GAS at the time of infection. Thus, individuals whose T-cells do not recognize the short synthetic peptide in the vaccine will be able to generate a protective and rapid memory antibody response at the time of infection. These studies significantly strengthen previous findings, which showed that protection by the J8-DT vaccine is antibody-mediated and suggest that in vaccine design for other organisms the source of T-cell help for antibody responses need not be limited to sequences from the organism itself. PMID:23401589

Maintenance of memory-type pathogenic Th2 cells in the pathophysiology of chronic airway inflammation.

PubMed

Hirahara, Kiyoshi; Shinoda, Kenta; Endo, Yusuke; Ichikawa, Tomomi; Nakayama, Toshinori

2018-01-01

Immunological memory is critical for long-standing protection against microorganisms; however, certain antigen-specific memory CD4 + T helper (Th) cells drive immune-related pathology, including chronic allergic inflammation such as asthma. The IL-5-producing memory-type Tpath2 subset is important for the pathogenesis of chronic allergic inflammation. This memory-type pathogenic Th2 cell population (Tpath2) can be detected in various allergic inflammatory lesions. However, how these pathogenic populations are maintained at the local inflammatory site has remained unclear. We performed a series of experiments using mice model for chronic airway inflammation. We also investigated the human samples from patients with eosinophilic chronic rhinosinusitis. We recently reported that inducible bronchus-associated lymphoid tissue (iBALT) was shaped during chronic inflammation in the lung. We also found that memory-type Tpath2 cells are maintained within iBALT. The maintenance of the Tpath2 cells within iBALT is supported by specific cell subpopulations within the lung. Furthermore, ectopic lymphoid structures consisting of memory CD4 + T cells were found in nasal polyps of eosinophilic chronic rhinosinusitis patients, indicating that the persistence of inflammation is controlled by these structures. Thus, the cell components that organize iBALT formation may be therapeutic targets for chronic allergic airway inflammation.

Inducible nitric oxide synthase in T cells regulates T cell death and immune memory

PubMed Central

Vig, Monika; Srivastava, Smita; Kandpal, Usha; Sade, Hadassah; Lewis, Virginia; Sarin, Apurva; George, Anna; Bal, Vineeta; Durdik, Jeannine M.; Rath, Satyajit

2004-01-01

The progeny of T lymphocytes responding to immunization mostly die rapidly, leaving a few long-lived survivors functioning as immune memory. Thus, control of this choice of death versus survival is critical for immune memory. There are indications that reactive radicals may be involved in this death pathway. We now show that, in mice lacking inducible nitric oxide synthase (iNOS), higher frequencies of both CD4 and CD8 memory T cells persist in response to immunization, even when iNOS+/+ APCs are used for immunization. Postactivation T cell death by neglect is reduced in iNOS–/– T cells, and levels of the antiapoptotic proteins Bcl-2 and Bcl-xL are increased. Inhibitors of the iNOS-peroxynitrite pathway also enhance memory responses and block postactivation death by neglect in both mouse and human T cells. However, early primary immune responses are not enhanced, which suggests that altered survival, rather than enhanced activation, is responsible for the persistent immunity observed. Thus, in primary immune responses, iNOS in activated T cells autocrinely controls their susceptibility to death by neglect to determine the level of persisting CD4 and CD8 T cell memory, and modulation of this pathway can enhance the persistence of immune memory in response to vaccination. PMID:15199408

Natural Killer Cell Memory

PubMed Central

O’Sullivan, Timothy E.; Sun, Joseph C.; Lanier, Lewis L.

2015-01-01

Natural killer (NK) cells have historically been considered short-lived cytolytic cells that can rapidly respond against pathogens and tumors in an antigen-independent manner, and then undergo cell death. Recently, however, NK cells have been shown to possess traits of adaptive immunity, and can acquire immunological memory in a similar manner to T and B cells. In this review, we discuss evidence for NK cell memory and the mechanisms involved in the generation and survival of these innate lymphocytes. PMID:26488815

Naive T-cell receptor transgenic T cells help memory B cells produce antibody

PubMed Central

Duffy, Darragh; Yang, Chun-Ping; Heath, Andrew; Garside, Paul; Bell, Eric B

2006-01-01

Injection of the same antigen following primary immunization induces a classic secondary response characterized by a large quantity of high-affinity antibody of an immunoglobulin G class produced more rapidly than in the initial response – the products of memory B cells are qualitatively distinct from that of the original naive B lymphocytes. Very little is known of the help provided by the CD4 T cells that stimulate memory B cells. Using antigen-specific T-cell receptor transgenic CD4 T cells (DO11.10) as a source of help, we found that naive transgenic T cells stimulated memory B cells almost as well (in terms of quantity and speed) as transgenic T cells that had been recently primed. There was a direct correlation between serum antibody levels and the number of naive transgenic T cells transferred. Using T cells from transgenic interleukin-2-deficient mice we showed that interleukin-2 was not required for a secondary response, although it was necessary for a primary response. The results suggested that the signals delivered by CD4 T cells and required by memory B cells for their activation were common to both antigen-primed and naive CD4 T cells. PMID:17067314

CD8α+ DC trans-presentation of IL-15 to naïve CD8+ T cells produces antigen inexperienced T cells in the periphery with memory phenotype and function

PubMed Central

Sosinowski, Tomasz; White, Jason T.; Cross, Eric; Haluszczak, Catherine; Marrack, Philippa; Gapin, Laurent; Kedl, Ross M.

2013-01-01

Various populations of memory phenotype CD8+ T cells have been described over the last 15–20 years, all of which possess elevated effector functions relative to naïve phenotype cells. Using a technique for isolating antigen specific cells from unprimed hosts, we recently identified a new subset of cells, specific for nominal antigen, but phenotypically and functionally similar to memory cells arising as a result of homeostatic proliferation (HP). We show here that these “Virtual Memory” cells are independent of previously identified “innate memory” cells, arising as a result of their response to IL-15 trans-presentation by lymphoid tissue-resident CD8α+ DCs in the periphery. The absence of IL-15, CD8+ T cell expression of either CD122 or Eomes, or of CD8a+ DCs all lead to the loss of Virtual Memory cells in the host. Our results show that CD8+ T cell homeostatic expansion is an active process within the non-lymphopenic environment, is mediated by IL-15, and produces antigen inexperienced memory cells which retain the capacity to respond to nominal antigen with memory-like function. Preferential engagement of these “Virtual Memory” T cells into a vaccine response could dramatically enhance the rate by which immune protection develops. PMID:23355737

Differences in Mouse and Human Non-Memory B Cell Pools1

PubMed Central

Benitez, Abigail; Weldon, Abby J.; Tatosyan, Lynnette; Velkuru, Vani; Lee, Steve; Milford, Terry-Ann; Francis, Olivia L.; Hsu, Sheri; Nazeri, Kavoos; Casiano, Carlos M.; Schneider, Rebekah; Gonzalez, Jennifer; Su, Rui-Jun; Baez, Ineavely; Colburn, Keith; Moldovan, Ioana; Payne, Kimberly J.

2014-01-01

Identifying cross-species similarities and differences in immune development and function is critical for maximizing the translational potential of animal models. Co-expression of CD21 and CD24 distinguishes transitional and mature B cell subsets in mice. Here, we validate these markers for identifying analogous subsets in humans and use them to compare the non-memory B cell pools in mice and humans, across tissues, during fetal/neonatal and adult life. Among human CD19+IgM+ B cells, the CD21/CD24 schema identifies distinct populations that correspond to T1 (transitional 1), T2 (transitional 2), FM (follicular mature), and MZ (marginal zone) subsets identified in mice. Markers specific to human B cell development validate the identity of MZ cells and the maturation status of human CD21/CD24 non-memory B cell subsets. A comparison of the non-memory B cell pools in bone marrow (BM), blood, and spleen in mice and humans shows that transitional B cells comprise a much smaller fraction in adult humans than mice. T1 cells are a major contributor to the non-memory B cell pool in mouse BM where their frequency is more than twice that in humans. Conversely, in spleen the T1:T2 ratio shows that T2 cells are proportionally ∼8 fold higher in humans than mouse. Despite the relatively small contribution of transitional B cells to the human non-memory pool, the number of naïve FM cells produced per transitional B cell is 3-6 fold higher across tissues than in mouse. These data suggest differing dynamics or mechanisms produce the non-memory B cell compartments in mice and humans. PMID:24719464

Immunophenotyping of rheumatoid arthritis reveals a linkage between HLA-DRB1 genotype, CXCR4 expression on memory CD4(+) T cells, and disease activity.

PubMed

Nagafuchi, Yasuo; Shoda, Hirofumi; Sumitomo, Shuji; Nakachi, Shinichiro; Kato, Rika; Tsuchida, Yumi; Tsuchiya, Haruka; Sakurai, Keiichi; Hanata, Norio; Tateishi, Shoko; Kanda, Hiroko; Ishigaki, Kazuyoshi; Okada, Yukinori; Suzuki, Akari; Kochi, Yuta; Fujio, Keishi; Yamamoto, Kazuhiko

2016-07-07

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that leads to destructive arthritis. Although the HLA class II locus is the strongest genetic risk factor for rheumatoid arthritis, the relationship between HLA class II alleles and lymphocyte activation remains unclear. We performed immunophenotyping of peripheral blood mononuclear cells on 91 HLA-DRB1-genotyped RA patients and 110 healthy donors. The frequency of memory CXCR4(+)CD4(+) T cells, and not Th1 and Th17 cells, was significantly associated with disease severity by multiple linear regression analysis. RA patients with one or more susceptible HLA-DR haplotypes (shared epitope: SE) displayed a significantly higher frequency of memory CXCR4(+)CD4(+) T cells. Moreover, the frequency of memory CXCR4(+)CD4(+) T cells significantly correlated with the expression level of HLA-DR on B cells, which was elevated in RA patients with SE. In vitro analysis and transcriptomic pathway analysis suggested that the interaction between HLA-DR and T cell receptors is an important regulator of memory CXCR4(+)CD4(+) T cells. Clinically, a higher frequency of memory CXCR4(+)CD4(+) T cells predicted a better response to CTLA4-Ig. Memory CXCR4(+)CD4(+) T cells may serve as a powerful biomarker for unraveling the linkage between HLA-DRB1 genotype and disease activity in RA.

Acute Infection with Epstein-Barr Virus Targets and Overwhelms the Peripheral Memory B-Cell Compartment with Resting, Latently Infected Cells

PubMed Central

Hochberg, Donna; Souza, Tatyana; Catalina, Michelle; Sullivan, John L.; Luzuriaga, Katherine; Thorley-Lawson, David A.

2004-01-01

In this paper we demonstrate that during acute infection with Epstein-Barr virus (EBV), the peripheral blood fills up with latently infected, resting memory B cells to the point where up to 50% of all the memory cells may carry EBV. Despite this massive invasion of the memory compartment, the virus remains tightly restricted to memory cells, such that, in one donor, fewer than 1 in 104 infected cells were found in the naive compartment. We conclude that, even during acute infection, EBV persistence is tightly regulated. This result confirms the prediction that during the early phase of infection, before cellular immunity is effective, there is nothing to prevent amplification of the viral cycle of infection, differentiation, and reactivation, causing the peripheral memory compartment to fill up with latently infected cells. Subsequently, there is a rapid decline in infected cells for the first few weeks that approximates the decay in the cytotoxic-T-cell responses to viral replicative antigens. This phase is followed by a slower decline that, even by 1 year, had not reached a steady state. Therefore, EBV may approach but never reach a stable equilibrium. PMID:15113901

Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells.

PubMed

Ceronie, Bryan; Jacobs, Benjamin M; Baker, David; Dubuisson, Nicolas; Mao, Zhifeng; Ammoscato, Francesca; Lock, Helen; Longhurst, Hilary J; Giovannoni, Gavin; Schmierer, Klaus

2018-05-01

The mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown. To determine whether cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells. A cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable cladribine. The relative proportions and absolute numbers of peripheral blood B lymphocyte subsets were measured using flow cytometry. Cell-subtype expression of genes involved in cladribine metabolism was examined from data in public repositories. Cladribine markedly depleted class-switched and unswitched memory B cells to levels comparable with alemtuzumab, but without the associated initial lymphopenia. CD3 + T cell depletion was modest. The mRNA expression of metabolism genes varied between lymphocyte subsets. A high ratio of deoxycytidine kinase to group I cytosolic 5' nucleotidase expression was present in B cells and was particularly high in mature, memory and notably germinal centre B cells, but not plasma cells. Selective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by cladribine. These may offer a new target, possibly with potential biomarker activity, for future drug development.

Asymptomatic memory CD8+ T cells

PubMed Central

Khan, Arif Azam; Srivastava, Ruchi; Lopes, Patricia Prado; Wang, Christine; Pham, Thanh T; Cochrane, Justin; Thai, Nhi Thi Uyen; Gutierrez, Lucas; BenMohamed, Lbachir

2014-01-01

Generation and maintenance of high quantity and quality memory CD8+ T cells determine the level of protection from viral, bacterial, and parasitic re-infections, and hence constitutes a primary goal for T cell epitope-based human vaccines and immunotherapeutics. Phenotypically and functionally characterizing memory CD8+ T cells that provide protection against herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) infections, which cause blinding ocular herpes, genital herpes, and oro-facial herpes, is critical for better vaccine design. We have recently categorized 2 new major sub-populations of memory symptomatic and asymptomatic CD8+ T cells based on their phenotype, protective vs. pathogenic function, and anatomical locations. In this report we are discussing a new direction in developing T cell-based human herpes vaccines and immunotherapeutics based on the emerging new concept of “symptomatic and asymptomatic memory CD8+ T cells.” PMID:24499824

Pediatric common variable immunodeficiency: immunologic and phenotypic associations with switched memory B cells.

PubMed

Yong, Pierre L; Orange, Jordan S; Sullivan, Kathleen E

2010-08-01

Recent studies suggest that patients with common variable immunodeficiency (CVID) and low numbers of switched memory B cells have lower IgG levels and higher rates of autoimmune disease, splenomegaly, and granulomatous disease; however, no prior literature has focused exclusively on pediatric cases. We examined the relationship between switched memory B cells and clinical and immunologic manifestations of CVID in a pediatric population. Forty-five patients were evaluated. Patients were categorized as Group I (<5 switched memory B cells/ml, n = 24) or Group II (> or =5 switched memory B cells/mL, n = 21). CD3(+) T-cell counts and CD19(+) B-cell levels were lower among Group I patients. Only those in Group I had meningitis, sepsis, bronchiectasis, granulomatous lung disease, autoimmune cytopenias, or hematologic malignancies. Segregation of pediatric patients into high risk (Group I) and average risk (Group II) may assist in targeting surveillance appropriately.

Immunologic considerations for generating memory CD8 T cells through vaccination.

PubMed

Butler, Noah S; Nolz, Jeffrey C; Harty, John T

2011-07-01

Following infection or vaccination, naïve CD8 T cells that receive the appropriate integration of antigenic, co-stimulatory and inflammatory signals undergo a programmed series of biological changes that ultimately results in the generation of memory cells. Memory CD8 T cells, in contrast to naïve cells, more effectively limit or prevent pathogen re-infection because of both qualitative and quantitative changes that occur following their induction. Unlike vaccination strategies aimed at generating antibody production, the ability to generate protective memory CD8 T cells has proven more complicated and problematic. However, recent experimental results have revealed important principles regarding the molecular and genetic basis for memory CD8 T cell formation, as well as identified ways to manipulate their development through vaccination, resulting in potential new avenues to enhance protective immunity. © 2011 Blackwell Publishing Ltd.

The Majority of HIV Type 1 DNA in Circulating CD4+ T Lymphocytes Is Present in Non-Gut-Homing Resting Memory CD4+ T Cells

PubMed Central

Xu, Yin; Bailey, Michelle; Seddiki, Nabila; Suzuki, Kazuo; Murray, John M.; Gao, Yuan; Yan, Celine; Cooper, David A.; Kelleher, Anthony D.; Koelsch, Kersten K.; Zaunders, John

2013-01-01

Abstract Memory CD4+ T lymphocytes in peripheral blood that express integrins α4ß7 preferentially recirculate through gut-associated lymphoid tissue (GALT), a proposed site of significant HIV-1 replication. Tregs and activated CD4+ T cells in GALT could also be particularly susceptible to infection. We therefore hypothesized that infection of these subsets of memory CD4+ T cells may contribute disproportionately to the HIV-1 reservoir. A cross-sectional study of CD4+ T cell subsets of memory CD45RO+ cells in peripheral blood mononuclear cells (PBMCs) was conducted using leukapheresis from eight subjects with untreated chronic HIV-1 infection. Real-time polymerase chain reaction (PCR) was used to quantify total and integrated HIV-1 DNA levels from memory CD4+ T cells sorted into integrin β7+ vs. β7−, CD25+CD127low Treg vs. CD127high, and activated CD38+ vs. CD38−. More than 80% of total HIV-1 DNA was found to reside in the integrin β7-negative non-gut-homing subset of CD45RO+ memory CD4+ T cells. Less than 10% was found in highly purified Tregs or CD38+ activated memory cells. Similarly, integrated HIV-1 DNA copies were found to be more abundant in resting non-gut-homing memory CD4+ T cells (76%) than in their activated counterparts (23%). Our investigations showed that the majority of both total and integrated HIV-1 DNA was found within non-gut-homing resting CD4+ T cells. PMID:23971972

Pharmacologic Induction of CD8+ T Cell Memory: Better Living Through Chemistry

PubMed Central

Gattinoni, Luca; Klebanoff, Christopher A.; Restifo, Nicholas P.

2011-01-01

The generation of a robust population of memory T cells is critical for effective vaccine and cell-based therapies to prevent and treat infectious diseases and cancer. A series of recent papers have established a new, cell-intrinsic approach in which small molecules target key metabolic and developmental pathways to enhance the formation and maintenance of highly functional CD8+ memory T cells. These findings raise the exciting new possibility of using small molecules, many of which are already approved for human use, for the pharmacologic induction of immunologic memory. PMID:20371454

Diet-induced obesity in mice reduces the maintenance of influenza-specific CD8+ memory T cells.

PubMed

Karlsson, Erik A; Sheridan, Patricia A; Beck, Melinda A

2010-09-01

Obesity has been associated with increasing the risk for type 2 diabetes and heart disease, but its influence on the immune response to viral infection is understudied. Memory T cells generated during a primary influenza infection are important for protection against subsequent influenza exposures. Previously, we have demonstrated that diet-induced obese (DIO) mice have increased morbidity and mortality following secondary influenza infection compared with lean mice. To determine whether the problem resided in a failure to maintain functional, influenza-specific CD8(+) memory T cells, male DIO and lean mice were infected with influenza X-31. At 84 d postinfection, DIO mice had a 10% reduction in memory T cell numbers. This reduction may have resulted from significantly reduced memory T cell expression of interleukin 2 receptor beta (IL-2R beta, CD122), but not IL-7 receptor alpha (CD127), which are both required for memory cell maintenance. Peripheral leptin resistance in the DIO mice may be a contributing factor to the impairment. Indeed, leptin receptor mRNA expression was significantly reduced in the lungs of obese mice, whereas suppressor of cytokine signaling (Socs)1 and Socs3 mRNA expression were increased. It is imperative to understand how the obese state alters memory T cells, because impairment in maintenance of functional memory responses has important implications for vaccine efficacy in an obese population.

Homeostasis of naive and memory CD4+ T cells: IL-2 and IL-7 differentially regulate the balance between proliferation and Fas-mediated apoptosis.

PubMed

Jaleco, Sara; Swainson, Louise; Dardalhon, Valérie; Burjanadze, Maryam; Kinet, Sandrina; Taylor, Naomi

2003-07-01

Cytokines play a crucial role in the maintenance of polyclonal naive and memory T cell populations. It has previously been shown that ex vivo, the IL-7 cytokine induces the proliferation of naive recent thymic emigrants (RTE) isolated from umbilical cord blood but not mature adult-derived naive and memory human CD4(+) T cells. We find that the combination of IL-2 and IL-7 strongly promotes the proliferation of RTE, whereas adult CD4(+) T cells remain relatively unresponsive. Immunological activity is controlled by a balance between proliferation and apoptotic cell death. However, the relative contributions of IL-2 and IL-7 in regulating these processes in the absence of MHC/peptide signals are not known. Following exposure to either IL-2 or IL-7 alone, RTE, as well as mature naive and memory CD4(+) T cells, are rendered only minimally sensitive to Fas-mediated cell death. However, in the presence of the two cytokines, Fas engagement results in a high level of caspase-dependent apoptosis in both RTE as well as naive adult CD4(+) T cells. In contrast, equivalently treated memory CD4(+) T cells are significantly less sensitive to Fas-induced cell death. The increased susceptibility of RTE and naive CD4(+) T cells to Fas-induced apoptosis correlates with a significantly higher IL-2/IL-7-induced Fas expression on these T cell subsets than on memory CD4(+) T cells. Thus, IL-2 and IL-7 regulate homeostasis by modulating the equilibrium between proliferation and apoptotic cell death in RTE and mature naive and memory T cell subsets.

Human Stem Cell-like Memory T Cells Are Maintained in a State of Dynamic Flux.

PubMed

Ahmed, Raya; Roger, Laureline; Costa Del Amo, Pedro; Miners, Kelly L; Jones, Rhiannon E; Boelen, Lies; Fali, Tinhinane; Elemans, Marjet; Zhang, Yan; Appay, Victor; Baird, Duncan M; Asquith, Becca; Price, David A; Macallan, Derek C; Ladell, Kristin

2016-12-13

Adaptive immunity requires the generation of memory T cells from naive precursors selected in the thymus. The key intermediaries in this process are stem cell-like memory T (T SCM ) cells, multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. In theory, antigen specificity within the T SCM pool may be imprinted statically as a function of largely dormant cells and/or retained dynamically by more transitory subpopulations. To explore the origins of immunological memory, we measured the turnover of T SCM cells in vivo using stable isotope labeling with heavy water. The data indicate that T SCM cells in both young and elderly subjects are maintained by ongoing proliferation. In line with this finding, T SCM cells displayed limited telomere length erosion coupled with high expression levels of active telomerase and Ki67. Collectively, these observations show that T SCM cells exist in a state of perpetual flux throughout the human lifespan. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

B-cell activating factor detected on both naïve and memory B cells in bullous pemphigoid.

PubMed

Qian, Hua; Kusuhara, Masahiro; Li, Xiaoguang; Tsuruta, Daisuke; Tsuchisaka, Atsunari; Ishii, Norito; Koga, Hiroshi; Hayakawa, Taihei; Ohara, Koji; Karashima, Tadashi; Ohyama, Bungo; Ohata, Chika; Furumura, Minao; Hashimoto, Takashi

2014-08-01

B-cell activating factor (BAFF), an important immune regulatory cytokine, is involved in development of autoimmune diseases. Although BAFF is expressed in various cells, including dendritic cells (DCs) and monocytes, BAFF expression on B cells has not been well documented. In the present study, BAFF molecules on DCs and naïve and memory B cells in autoimmune bullous diseases, including pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid (BP), were analysed by flow cytometry. Compared with healthy controls (HC), BAFF expression on naïve and memory B cells increased significantly in BP. No difference in BAFF receptor expression in naïve and memory B cells was shown among all study groups. Furthermore, BAFF expression in both naïve and memory B cells of BP, but not HC, was detected by confocal microscopic analysis. These results implied that BAFF expressed by B cells may play a pathogenic role in autoimmune bullous diseases, particularly BP. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Switched memory B cells maintain specific memory independently of serum antibodies: the hepatitis B example.

PubMed

Rosado, M Manuela; Scarsella, Marco; Pandolfi, Elisabetta; Cascioli, Simona; Giorda, Ezio; Chionne, Paola; Madonne, Elisabetta; Gesualdo, Francesco; Romano, Mariateresa; Ausiello, Clara M; Rapicetta, Maria; Zanetti, Alessandro R; Tozzi, Alberto; Carsetti, Rita

2011-06-01

The immunogenicity of a vaccine is conventionally measured through the level of serum Abs early after immunization, but to ensure protection specific Abs should be maintained long after primary vaccination. For hepatitis B, protective levels often decline over time, but breakthrough infections do not seem to occur. The aim of this study was to demonstrate whether, after hepatitis B vaccination, B-cell memory persists even when serum Abs decline. We compared the frequency of anti-hepatitis-specific memory B cells that remain in the blood of 99 children five years after priming with Infanrix -hexa (GlaxoSmithKline) (n=34) or with Hexavac (Sanofi Pasteur MSD) (n=65). These two vaccines differ in their ability to generate protective levels of IgG. Children with serum Abs under the protective level, <10 mIU/mL, received a booster dose of hepatitis B vaccine, and memory B cells and serum Abs were measured 2 wk later. We found that specific memory B cells had a similar frequency in all children independently of primary vaccine. Booster injection resulted in the increase of memory B cell frequencies (from 11.3 in 10(6) cells to 28.2 in 10(6) cells, p<0.01) and serum Abs (geometric mean concentration, GMC from 2.9 to 284 mIU/mL), demonstrating that circulating memory B cells effectively respond to Ag challenge even when specific Abs fall under the protective threshold. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Factors associated with poor sleep quality in women with cancer.

PubMed

Mansano-Schlosser, Thalyta Cristina; Ceolim, Maria Filomena

2017-03-02

to analyze the factors associated with poor sleep quality, its characteristics and components in women with breast cancer prior to surgery for removing the tumor and throughout the follow-up. longitudinal study in a teaching hospital, with a sample of 102 women. The following were used: a questionnaire for sociodemographic and clinical characterization, the Pittsburgh Sleep Quality Index; the Beck Depression Inventory; and the Herth Hope Scale. Data collection covered from prior to the surgery for removal of the tumor (T0) to T1, on average 3.2 months; T2, on average 6.1 months; and T3, on average 12.4 months. Descriptive statistics and the Generalized Estimating Equations model were used. depression and pain contributed to the increase in the score of the Pittsburgh Sleep Quality Index, and hope, to the reduction of the score - independently - throughout follow-up. Sleep disturbances were the component with the highest score throughout follow-up. the presence of depression and pain, prior to the surgery, contributed to the increase in the global score of the Pittsburgh Sleep Quality Index, which indicates worse quality of sleep throughout follow-up; greater hope, in its turn, influenced the reduction of the score of the Pittsburgh Sleep Quality Index. analizar los factores asociados a la mala calidad del sueño, sus características y componentes en mujeres con cáncer de mama, antes de la cirugía de retirada del tumor y a lo largo del seguimiento. estudio longitudinal, en hospital universitario con muestra de 102 mujeres. Fueron utilizados: un cuestionario de caracterización sociodemográfica y clínica; el Índice de Calidad del Sueño de Pittsburgh; el Inventario de Depresión de Beck; y la Escala de Esperanza de Herth. La recolección comprendió los momentos: antes de la cirugía de retirada del tumor (T0), en (T1) en promedio 3,2 meses, en (T2) en promedio 6,1 meses y en (T3) en promedio 12,4 meses. Se utilizó estadística descriptiva y el modelo de Ecuaciones de Estimación Generalizada. la depresión y el dolor contribuyeron para el aumento del puntaje del Índice de Calidad del Sueño de Pittsburgh y la esperanza para la reducción del puntaje, de manera independiente, a lo largo del seguimiento. Los trastornos del sueño fueron el componente con puntuación más elevada, a lo largo del seguimiento. la presencia de la depresión y del dolor, previos a la cirugía, contribuyeron para el aumento del puntaje global del Índice de Calidad del Sueño de Pittsburgh, lo que indica peor calidad del sueño, a lo largo del seguimiento y, la mayor esperanza, a su vez, influenció en la reducción del puntaje del Índice de Calidad del Sueño de Pittsburgh. analisar os fatores associados à má qualidade do sono, suas características e componentes em mulheres com câncer de mama antes da cirurgia de retirada do tumor e ao longo do seguimento. estudo longitudinal, em hospital universitário com amostra de 102 mulheres. Foram utilizados: questionário de caracterização sociodemográfica e clínica, Índice de Qualidade do Sono de Pittsburgh; Inventário de Depressão de Beck; Escala de Esperança de Herth. Coleta compreendeu antes da cirurgia de retirada do tumor (T0) em T1, em média 3,2 meses; T2, em média 6,1 meses; T3, em média 12,4 meses. Utilizou-se estatística descritiva e o modelo de Equações de Estimação Generalizada. a depressão e a dor contribuíram para o aumento do escore do Índice de Qualidade de Sono de Pittsburgh, e a esperança, para a redução do escore, de maneira independente, ao longo do seguimento. Os transtornos do sono foram o componente com pontuação mais elevada, ao longo do seguimento. a presença de depressão e de dor, previamente à cirurgia, contribuiu para o aumento do escore global do Índice de Qualidade do Sono de Pittsburgh, o que indica pior qualidade do sono, ao longo do seguimento e, a maior esperança, por sua vez, influenciou na redução do escore do Índice de Qualidade do Sono de Pittsburgh.

Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses.

PubMed

Paust, Silke; Gill, Harvinder S; Wang, Bao-Zhong; Flynn, Michael P; Moseman, E Ashley; Senman, Balimkiz; Szczepanik, Marian; Telenti, Amalio; Askenase, Philip W; Compans, Richard W; von Andrian, Ulrich H

2010-12-01

Hepatic natural killer (NK) cells mediate antigen-specific contact hypersensitivity (CHS) in mice deficient in T cells and B cells. We report here that hepatic NK cells, but not splenic or naive NK cells, also developed specific memory of vaccines containing antigens from influenza, vesicular stomatitis virus (VSV) or human immunodeficiency virus type 1 (HIV-1). Adoptive transfer of virus-sensitized NK cells into naive recipient mice enhanced the survival of the mice after lethal challenge with the sensitizing virus but not after lethal challenge with a different virus. NK cell memory of haptens and viruses depended on CXCR6, a chemokine receptor on hepatic NK cells that was required for the persistence of memory NK cells but not for antigen recognition. Thus, hepatic NK cells can develop adaptive immunity to structurally diverse antigens, an activity that requires NK cell-expressed CXCR6.

Keeping STATs on memory CD8+ T cells.

PubMed

Olson, Janelle A; Jameson, Stephen C

2011-11-23

The CD8(+) T cell response is characterized by generation of a population of effector cells and establishment of a persistent memory pool. In this issue, Cui et al. (2011) and Siegel et al. (2011) show that cytokine receptor signaling through the transcription factor STAT3 establishes stable memory CD8(+) T cells. Copyright © 2011 Elsevier Inc. All rights reserved.

Maintenance of CCL5 mRNA stores by post-effector and memory CD8 T cells is dependent on transcription and is coupled to increased mRNA stability.

PubMed

Marçais, Antoine; Tomkowiak, Martine; Walzer, Thierry; Coupet, Charles-Antoine; Ravel-Chapuis, Aymeric; Marvel, Jacqueline

2006-10-01

Immunological memory is associated with the display of improved effector functions by cells of the adaptive immune system. The storage of untranslated mRNA coding for the CCL5 chemokine by CD8 memory cells is a new process supporting the immediate display of an effector function. Here, we show that, after induction during the primary response, high CCL5 mRNA levels are specifically preserved in CD8 T cells. We have investigated the mechanisms involved in the long-term maintenance of CCL5 mRNA levels by memory CD8 T cells. We demonstrate that the CCL5 mRNA half-life is increased in memory CD8 T cells and that these cells constitutively transcribe ccl5 gene. By inhibiting ccl5 transcription using IL-4, we demonstrate the essential role of transcription in the maintenance of CCL5 mRNA stores. Finally, we show that these stores are spontaneously reconstituted when the inhibitory signal is removed, indicating that the transcription of ccl5 is a default feature of memory CD8 T cells imprinted in their genetic program.

Human IgG2- and IgG4-expressing memory B cells display enhanced molecular and phenotypic signs of maturity and accumulate with age.

PubMed

de Jong, Britt G; IJspeert, Hanna; Marques, Lemelinda; van der Burg, Mirjam; van Dongen, Jacques Jm; Loos, Bruno G; van Zelm, Menno C

2017-10-01

The mechanisms involved in sequential immunoglobulin G (IgG) class switching are still largely unknown. Sequential IG class switching is linked to higher levels of somatic hypermutation (SHM) in vivo, but it remains unclear if these are generated temporally during an immune response or upon activation in a secondary response. We here aimed to uncouple these processes and to distinguish memory B cells from primary and secondary immune responses. SHM levels and IgG subclasses were studied with 454 pyrosequencing on blood mononuclear cells from young children and adults as models for primary and secondary immunological memory. Additional sequencing and detailed immunophenotyping with IgG subclass-specific antibodies was performed on purified IgG + memory B-cell subsets. In both children and adults, SHM levels were higher in transcripts involving more downstream-located IGHG genes (esp. IGHG2 and IGHG4). In adults, SHM levels were significantly higher than in children, and downstream IGHG genes were more frequently utilized. This was associated with increased frequencies of CD27 + IgG + memory B cells, which contained higher levels of SHM, more IGHG2 usage, and higher expression levels of activation markers than CD27 - IgG + memory B cells. We conclude that secondary immunological memory accumulates with age and these memory B cells express CD27, high levels of activation markers, and carry high SHM levels and frequent usage of IGHG2. These new insights contribute to our understanding of sequential IgG subclass switching and show a potential relevance of using serum IgG2 levels or numbers of IgG2-expressing B cells as markers for efficient generation of memory responses.

Enhanced Requirement for TNFR2 in Graft Rejection Mediated by Low Affinity Memory CD8+ T Cells During Heterologous Immunity

PubMed Central

Krummey, Scott M.; Chen, Ching-Wen; Guasch, Sara A.; Liu, Danya; Wagener, Maylene; Larsen, Christian P; Ford, Mandy L.

2016-01-01

The affinity of a T cell receptor (TCR) binding to peptide:MHC profoundly impacts the phenotype and function of effector and memory cell differentiation. Little is known about the effect of low affinity priming on memory cell generation and function, which is particularly important in heterologous immunity, when microbe-specific T cells cross-react with allogeneic antigen and mediate graft rejection. We found that low affinity primed memory CD8+ T cells produced high levels of TNF ex vivo in response to heterologous rechallenge compared to high affinity primed memory T cells. Low affinity secondary effectors significantly upregulated TNFR2 on the cell surface and contained a higher frequency of TNFR2hi proliferating cells. Low affinity primed secondary effectors concurrently downregulated TNF production. Importantly, blockade of TNFR2 attenuated graft rejection in low but not high affinity primed animals. These data establish a functional connection between TNF signaling and TCR priming affinity and have implications for the immunomodulation of pathogenic T cell responses during transplantation. PMID:27481849

Brief Report: CD14brightCD16- monocytes and sCD14 level negatively associate with CD4-memory T-cell frequency and predict HCV-decline on therapy.

PubMed

Judge, Chelsey J; Sandberg, Johan K; Funderburg, Nicholas T; Sherman, Kenneth E; Butt, Adeel A; Kang, Minhee; Landay, Alan L; Lederman, Michael M; Anthony, Donald D

2016-11-01

During HIV+ hepatitis C virus (HCV)+ coinfection CD14CD16 monocytes produce soluble immune-activation markers that predict disease progression and poor response to interferon (IFN)-α treatment. We evaluated relationships among immune activation, monocyte phenotype, CD4-memory T cells, and HCV-, cytomegalovirus-, and cytomegalovirus/Epstein-Barr virus/influenza-specific IFN-γ-response before and during IFN-α treatment. Effector-memory and central-memory CD4 T-cell frequencies were lower in HCV+ HIV+ donors than in uninfected donors and correlated negatively with HCV level, CD14CD16 monocytes, and plasma sCD14. sCD14 and CD14CD16 monocytes negatively correlated with IFN-α-dependent HCV decline. CD4 effector-memory T cells positively associated with cytomegalovirus/Epstein-Barr virus/influenza(CEF)-specific IFN-γ response, while sCD14 negatively associated with both CD4 effector-memory T cells and CEF-specific IFN-γ response. These data support a role for memory-CD4 T cells in HCV containment and link immune activation and CD14CD16-monocyte frequency to the failure of IFN-dependent HCV clearance.

Place Cells, Grid Cells, and Memory

PubMed Central

Moser, May-Britt; Rowland, David C.; Moser, Edvard I.

2015-01-01

The hippocampal system is critical for storage and retrieval of declarative memories, including memories for locations and events that take place at those locations. Spatial memories place high demands on capacity. Memories must be distinct to be recalled without interference and encoding must be fast. Recent studies have indicated that hippocampal networks allow for fast storage of large quantities of uncorrelated spatial information. The aim of the this article is to review and discuss some of this work, taking as a starting point the discovery of multiple functionally specialized cell types of the hippocampal–entorhinal circuit, such as place, grid, and border cells. We will show that grid cells provide the hippocampus with a metric, as well as a putative mechanism for decorrelation of representations, that the formation of environment-specific place maps depends on mechanisms for long-term plasticity in the hippocampus, and that long-term spatiotemporal memory storage may depend on offline consolidation processes related to sharp-wave ripple activity in the hippocampus. The multitude of representations generated through interactions between a variety of functionally specialized cell types in the entorhinal–hippocampal circuit may be at the heart of the mechanism for declarative memory formation. PMID:25646382

Dissecting the human immunologic memory for pathogens.

PubMed

Zielinski, Christina E; Corti, Davide; Mele, Federico; Pinto, Dora; Lanzavecchia, Antonio; Sallusto, Federica

2011-03-01

Studies on immunologic memory in animal models and especially in the human system are instrumental to identify mechanisms and correlates of protection necessary for vaccine development. In this article, we provide an overview of the cellular basis of immunologic memory. We also describe experimental approaches based on high throughput cell cultures, which we have developed to interrogate human memory T cells, B cells, and plasma cells. We discuss how these approaches can provide new tools and information for vaccine design, in a process that we define as 'analytic vaccinology'. © 2011 John Wiley & Sons A/S.

Single-poly EEPROM cell with lightly doped MOS capacitors

DOEpatents

Riekels, James E [New Hope, MN; Lucking, Thomas B [Maple Grove, MN; Larsen, Bradley J [Mound, MN; Gardner, Gary R [Golden Valley, MN

2008-05-27

An Electrically Erasable Programmable Read Only Memory (EEPROM) memory cell and a method of operation are disclosed for creating an EEPROM memory cell in a standard CMOS process. A single polysilicon layer is used in combination with lightly doped MOS capacitors. The lightly doped capacitors employed in the EEPROM memory cell can be asymmetrical in design. Asymmetrical capacitors reduce area. Further capacitance variation caused by inversion can also be reduced by using multiple control capacitors. In addition, the use of multiple tunneling capacitors provides the benefit of customized tunneling paths.

N-ras couples antigen receptor signaling to Eomesodermin and to functional CD8+ T cell memory but not to effector differentiation

PubMed Central

Iborra, Salvador; Ramos, Manuel; Arana, David M.; Lázaro, Silvia; Aguilar, Francisco; Santos, Eugenio; López, Daniel

2013-01-01

Signals from the TCR that specifically contribute to effector versus memory CD8+ T cell differentiation are poorly understood. Using mice and adoptively transferred T lymphocytes lacking the small GTPase N-ras, we found that N-ras–deficient CD8+ T cells differentiate efficiently into antiviral primary effectors but have a severe defect in generating protective memory cells. This defect was rescued, although only partly, by rapamycin-mediated inhibition of mammalian target of rapamycin (mTOR) in vivo. The memory defect correlated with a marked impairment in vitro and in vivo of the antigen-mediated early induction of T-box transcription factor Eomesodermin (Eomes), whereas T-bet was unaffected. Besides N-ras, early Eomes induction in vitro required phosphoinositide 3-kinase (PI3K)–AKT but not extracellular signal-regulated kinase (ERK) activation, and it was largely insensitive to rapamycin. Consistent with N-ras coupling Eomes to T cell memory, retrovirally enforced expression of Eomes in N-ras–deficient CD8+ T cells effectively rescued their memory differentiation. Thus, our study identifies a critical role for N-ras as a TCR-proximal regulator of Eomes for early determination of the CD8+ T cell memory fate. PMID:23776078

Thy1+ Nk Cells from Vaccinia Virus-Primed Mice Confer Protection against Vaccinia Virus Challenge in the Absence of Adaptive Lymphocytes

PubMed Central

Gillard, Geoffrey O.; Bivas-Benita, Maytal; Hovav, Avi-Hai; Grandpre, Lauren E.; Panas, Michael W.; Seaman, Michael S.; Haynes, Barton F.; Letvin, Norman L.

2011-01-01

While immunological memory has long been considered the province of T- and B- lymphocytes, it has recently been reported that innate cell populations are capable of mediating memory responses. We now show that an innate memory immune response is generated in mice following infection with vaccinia virus, a poxvirus for which no cognate germline-encoded receptor has been identified. This immune response results in viral clearance in the absence of classical adaptive T and B lymphocyte populations, and is mediated by a Thy1+ subset of natural killer (NK) cells. We demonstrate that immune protection against infection from a lethal dose of virus can be adoptively transferred with memory hepatic Thy1+ NK cells that were primed with live virus. Our results also indicate that, like classical immunological memory, stronger innate memory responses form in response to priming with live virus than a highly attenuated vector. These results demonstrate that a defined innate memory cell population alone can provide host protection against a lethal systemic infection through viral clearance. PMID:21829360

Comparison of transducers with different frequencies in breast contrast-enhanced ultrasound (CEUS) using SonoVue as contrast agent.

PubMed

Wang, Yong-Mei; Fan, Wei; Zhang, Kai; Zhang, Li; Tan, Zhen; Ma, Rong

2016-07-01

To explore the effectiveness of different transducers in breast contrast-enhanced ultrasound (CEUS) using SonoVue(®) (Bracco, Plan-Les-Ouates, Switzerland) as the contrast agent. Breast CEUS was performed in 51 patients with 51 breast lesions using a low-frequency transducer (probe C5-1) and a high-frequency transducer (probe L12-5) separately. All image processes were reviewed for the presence of local blood perfusion defects and surrounding vessels. McNemar's test was conducted to compare the detection effectiveness between these two transducers. Pathological results revealed 38 malignant and 13 benign lesions. The two transducers showed no difference in detecting benign lesions. Among malignant lesions, CEUS conducted by probe C5-1 (frequency range from 1 to 5 MHz) presented 23 (60.5%) lesions with local blood perfusion defects and 26 (68.4%) lesions with surrounding vessels. Meanwhile, probe L12-5 (frequency range from 5 to 12 MHz) showed only 12 (31.6%) lesions with local blood perfusion defects and 12 (31.6%) lesions with surrounding vessel. Probe C5-1 was more sensitive than probe L12-5 in detecting malignant CEUS characteristics (p-value < 0.05). The low-frequency transducer was more sensitive than the high-frequency transducer in breast CEUS using SonoVue as the contrast agent. A new contrast agent with a higher resonance frequency, specially designed for high-frequency transducers, may be helpful in improving the clinical value of breast CEUS. The first study comparing different frequency transducers in breast CEUS of the same patient lesions. We brought out the requirement for CEUS contrast agents which are more suitable for high-frequency examinations.

[Mortality from respiratory diseases in the provinces of Apulia Region (Southern Italy) from 1933 to 2010].

PubMed

Montinari, Maria Rosa; Gianicolo, Emilio Antonio Luca; Vigotti, Maria Angela

2016-01-01

OBIETTIVI: valutare l'andamento temporale della mortalità per patologie respiratorie nelle province pugliesi utilizzando dati omogenei per fonte e metodologia di calcolo. DISEGNO: analisi ecologica storica degli andamenti temporali di mortalità per tumori e patologie dell'apparato respiratorio nelle province pugliesi, in Puglia e nelle ripartizioni geografiche italiane dal 1933 al 2010. SETTING E PARTECIPANTI: i dati di mortalità e le popolazioni residenti sono di fonte Istat. Sono state esaminate tutte le cause di decesso, il tumore della laringe, il tumore del polmone, l'insieme dei tumori respiratori, la bronchite, la polmonite e la broncopolmonite considerate congiuntamente, e l'insieme delle patologie respiratorie. Le analisi sono disaggregate per sesso dal 1969. PRINCIPALI MISURE DI OUTCOME: rapporti standardizzati di mortalità (SMR%) in riferimento all'Italia, con intervalli di confidenza al 95%, e tassi di mortalità standardizzati col metodo diretto (TSD ) in riferimento alla popolazione standard europea. RISULTATI: dal 1933 al 2010, i TSD per tumori respiratori e per bronchiti diminuiscono in tutte le aree analizzate. Tuttavia, nelle province di Taranto, Brindisi e Lecce, l'SMR% per tumori respiratori, inferiore al riferimento nazionale fino agli anni Sessanta, si allinea (a Brindisi) e supera (a Lecce e Taranto) il riferimento negli anni successivi. Nelle province di Foggia e Bari il numero dei decessi per tumore del polmone è costantemente inferiore all'atteso. CONCLUSIONI: la ricostruzione storica e l'analisi dei trend temporali di mortalità dal 1933 al 2010 mostrano alcune criticità sanitarie in periodi specifici. L'elaborazione dei dati di mortalità per un arco temporale di circa 80 anni ha messo in evidenza la maggiore rilevanza di queste criticità con l'avvio dello sviluppo industriale.

Evaluation of optimal parameters for using low-dose computed tomography to diagnose urolithiasis

NASA Astrophysics Data System (ADS)

Chen, Hui-Hsien; Yu, Cheng-Ching; Hsu, Fang-Yuh

2017-11-01

Urolithiasis is a common disease; patients suspected of suffering from urolithiasis will be examined by abdomen x-ray, Sono, Intraudio Videonous Urography (IVU) and Computed Tomography (CT). The detection rates for calculus in above examinations are respectively: 50-70% (x-ray), 50-60% (Sono), 70-90% (IVU) and 97% (CT). In addition, the effective doses are respectively: 0.63 mSv (x-ray), no radiation dose (Sono), 2.6 mSv (IVU) and 8-16 mSv (CT). Although CT has the highest detection rate for calculus, it also has the highest radiation dose. This research sought to lower the radiation dose by using CT scans with different dose conditions of standard dose (SD), 50% SD, 25% SD, and 15% SD to diagnose patients who suffer from urolithiasis and thus explore the feasibility of examining urolithiasis via CT with lower dose conditions. This research simulated the examination of patients with RANDO phantom, collocating PMMA slice phantom and pig's kidney. Fake calculuses made of five different materials of different sizes were put into the phantom and scanned individually. The results of the scanned images were given to two physicians who had many years of diagnostic experience to interpret the urolithiasis images. This study explored the different image qualities of CT with different dose conditions. In addition, this research used thermoluminescent dosimeters (TLD) to measure the radiation doses and compared the results with the dose values shown on the screen of the CT scanner to estimate the dose conversion factor (k). The research results showed that a low-dose CT was able to provide good image quality and thus have a lower radiation dose. Therefore, a low-dose CT is suggested the main examination method to diagnose patients with urolithiasis.

Identification and Manipulation of Memory Engram Cells.

PubMed

Liu, Xu; Ramirez, Steve; Redondo, Roger L; Tonegawa, Susumu

2014-01-01

How memories are formed and stored in the brain remains a fascinating question in neuroscience. Here we discuss the memory engram theory, our recent attempt to identify and manipulate memory engram cells in the brain with optogenetics, and how these methods are used to address questions such as how false memory is formed and how the valence of a memory can be changed in the brain. Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Negative regulation of NKG2D expression by IL-4 in memory CD8 T cells.

PubMed

Ventre, Erwan; Brinza, Lilia; Schicklin, Stephane; Mafille, Julien; Coupet, Charles-Antoine; Marçais, Antoine; Djebali, Sophia; Jubin, Virginie; Walzer, Thierry; Marvel, Jacqueline

2012-10-01

IL-4 is one of the main cytokines produced during Th2-inducing pathologies. This cytokine has been shown to affect a number of immune processes such as Th differentiation and innate immune responses. However, the impact of IL-4 on CD8 T cell responses remains unclear. In this study, we analyzed the effects of IL-4 on global gene expression profiles of Ag-induced memory CD8 T cells in the mouse. Gene ontology analysis of this signature revealed that IL-4 regulated most importantly genes associated with immune responses. Moreover, this IL-4 signature overlapped with the set of genes preferentially expressed by memory CD8 T cells over naive CD8 T cells. In particular, IL-4 downregulated in vitro and in vivo in a STAT6-dependent manner the memory-specific expression of NKG2D, thereby increasing the activation threshold of memory CD8 T cells. Furthermore, IL-4 impaired activation of memory cells as well as their differentiation into effector cells. This phenomenon could have an important clinical relevance as patients affected by Th2 pathologies such as parasitic infections or atopic dermatitis often suffer from viral-induced complications possibly linked to inefficient CD8 T cell responses.

Memory CD4+ T cells: beyond “helper” functions

PubMed Central

Boonnak, Kobporn; Subbarao, Kanta

2012-01-01

In influenza virus infection, antibodies, memory CD8+ T cells, and CD4+ T cells have all been shown to mediate immune protection, but how they operate and interact with one another to mediate efficient immune responses against virus infection is not well understood. In this issue of the JCI, McKinstry et al. have identified unique functions of memory CD4+ T cells beyond providing “help” for B cell and CD8+ T cell responses during influenza virus infection. PMID:22820285

Chemoprophylaxis with sporozoite immunization in P. knowlesi rhesus monkeys confers protection and elicits sporozoite-specific memory T cells in the liver

PubMed Central

Spring, Michele D.; Yongvanitchit, Kosol; Kum-Arb, Utaiwan; Limsalakpetch, Amporn; Im-Erbsin, Rawiwan; Ubalee, Ratawan; Vanachayangkul, Pattaraporn; Remarque, Edmond J.; Angov, Evelina; Smith, Philip L.; Saunders, David L.

2017-01-01

Whole malaria sporozoite vaccine regimens are promising new strategies, and some candidates have demonstrated high rates of durable clinical protection associated with memory T cell responses. Little is known about the anatomical distribution of memory T cells following whole sporozoite vaccines, and immunization of nonhuman primates can be used as a relevant model for humans. We conducted a chemoprophylaxis with sporozoite (CPS) immunization in P. knowlesi rhesus monkeys and challenged via mosquito bites. Half of CPS immunized animals developed complete protection, with a marked delay in parasitemia demonstrated in the other half. Antibody responses to whole sporozoites, CSP, and AMA1, but not CelTOS were detected. Peripheral blood T cell responses to whole sporozoites, but not CSP and AMA1 peptides were observed. Unlike peripheral blood, there was a high frequency of sporozoite-specific memory T cells observed in the liver and bone marrow. Interestingly, sporozoite-specific CD4+ and CD8+ memory T cells in the liver highly expressed chemokine receptors CCR5 and CXCR6, both of which are known for liver sinusoid homing. The majority of liver sporozoite-specific memory T cells expressed CD69, a phenotypic marker of tissue-resident memory (TRM) cells, which are well positioned to rapidly control liver-stage infection. Vaccine strategies that aim to elicit large number of liver TRM cells may efficiently increase the efficacy and durability of response against pre-erythrocytic parasites. PMID:28182750

Synergy of brief activation of CD8 T-cells in the presence of IL-12 and adoptive transfer into lymphopenic hosts promotes tumor clearance and anti-tumor memory

PubMed Central

Díaz-Montero, C Marcela; Naga, Osama; Zidan, Abdel-Aziz A; Salem, Mohamed L; Pallin, Maria; Parmigiani, Anita; Walker, Gail; Wieder, Eric; Komanduri, Krishna; Cole, David J; Montero, Alberto J; Lichtenheld, Mathias G

2011-01-01

Adoptive T-cell therapy holds great promise for the treatment of metastatic melanoma. However, prohibitive costs associated with current technology required for culture and expansion of tumor-reactive T-cells, the need for intense preconditioning regimens to induce lymphopenia, and the unpredictable anti-tumor effect of adoptively transferred T-cells remain significant impediments for its clinical implementation. Here we report a simplified combinatorial approach that involves short activation of CD8+ T cells in the presence of IL-12 followed by adoptive transfer into tumor bearing animals after a single injection of cyclophosphamide. This approach resulted in complete eradication of B16 melanoma, and the establishment of long term immunological memory capable of fully protecting mice after a second B16 melanoma challenge. The activated donor cells were unique because they simultaneously exhibited traits for cytotoxic effector function, central memory-like, homing, and senescence. After tumor eradication and within three months after transfer, CD8+ cells exhibited a conventional memory CTL phenotype. Moreover, these memory CTLs acquired functional attributes characteristic of memory stem cells, including the ability to resist chemotherapy-induced toxicity. Our results suggest that short-term T-cell receptor signaling in the presence of IL-12 promotes promiscuous qualities in naïve CTL which - upon transfer into lymphopenic hosts- are sufficient to eradicate tumors and generate life-long tumor-specific memory. PMID:21915391

Skin vaccination with live virus vectored microneedle arrays induce long lived CD8(+) T cell memory.

PubMed

Becker, Pablo D; Hervouet, Catherine; Mason, Gavin M; Kwon, Sung-Yun; Klavinskis, Linda S

2015-09-08

A simple dissolvable microneedle array (MA) platform has emerged as a promising technology for vaccine delivery, due to needle-free injection with a formulation that preserves the immunogenicity of live viral vectored vaccines dried in the MA matrix. While recent studies have focused largely on design parameters optimized to induce primary CD8(+) T cell responses, the hallmark of a vaccine is synonymous with engendering long-lasting memory. Here, we address the capacity of dried MA vaccination to programme phenotypic markers indicative of effector/memory CD8(+) T cell subsets and also responsiveness to recall antigen benchmarked against conventional intradermal (ID) injection. We show that despite a slightly lower frequency of dividing T cell receptor transgenic CD8(+) T cells in secondary lymphoid tissue at an early time point, the absolute number of CD8(+) T cells expressing an effector memory (CD62L(-)CD127(+)) and central memory (CD62L(+)CD127(+)) phenotype during peak expansion were comparable after MA and ID vaccination with a recombinant human adenovirus type 5 vector (AdHu5) encoding HIV-1 gag. Similarly, both vaccination routes generated CD8(+) memory T cell subsets detected in draining LNs for at least two years post-vaccination capable of responding to secondary antigen. These data suggest that CD8(+) T cell effector/memory generation and long-term memory is largely unaffected by physical differences in vaccine delivery to the skin via dried MA or ID suspension. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exposure of FVIII in the Presence of Phosphatidyl Serine Reduces Generation of Memory B-Cells and Induces Regulatory T-Cell-Mediated Hyporesponsiveness in Hemophilia A Mice.

PubMed

Ramakrishnan, Radha; Davidowitz, Andrew; Balu-Iyer, Sathy V

2015-08-01

A major complication of replacement therapy with Factor VIII (FVIII) for hemophilia A (HA) is the development of unwanted immune responses. Previous studies showed that administration of FVIII in the presence of phosphatidyl serine (PS) reduced the development of anti-FVIII antibodies in HA mice. However, the impact of PS-mediated effects on immunological memory, such as generation of memory B-cells, is not clear. The effect of PS on memory B-cells was therefore investigated using adoptive transfer approach in FVIII(-/-) HA mice. Adoptive transfer of memory B-cells from a PS-FVIII-treated group to naïve mice followed by challenge of the recipient mice with FVIII showed a significantly reduced anti-FVIII antibody response in the recipient mice, compared with animals that received memory B-cells from free FVIII and FVIII-charge matched phosphatidyl glycerol (PG) group. The decrease in memory B-cell response is accompanied by an increase in FoxP3 expressing regulatory T-cells (Tregs). Flow cytometry studies showed that the generation of Tregs is higher in PS-treated animals as compared with FVIII and FVIII-PG treated animals. The PS-mediated hyporesponsiveness was found to be antigen-specific. The PS-FVIII immunization showed hyporesponsiveness toward FVIII rechallenge but not against ovalbumin (OVA) rechallenge, an unrelated antigen. This demonstrates that PS reduces immunologic memory of FVIII and induces antigen-specific peripheral tolerance in HA mice. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

T-Cell Tropism of Simian Varicella Virus during Primary Infection

PubMed Central

Ouwendijk, Werner J. D.; Mahalingam, Ravi; de Swart, Rik L.; Haagmans, Bart L.; van Amerongen, Geert; Getu, Sarah; Gilden, Don; Osterhaus, Albert D. M. E.; Verjans, Georges M. G. M.

2013-01-01

Varicella-zoster virus (VZV) causes varicella, establishes a life-long latent infection of ganglia and reactivates to cause herpes zoster. The cell types that transport VZV from the respiratory tract to skin and ganglia during primary infection are unknown. Clinical, pathological, virological and immunological features of simian varicella virus (SVV) infection of non-human primates parallel those of primary VZV infection in humans. To identify the host cell types involved in virus dissemination and pathology, we infected African green monkeys intratracheally with recombinant SVV expressing enhanced green fluorescent protein (SVV-EGFP) and with wild-type SVV (SVV-wt) as a control. The SVV-infected cell types and virus kinetics were determined by flow cytometry and immunohistochemistry, and virus culture and SVV-specific real-time PCR, respectively. All monkeys developed fever and skin rash. Except for pneumonitis, pathology produced by SVV-EGFP was less compared to SVV-wt. In lungs, SVV infected alveolar myeloid cells and T-cells. During viremia the virus preferentially infected memory T-cells, initially central memory T-cells and subsequently effector memory T-cells. In early non-vesicular stages of varicella, SVV was seen mainly in perivascular skin infiltrates composed of macrophages, dendritic cells, dendrocytes and memory T-cells, implicating hematogenous spread. In ganglia, SVV was found primarily in neurons and occasionally in memory T-cells adjacent to neurons. In conclusion, the data suggest the role of memory T-cells in disseminating SVV to its target organs during primary infection of its natural and immunocompetent host. PMID:23675304

B Cells and B Cell Blasts Withstand Cryopreservation While Retaining Their Functionality for Producing Antibody.

PubMed

Fecher, Philipp; Caspell, Richard; Naeem, Villian; Karulin, Alexey Y; Kuerten, Stefanie; Lehmann, Paul V

2018-05-31

In individuals who have once developed humoral immunity to an infectious/foreign antigen, the antibodies present in their body can mediate instant protection when the antigen re-enters. Such antigen-specific antibodies can be readily detected in the serum. Long term humoral immunity is, however, also critically dependent on the ability of memory B cells to engage in a secondary antibody response upon re-exposure to the antigen. Antibody molecules in the body are short lived, having a half-life of weeks, while memory B cells have a life span of decades. Therefore, the presence of serum antibodies is not always a reliable indicator of B cell memory and comprehensive monitoring of humoral immunity requires that both serum antibodies and memory B cells be assessed. The prevailing view is that resting memory B cells and B cell blasts in peripheral blood mononuclear cells (PBMC) cannot be cryopreserved without losing their antibody secreting function, and regulated high throughput immune monitoring of B cell immunity is therefore confined to-and largely limited by-the need to test freshly isolated PBMC. Using optimized protocols for freezing and thawing of PBMC, and four color ImmunoSpot ® analysis for the simultaneous detection of all immunoglobulin classes/subclasses we show here that both resting memory B cells and B cell blasts retain their ability to secrete antibody after thawing, and thus demonstrate the feasibility of B cell immune monitoring using cryopreserved PBMC.

Postthymic maturation influences the CD8 T cell response to antigen.

PubMed

Makaroff, Lydia E; Hendricks, Deborah W; Niec, Rachel E; Fink, Pamela J

2009-03-24

Complete T cell development requires postthymic maturation, and we investigated the influence of this ontological period on the CD8 T cell response to infection by comparing responses of mature CD8 T cells with those of recent thymic emigrants (RTEs). When activated with a noninflammatory stimulus or a bacterial or viral pathogen, CD8 RTEs generated a lower proportion of cytokine-producing effector cells and long-lived memory precursors compared with their mature counterparts. Although peripheral T cell maturation is complete within several weeks after thymic egress, RTE-derived memory cells continued to express inappropriate levels of memory cell markers and display an altered pattern of cytokine production, even 8 weeks after infection. When rechallenged, RTE-derived memory cells generated secondary effector cells that were phenotypically and functionally equivalent to those generated by their mature counterparts. The defects at the effector and memory stages were not associated with differences in the expression of T cell receptor-, costimulation-, or activation-associated cell surface markers yet were associated with lower Ly6C expression levels at the effector stage. This work demonstrates that the stage of postthymic maturation influences cell fate decisions and cytokine profiles of stimulated CD8 T cells, with repercussions that are apparent long after cells have progressed from the RTE compartment.

Effect of memory CD4+ T cells' signal transducer and activator of transcription (STATs) functional shift on cytokine-releasing properties in asthma.

PubMed

Chen, Zhihong; Pan, Jue; Jia, Yi; Li, Dandan; Min, Zhihui; Su, Xiaoqiong; Yuan, Honglei; Shen, Geng; Cao, Shengxuan; Zhu, Lei; Wang, Xiangdong

2017-02-01

Recent data have demonstrated that long-lived memory T cells are present in the human lung and can play significant roles in the pathogenesis of specific allergic and autoimmune diseases. However, most evidence has been obtained from mouse studies, and the potential roles of memory T cells in human allergic diseases, such as asthma, remain largely unknown. Thirty-three asthmatics, 26 chronic obstructive pulmonary disease (COPD) patients, and 22 healthy volunteers were enrolled in this study. Peripheral blood mononuclear cells (PBMCs) were isolated from the peripheral blood, and cell surface staining (CD4, CD45RO, CRTH2, CD62L, and CCR7) was performed for the detection of memory CD4 + T cells in blood. After stimulation with interleukin-27 (IL-27) or IL-4 for 15 min, the STAT1/STAT6 phosphorylation of memory CD4 + T cells was measured separately by flow cytometric techniques. The cytokine-releasing profiles after 6 days of culture under neutralization, T H 2, T H 2 + lipopolysaccharide (LPS), and T H 2 + house dust mite (HDM) conditions were detected by intracellular protein (IL-5, IL-17, and interferon (IFN)-γ) staining. Correlation analyses between the profile of memory CD4 + T cells and clinical characteristics of asthma were performed. The number of circulating memory CD4 + T (CD4 + Tm) cells in asthmatics was increased compared with that in the healthy subjects (48 ± 5.7 % vs. 32 ± 4.1 %, p < 0.05). Compared with COPD and healthy subjects, the phosphorylation of signal transducer and activator of transcription 1 (STAT1-py) was impaired in asthmatics, whereas the phosphorylation of signal transducer and activator of transcription 6 (STAT6-py) was slightly enhanced. This imbalance of STAT1-py/STAT6-py was attributed to T H 2 memory cells but not non-T H 2 memory cells in blood. The cytokine-releasing profiles of asthmatics was unique, specifically IL-5 high , IL-17 high , and IFN-r low , compared with those of COPD patients and healthy subjects. The IL-17 production levels in CD4 + Tm cells are associated with disease severity and positively correlated with medication consumption in asthma. The long-lived, antigen-specific memory CD4 + T cells, rather than PBMCs or peripheral lymphocytes, might be the ideal T cell subset candidates for analyzing the endotype of asthma. Memory CD4 + T cells exhibiting a shift in STAT phosphorylation and specific cytokine-releasing profiles have the potential to facilitate the understanding of disease heterogeneity and severity, allowing the more personalized treatment of patients.

The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response.

PubMed

Akondy, Rama S; Monson, Nathan D; Miller, Joseph D; Edupuganti, Srilatha; Teuwen, Dirk; Wu, Hong; Quyyumi, Farah; Garg, Seema; Altman, John D; Del Rio, Carlos; Keyserling, Harry L; Ploss, Alexander; Rice, Charles M; Orenstein, Walter A; Mulligan, Mark J; Ahmed, Rafi

2009-12-15

The live yellow fever vaccine (YF-17D) offers a unique opportunity to study memory CD8(+) T cell differentiation in humans following an acute viral infection. We have performed a comprehensive analysis of the virus-specific CD8(+) T cell response using overlapping peptides spanning the entire viral genome. Our results showed that the YF-17D vaccine induces a broad CD8(+) T cell response targeting several epitopes within each viral protein. We identified a dominant HLA-A2-restricted epitope in the NS4B protein and used tetramers specific for this epitope to track the CD8(+) T cell response over a 2 year period. This longitudinal analysis showed the following. 1) Memory CD8(+) T cells appear to pass through an effector phase and then gradually down-regulate expression of activation markers and effector molecules. 2) This effector phase was characterized by down-regulation of CD127, Bcl-2, CCR7, and CD45RA and was followed by a substantial contraction resulting in a pool of memory T cells that re-expressed CD127, Bcl-2, and CD45RA. 3) These memory cells were polyfunctional in terms of degranulation and production of the cytokines IFN-gamma, TNF-alpha, IL-2, and MIP-1beta. 4) The YF-17D-specific memory CD8(+) T cells had a phenotype (CCR7(-)CD45RA(+)) that is typically associated with terminally differentiated cells with limited proliferative capacity (T(EMRA)). However, these cells exhibited robust proliferative potential showing that expression of CD45RA may not always associate with terminal differentiation and, in fact, may be an indicator of highly functional memory CD8(+) T cells generated after acute viral infections.

Central memory CD8+ T lymphocytes mediate lung allograft acceptance

PubMed Central

Krupnick, Alexander Sasha; Lin, Xue; Li, Wenjun; Higashikubo, Ryuiji; Zinselmeyer, Bernd H.; Hartzler, Hollyce; Toth, Kelsey; Ritter, Jon H.; Berezin, Mikhail Y.; Wang, Steven T.; Miller, Mark J.; Gelman, Andrew E.; Kreisel, Daniel

2014-01-01

Memory T lymphocytes are commonly viewed as a major barrier for long-term survival of organ allografts and are thought to accelerate rejection responses due to their rapid infiltration into allografts, low threshold for activation, and ability to produce inflammatory mediators. Because memory T cells are usually associated with rejection, preclinical protocols have been developed to target this population in transplant recipients. Here, using a murine model, we found that costimulatory blockade–mediated lung allograft acceptance depended on the rapid infiltration of the graft by central memory CD8+ T cells (CD44hiCD62LhiCCR7+). Chemokine receptor signaling and alloantigen recognition were required for trafficking of these memory T cells to lung allografts. Intravital 2-photon imaging revealed that CCR7 expression on CD8+ T cells was critical for formation of stable synapses with antigen-presenting cells, resulting in IFN-γ production, which induced NO and downregulated alloimmune responses. Thus, we describe a critical role for CD8+ central memory T cells in lung allograft acceptance and highlight the need for tailored approaches for tolerance induction in the lung. PMID:24569377

Virus-specific CD4+ memory phenotype T cells are abundant in unexposed adults

PubMed Central

Su, Laura F.; Kidd, Brian A.; Han, Arnold; Kotzin, Jonathan J.; Davis, Mark M.

2013-01-01

While T cell memory is generally thought to require direct antigen exposure, we find an abundance of memory phenotype cells (20–90%, averaging over 50%) of CD4+ T cells specific for viral antigens in adults that have never been infected. These cells express the appropriate memory markers and genes, rapidly produce cytokines, and have clonally expanded. This contrasts with newborns where the same T cell receptor (TCR) specificities are almost entirely naïve, which may explain the vulnerability of young children to infections. One mechanism for this phenomenon is TCR cross-reactivity to environmental antigens and in support of this we find extensive cross-recognition by HIV-1 and influenza-reactive T lymphocytes to other microbial peptides and the expansion of one of these following influenza vaccination. Thus the presence of these memory phenotype T cells has significant implications for immunity to novel pathogens, child and adult health, and the influence of pathogen-rich versus hygienic environments. PMID:23395677

Tracking KLRC2 (NKG2C)+ memory-like NK cells in SIV+ and rhCMV+ rhesus macaques.

PubMed

Ram, Daniel R; Manickam, Cordelia; Hueber, Brady; Itell, Hannah L; Permar, Sallie R; Varner, Valerie; Reeves, R Keith

2018-05-01

Natural killer (NK) cells classically typify the nonspecific effector arm of the innate immune system, but have recently been shown to possess memory-like properties against multiple viral infections, most notably CMV. Expression of the activating receptor NKG2C is elevated on human NK cells in response to infection with CMV as well as HIV, and may delineate cells with memory and memory-like functions. A better understanding of how NKG2C+ NK cells specifically respond to these pathogens could be significantly advanced using nonhuman primate (NHP) models but, to date, it has not been possible to distinguish NKG2C from its inhibitory counterpart, NKG2A, in NHP because of unfaithful antibody cross-reactivity. Using novel RNA-based flow cytometry, we identify for the first time true memory NKG2C+ NK cells in NHP by gene expression (KLRC2), and show that these cells have elevated frequencies and diversify their functional repertoire specifically in response to rhCMV and SIV infections.

Distinct roles of basal forebrain cholinergic neurons in spatial and object recognition memory.

PubMed

Okada, Kana; Nishizawa, Kayo; Kobayashi, Tomoko; Sakata, Shogo; Kobayashi, Kazuto

2015-08-06

Recognition memory requires processing of various types of information such as objects and locations. Impairment in recognition memory is a prominent feature of amnesia and a symptom of Alzheimer's disease (AD). Basal forebrain cholinergic neurons contain two major groups, one localized in the medial septum (MS)/vertical diagonal band of Broca (vDB), and the other in the nucleus basalis magnocellularis (NBM). The roles of these cell groups in recognition memory have been debated, and it remains unclear how they contribute to it. We use a genetic cell targeting technique to selectively eliminate cholinergic cell groups and then test spatial and object recognition memory through different behavioural tasks. Eliminating MS/vDB neurons impairs spatial but not object recognition memory in the reference and working memory tasks, whereas NBM elimination undermines only object recognition memory in the working memory task. These impairments are restored by treatment with acetylcholinesterase inhibitors, anti-dementia drugs for AD. Our results highlight that MS/vDB and NBM cholinergic neurons are not only implicated in recognition memory but also have essential roles in different types of recognition memory.

TLR agonists are highly effective at eliciting functional memory CTLs of effector memory phenotype in peptide immunization

USDA-ARS?s Scientific Manuscript database

Given the importance of memory cytotoxic T lymphocytes (CTLs) in eliminating altered self-cells, including virus-infected and tumor cells, devising effective vaccination strategies for generating memory CTLs is a priority in the field of immunology. Herein, we elaborate upon a novel boosting approac...

FE Yurchikhin poses for a photo with SonoCard

NASA Image and Video Library

2010-06-25

ISS024-E-006664 (25 June 2010) --- With most of his body tucked away in a sleeping bag, Russian cosmonaut Fyodor Yurchikhin, Expedition 24 flight engineer, is pictured in his crew quarters compartment in the Zvezda Service Module of the International Space Station.

Sono-photoacoustic imaging of gold nanoemulsions: Part II. Real time imaging

PubMed Central

Arnal, Bastien; Wei, Chen-Wei; Perez, Camilo; Nguyen, Thu-Mai; Lombardo, Michael; Pelivanov, Ivan; Pozzo, Lilo D.; O’Donnell, Matthew

2015-01-01

Photoacoustic (PA) imaging using exogenous agents can be limited by degraded specificity due to strong background signals. This paper introduces a technique called sono-photoacoustics (SPA) applied to perfluorohexane nanodroplets coated with gold nanospheres. Pulsed laser and ultrasound (US) excitations are applied simultaneously to the contrast agent to induce a phase-transition ultimately creating a transient microbubble. The US field present during the phase transition combined with the large thermal expansion of the bubble leads to 20–30 dB signal enhancement. Aqueous solutions and phantoms with very low concentrations of this agent were probed using pulsed laser radiation at diagnostic exposures and a conventional US array used both for excitation and imaging. Contrast specificity of the agent was demonstrated with a coherent differential scheme to suppress US and linear PA background signals. SPA shows great potential for molecular imaging with ultrasensitive detection of targeted gold coated nanoemulsions and cavitation-assisted theranostic approaches. PMID:25893170

Electrosynthesis of hydrogen peroxide via the reduction of oxygen assisted by power ultrasound.

PubMed

González-García, José; Banks, Craig E; Sljukić, Biljana; Compton, Richard G

2007-04-01

The electrosynthesis of hydrogen peroxide using the oxygen reduction reaction has been studied in the absence and presence of power ultrasound in a non-optimized sono-electrochemical flow reactor (20 cm cathodic compartment length with 6.5 cm inner diameter) with reticulated vitreous glassy carbon electrode (30 x 40 x 10 mm, 10 ppi, 7 cm(2)cm(-3)) as the cathode. The effect of several electrochemical operational variables (pH, volumetric flow, potential) and of the sono-electrochemical parameters (ultrasound amplitude and horn-to-electrode distance) on the cumulative concentration of hydrogen peroxide and current efficiency of the electrosynthesis process have been explored. The application of power ultrasound was found to increase both the cumulative concentration of hydrogen peroxide and the current efficiency. The application of ultrasound is therefore a promising approach to the increased efficiency of production of hydrogen peroxide by electrosynthesis, even in the solutions of lower pH (<12). The results demonstrate the feasibility of at-site-of-use green synthesis of hydrogen peroxide.

Oseltamivir Prophylaxis Reduces Inflammation and Facilitates Establishment of Cross-Strain Protective T Cell Memory to Influenza Viruses

PubMed Central

Hurt, Aeron C.; Oshansky, Christine M.; Oh, Ding Yuan; Reading, Patrick C.; Chua, Brendon Y.; Sun, Yilun; Tang, Li; Handel, Andreas; Jackson, David C.; Turner, Stephen J.; Thomas, Paul G.; Kedzierska, Katherine

2015-01-01

CD8+ T cells directed against conserved viral regions elicit broad immunity against distinct influenza viruses, promote rapid virus elimination and enhanced host recovery. The influenza neuraminidase inhibitor, oseltamivir, is prescribed for therapy and prophylaxis, although it remains unclear how the drug impacts disease severity and establishment of effector and memory CD8+ T cell immunity. We dissected the effects of oseltamivir on viral replication, inflammation, acute CD8+ T cell responses and the establishment of immunological CD8+ T cell memory. In mice, ferrets and humans, the effect of osteltamivir on viral titre was relatively modest. However, prophylactic oseltamivir treatment in mice markedly reduced morbidity, innate responses, inflammation and, ultimately, the magnitude of effector CD8+ T cell responses. Importantly, functional memory CD8+ T cells established during the drug-reduced effector phase were capable of mounting robust recall responses. Moreover, influenza-specific memory CD4+ T cells could be also recalled after the secondary challenge, while the antibody levels were unaffected. This provides evidence that long-term memory T cells can be generated during an oseltamivir-interrupted infection. The anti-inflammatory effect of oseltamivir was verified in H1N1-infected patients. Thus, in the case of an unpredicted influenza pandemic, while prophylactic oseltamivir treatment can reduce disease severity, the capacity to generate memory CD8+ T cells specific for the newly emerged virus is uncompromised. This could prove especially important for any new influenza pandemic which often occurs in separate waves. PMID:26086392

Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells.

PubMed

Hurton, Lenka V; Singh, Harjeet; Najjar, Amer M; Switzer, Kirsten C; Mi, Tiejuan; Maiti, Sourindra; Olivares, Simon; Rabinovich, Brian; Huls, Helen; Forget, Marie-Andrée; Datar, Vrushali; Kebriaei, Partow; Lee, Dean A; Champlin, Richard E; Cooper, Laurence J N

2016-11-29

Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (T SCM ) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR + T cells with preserved T SCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19 + leukemia. Long-lived T cells were CD45RO neg CCR7 + CD95 + , phenotypically most similar to T SCM , and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR + T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials.

Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells

PubMed Central

Hurton, Lenka V.; Singh, Harjeet; Najjar, Amer M.; Switzer, Kirsten C.; Mi, Tiejuan; Maiti, Sourindra; Olivares, Simon; Rabinovich, Brian; Huls, Helen; Forget, Marie-Andrée; Datar, Vrushali; Kebriaei, Partow; Lee, Dean A.; Champlin, Richard E.; Cooper, Laurence J. N.

2016-01-01

Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (TSCM) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR+ T cells with preserved TSCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19+ leukemia. Long-lived T cells were CD45ROnegCCR7+CD95+, phenotypically most similar to TSCM, and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR+ T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials. PMID:27849617

Abnormal B cell memory subsets dominate HIV-specific responses in infected individuals

PubMed Central

Kardava, Lela; Moir, Susan; Shah, Naisha; Wang, Wei; Wilson, Richard; Buckner, Clarisa M.; Santich, Brian H.; Kim, Leo J.Y.; Spurlin, Emily E.; Nelson, Amy K.; Wheatley, Adam K.; Harvey, Christopher J.; McDermott, Adrian B.; Wucherpfennig, Kai W.; Chun, Tae-Wook; Tsang, John S.; Li, Yuxing; Fauci, Anthony S.

2014-01-01

Recently, several neutralizing anti-HIV antibodies have been isolated from memory B cells of HIV-infected individuals. Despite extensive evidence of B cell dysfunction in HIV disease, little is known about the cells from which these rare HIV-specific antibodies originate. Accordingly, we used HIV envelope gp140 and CD4 or coreceptor (CoR) binding site (bs) mutant probes to evaluate HIV-specific responses in peripheral blood B cells of HIV-infected individuals at various stages of infection. In contrast to non-HIV responses, HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated and exhausted memory subsets, which are largely absent in the blood of uninfected individuals. Responses against the CoRbs, which is a poorly neutralizing epitope, arose early, whereas those against the well-characterized neutralizing epitope CD4bs were delayed and infrequent. Enrichment of the HIV-specific response within resting memory B cells, the predominant subset in uninfected individuals, did occur in certain infected individuals who maintained low levels of plasma viremia and immune activation with or without antiretroviral therapy. The distribution of HIV-specific responses among memory B cell subsets was corroborated by transcriptional analyses. Taken together, our findings provide valuable insight into virus-specific B cell responses in HIV infection and demonstrate that memory B cell abnormalities may contribute to the ineffectiveness of the antibody response in infected individuals. PMID:24892810

Enhancement of Immune Memory Responses to Respiratory Infection

DTIC Science & Technology

2017-08-01

Unlimited Distribution 13. SUPPLEMENTARY NOTES 14. ABSTRACT Maintenance of long - term immunological memory against pathogens is crucial for the rapid...highly expressed in memory B cells in mice, and Atg7 is required for maintenance of long - term memory B cells needed to protect against influenza...AWARD NUMBER: W81XWH-16-1-0360 TITLE: Enhancement of Immune Memory Responses to Respiratory Infection PRINCIPAL INVESTIGATORs: Dr Min Chen PhD

Initiation of Antiretroviral Therapy Restores CD4+ T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques.

PubMed

Cartwright, Emily K; Palesch, David; Mavigner, Maud; Paiardini, Mirko; Chahroudi, Ann; Silvestri, Guido

2016-08-01

Treatment of human immunodeficiency virus (HIV) infection with antiretroviral therapy (ART) has significantly improved prognosis. Unfortunately, interruption of ART almost invariably results in viral rebound, attributed to a pool of long-lived, latently infected cells. Based on their longevity and proliferative potential, CD4(+) T memory stem cells (TSCM) have been proposed as an important site of HIV persistence. In a previous study, we found that in simian immunodeficiency virus (SIV)-infected rhesus macaques (RM), CD4(+) TSCM are preserved in number but show (i) a decrease in the frequency of CCR5(+) cells, (ii) an expansion of the fraction of proliferating Ki-67(+) cells, and (iii) high levels of SIV DNA. To understand the impact of ART on both CD4(+) TSCM homeostasis and virus persistence, we conducted a longitudinal analysis of these cells in the blood and lymph nodes of 25 SIV-infected RM. We found that ART induced a significant restoration of CD4(+) CCR5(+) TSCM both in blood and in lymph nodes and a reduction in the fraction of proliferating CD4(+) Ki-67(+) TSCM in blood (but not lymph nodes). Importantly, we found that the level of SIV DNA in CD4(+) transitional memory (TTM) and effector memory (TEM) T cells declined ∼100-fold after ART in both blood and lymph nodes, while the level of SIV DNA in CD4(+) TSCM and central memory T cells (TCM-) did not significantly change. These data suggest that ART is effective at partially restoring CD4(+) TSCM homeostasis, and the observed stable level of virus in TSCM supports the hypothesis that these cells are a critical contributor to SIV persistence. Understanding the roles of various CD4(+) T cell memory subsets in immune homeostasis and HIV/SIV persistence during antiretroviral therapy (ART) is critical to effectively treat and cure HIV infection. T memory stem cells (TSCM) are a unique memory T cell subset with enhanced self-renewal capacity and the ability to differentiate into other memory T cell subsets, such as central and transitional memory T cells (TCM and TTM, respectively). CD4(+) TSCM are disrupted but not depleted during pathogenic SIV infection. We find that ART is partially effective at restoring CD4(+) TSCM homeostasis and that SIV DNA harbored within this subset contracts more slowly than virus harbored in shorter-lived subsets, such as TTM and effector memory (TEM). Because of their ability to persist long-term in an individual, understanding the dynamics of virally infected CD4(+) TSCM during suppressive ART is important for future therapeutic interventions aimed at modulating immune activation and purging the HIV reservoir. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Initiation of Antiretroviral Therapy Restores CD4+ T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques

PubMed Central

Cartwright, Emily K.; Palesch, David; Mavigner, Maud; Paiardini, Mirko; Chahroudi, Ann

2016-01-01

ABSTRACT Treatment of human immunodeficiency virus (HIV) infection with antiretroviral therapy (ART) has significantly improved prognosis. Unfortunately, interruption of ART almost invariably results in viral rebound, attributed to a pool of long-lived, latently infected cells. Based on their longevity and proliferative potential, CD4+ T memory stem cells (TSCM) have been proposed as an important site of HIV persistence. In a previous study, we found that in simian immunodeficiency virus (SIV)-infected rhesus macaques (RM), CD4+ TSCM are preserved in number but show (i) a decrease in the frequency of CCR5+ cells, (ii) an expansion of the fraction of proliferating Ki-67+ cells, and (iii) high levels of SIV DNA. To understand the impact of ART on both CD4+ TSCM homeostasis and virus persistence, we conducted a longitudinal analysis of these cells in the blood and lymph nodes of 25 SIV-infected RM. We found that ART induced a significant restoration of CD4+ CCR5+ TSCM both in blood and in lymph nodes and a reduction in the fraction of proliferating CD4+ Ki-67+ TSCM in blood (but not lymph nodes). Importantly, we found that the level of SIV DNA in CD4+ transitional memory (TTM) and effector memory (TEM) T cells declined ∼100-fold after ART in both blood and lymph nodes, while the level of SIV DNA in CD4+ TSCM and central memory T cells (TCM-) did not significantly change. These data suggest that ART is effective at partially restoring CD4+ TSCM homeostasis, and the observed stable level of virus in TSCM supports the hypothesis that these cells are a critical contributor to SIV persistence. IMPORTANCE Understanding the roles of various CD4+ T cell memory subsets in immune homeostasis and HIV/SIV persistence during antiretroviral therapy (ART) is critical to effectively treat and cure HIV infection. T memory stem cells (TSCM) are a unique memory T cell subset with enhanced self-renewal capacity and the ability to differentiate into other memory T cell subsets, such as central and transitional memory T cells (TCM and TTM, respectively). CD4+ TSCM are disrupted but not depleted during pathogenic SIV infection. We find that ART is partially effective at restoring CD4+ TSCM homeostasis and that SIV DNA harbored within this subset contracts more slowly than virus harbored in shorter-lived subsets, such as TTM and effector memory (TEM). Because of their ability to persist long-term in an individual, understanding the dynamics of virally infected CD4+ TSCM during suppressive ART is important for future therapeutic interventions aimed at modulating immune activation and purging the HIV reservoir. PMID:27170752

Autophagy is essential for effector CD8 T cell survival and memory formation

PubMed Central

Xu, Xiaojin; Araki, Koichi; Li, Shuzhao; Han, Jin-Hwan; Ye, Lilin; Tan, Wendy G.; Konieczny, Bogumila T.; Bruinsma, Monique W.; Martinez, Jennifer; Pearce, Erika L; Green, Douglas R.; Jones, Dean P.; Virgin, Herbert W.; Ahmed, Rafi

2014-01-01

The importance of autophagy in memory CD8 T cell differentiation in vivo is not well defined. We show here that autophagy is dynamically regulated in virus-specific CD8 T cells during acute lymphocytic choriomeningitis virus infection. Autophagy decreased in activated proliferating T cells, and was then upregulated at the peak of the effector T cell response. Consistent with this model, deletion of the key autophagy genes Atg7 or Atg5 in virus-specific CD8 T cells had minimal effect on generating effector cells but greatly enhanced their death during the contraction phase resulting in compromised memory formation. These findings provide insight into when autophagy is needed during effector and memory T cell differentiation in vivo and also warrant a re-examination of our current concepts about the relationship between T cell activation and autophagy. PMID:25362489

Human Epidermal Langerhans Cells Maintain Immune Homeostasis in Skin by Activating Skin Resident Regulatory T Cells

PubMed Central

Seneschal, Julien; Clark, Rachael A.; Gehad, Ahmed; Baecher-Allan, Clare M.; Kupper, Thomas S.

2013-01-01

Recent discoveries indicate that the skin of a normal individual contains 10-20 billion resident memory T cells ( which include various T helper, T cytotoxic, and T regulatory subsets, that are poised to respond to environmental antigens. Using only autologous human tissues, we report that both in vitro and in vivo, resting epidermal Langerhan cells (LC) selectively and specifically induced the activation and proliferation of skin resident regulatory T cells (Treg), a minor subset of skin resident memory T cells. In the presence of foreign pathogen, however, the same LC activated and induced proliferation of effector memory T (Tem) cells and limited Treg cells activation. These underappreciated properties of LC: namely maintenance of tolerance in normal skin, and activation of protective skin resident memory T cells upon infectious challenge, help clarify the role of LC in skin. PMID:22560445

Low-voltage-operated organic one-time programmable memory using printed organic thin-film transistors and antifuse capacitors.

PubMed

Jung, Soon-Won; Na, Bock Soon; Park, Chan Woo; Koo, Jae Bon

2014-11-01

We demonstrate an organic one-time programmable memory cell formed entirely at plastic-compatible temperatures. All the processes are performed at below 130 degrees C. Our memory cell consists of a printed organic transistor and an organic capacitor. Inkjet-printed organic transistors are fabricated by using high-k polymer dielectric blends comprising poly(vinylidenefluoride-trifluoroethylene) [P(VDF-TrFE)] and poly(methyl methacrylate) (PMMA) for low-voltage operation. P(NDI2OD-T2) transistors have a high field-effect mobility of 0.2 cm2/Vs and a low operation gate voltage of less than 10 V. The operation voltage effectively decreases owing to the high permittivity of the P(VDF-TrFE):PMMA blended film. The data in the memory cell are programmed by electrically breaking the organic capacitor. The organic capacitor acts like an antifuse capacitor, because it is initially open, and it becomes permanently short-circuited by applying a high voltage. The organic memory cells are programmed with 4 V, and they are read out with 2 V. The memory data are read out by sensing the current in the memory cell. The printed organic one-time programmable memory is suitable for applications storing small amount of data, such as low-cost radio-frequency identification (RFID) tag.

Autoreactive T effector memory differentiation mirrors β-cell function in type 1 diabetes.

PubMed

Yeo, Lorraine; Woodwyk, Alyssa; Sood, Sanjana; Lorenc, Anna; Eichmann, Martin; Pujol-Autonell, Irma; Melchiotti, Rossella; Skowera, Ania; Fidanis, Efthymios; Dolton, Garry M; Tungatt, Katie; Sewell, Andrew K; Heck, Susanne; Saxena, Alka; Beam, Craig A; Peakman, Mark

2018-05-31

In type 1 diabetes, cytotoxic CD8 T cells with specificity for β-cell autoantigens are found in the pancreatic islets where they are implicated in the destruction of insulin-secreting β cells. In contrast, the disease relevance of β-cell-reactive CD8 T cells that are detectable in the circulation, and their relationship to β-cell function, are not known. Here, we tracked multiple, circulating β-cell-reactive CD8 T cell subsets and measured β-cell function longitudinally for two years, starting immediately after diagnosis of type 1 diabetes. We found that change in β-cell-specific effector memory CD8 T cells expressing CD57 was positively correlated with C-peptide change in subjects below 12 years of age. Autoreactive CD57+ effector memory CD8 T cells bore the signature of enhanced effector function (higher expression of granzyme B, killer specific protein 37 and CD16, and reduced expression of CD28) compared with their CD57-negative counterparts, and network association modelling indicated that the dynamics of β-cell-reactive CD57+ effector memory CD8 T cell subsets were strongly linked. Thus, coordinated changes in circulating β-cell-specific CD8 T cells within the CD57+ effector memory subset calibrate to functional insulin reserve in type 1 diabetes, providing a tool for immune monitoring and a mechanism-based target for immunotherapy.

Regulation of Memory T Cells by Interleukin-23.

PubMed

Li, Yanchun; Wang, Hongbo; Lu, Honghua; Hua, Shucheng

2016-01-01

Interleukin-23 (IL-23), a member of the IL-12 family of cytokines, is a heterodimeric cytokine. It is composed of subunits p40 (shared with IL-12) and p19 (an IL-12 p35-related subunit) and is secreted by several types of immune cells, such as natural killer cells and dendritic cells. The IL-23 receptor is composed of the subunit IL-12Rβ1 and the IL-23-specific subunit IL-23R. The binding of IL-23 to its specific cell surface receptor regulates a number of functions, including proliferation and differentiation of cells and secretion of cell factors. Memory T cells are a subset of T cells that secrete numerous important cell factors, and they function in the immune response to infection and diseases like cancer, autoimmune disease and bronchial asthma. IL-23R is expressed on the surface of memory T cells, which suggests that it can specifically regulate memory T cell function. IL-23 has been widely used as a clinical indicator in immune-related diseases and shows potential for use in disease treatment. Here we review the current progress in the study of the role of IL-23 in the regulation of memory T cells. © 2016 S. Karger AG, Basel.

Specific memory B cell response and participation of CD4+ central and effector memory T cells in mice immunized with liposome encapsulated recombinant NE protein based Hepatitis E vaccine candidate.

PubMed

Kulkarni, Shruti P; Thanapati, Subrat; Arankalle, Vidya A; Tripathy, Anuradha S

2016-11-21

Liposome encapsulated neutralizing epitope protein of Hepatitis E virus (HEV), rNEp, our Hepatitis E vaccine candidate, was shown to be immunogenic and safe in pregnant and non-pregnant mice and yielded sterilizing immunity in rhesus monkeys. The current study in Balb/c mice assessed the levels and persistence of anti-HEV IgG antibodies by ELISA, frequencies of B, memory B, T and memory T cells by flow cytometry and HEV-specific IgG secreting memory B cells by ELISPOT till 420days post immunization (PI) with 5?g rNEp encapsulated in liposome based adjuvant (2 doses, 4weeks apart). Mice immunized with a lower dose (1?g) were assessed only for anamnestic response post booster dose. Vaccine candidate immunized mice (5?g dose) elicited strong anti-HEV IgG response that was estimated to persist for lifetime. At day 120 PI, frequency of memory B cells was higher in immunized mice than those receiving adjuvant alone. Anti-HEV IgG titers were lower in mice immunized with 1?g dose. A booster dose yielded a heightened antibody response in mice with both high (>800GMT, 5?g) and low (?100GMT, 1?g) anti-HEV IgG titers. At day 6th post booster dose, HEV-specific antibody secreting plasma cells (ASCs) were detected in 100% and 50% of mice with high and low anti-HEV IgG titers, respectively, whereas the frequencies of CD4 + central and effector memory T cells were high in mice with high anti-HEV IgG titers only. Taken together, the vaccine candidate effectively generates persistent and anamnestic antibody response, elicits participation of CD4 + memory T cells and triggers memory B cells to differentiate into ASCs upon boosting. This approach of assessing the immunogenicity of vaccine candidate could be useful to explore the longevity of HEV-specific memory response in future HEV vaccine trials in human. Copyright © 2016. Published by Elsevier Ltd.

Fluorescently labeled dengue viruses as probes to identify antigen-specific memory B cells by multiparametric flow cytometry

PubMed Central

Woda, Marcia; Mathew, Anuja

2015-01-01

Low frequencies of memory B cells in the peripheral blood make it challenging to measure the functional and phenotypic characteristics of this antigen experienced subset of B cells without in vitro culture. To date, reagents are lacking to measure ex vivo frequencies of dengue virus (DENV)-specific memory B cells. We wanted to explore the possibility of using fluorescently labeled DENV as probes to detect antigen-specific memory B cells in the peripheral blood of DENV immune individuals. Alexa Fluor dye-labeled DENV yielded viable virus that could be stored at −80°C for long periods of time. Using a careful gating strategy and methods to decrease non-specific binding, we were able to identify a small frequency of B cells from dengue immune individuals that bound labeled DENV. Sorted DENV+ B cells from immune, but not naïve donors secreted antibodies that bound intact virions after in vitro stimulation. Overall, Alexa Fluor dye labeled -DENV are useful reagents to enable the detection and characterization of memory B cells in DENV immune individuals. PMID:25497702

Optimization of a human IgG B-cell ELISpot assay for the analysis of vaccine-induced B-cell responses.

PubMed

Jahnmatz, Maja; Kesa, Gun; Netterlid, Eva; Buisman, Anne-Marie; Thorstensson, Rigmor; Ahlborg, Niklas

2013-05-31

B-cell responses after infection or vaccination are often measured as serum titers of antigen-specific antibodies. Since this does not address the aspect of memory B-cell activity, it may not give a complete picture of the B-cell response. Analysis of memory B cells by ELISpot is therefore an important complement to conventional serology. B-cell ELISpot was developed more than 25 years ago and many assay protocols/reagents would benefit from optimization. We therefore aimed at developing an optimized B-cell ELISpot for the analysis of vaccine-induced human IgG-secreting memory B cells. A protocol was developed based on new monoclonal antibodies to human IgG and biotin-avidin amplification to increase the sensitivity. After comparison of various compounds commonly used to in vitro-activate memory B cells for ELISpot analysis, the TLR agonist R848 plus interleukin (IL)-2 was selected as the most efficient activator combination. The new protocol was subsequently compared to an established protocol, previously used in vaccine studies, based on polyclonal antibodies without biotin avidin amplification and activation of memory B-cells using a mix of antigen, CpG, IL-2 and IL-10. The new protocol displayed significantly better detection sensitivity, shortened the incubation time needed for the activation of memory B cells and reduced the amount of antigen required for the assay. The functionality of the new protocol was confirmed by analyzing specific memory B cells to five different antigens, induced in a limited number of subjects vaccinated against tetanus, diphtheria and pertussis. The limited number of subjects did not allow for a direct comparison with other vaccine studies. Optimization of the B-cell ELISpot will facilitate an improved analysis of IgG-secreting B cells in vaccine studies. Copyright © 2013 Elsevier B.V. All rights reserved.

CD8+ T Cell Exhaustion, Suppressed Gamma Interferon Production, and Delayed Memory Response Induced by Chronic Brucella melitensis Infection

PubMed Central

Durward-Diioia, Marina; Harms, Jerome; Khan, Mike; Hall, Cherisse; Smith, Judith A.

2015-01-01

Brucella melitensis is a well-adapted zoonotic pathogen considered a scourge of mankind since recorded history. In some cases, initial infection leads to chronic and reactivating brucellosis, incurring significant morbidity and economic loss. The mechanism by which B. melitensis subverts adaptive immunological memory is poorly understood. Previous work has shown that Brucella-specific CD8+ T cells express gamma interferon (IFN-γ) and can transition to long-lived memory cells but are not polyfunctional. In this study, chronic infection of mice with B. melitensis led to CD8+ T cell exhaustion, manifested by programmed cell death 1 (PD-1) and lymphocyte activation gene 3 (LAG-3) expression and a lack of IFN-γ production. The B. melitensis-specific CD8+ T cells that produced IFN-γ expressed less IFN-γ per cell than did CD8+ cells from uninfected mice. Both memory precursor (CD8+ LFA1HI CD127HI KLRG1LO) and long-lived memory (CD8+ CD27HI CD127HI KLRG1LO) cells were identified during chronic infection. Interestingly, after adoptive transfer, mice receiving cells from chronically infected animals were able to contain infection more rapidly than recipients of cells from acutely infected or uninfected donors, although the proportions of exhausted CD8+ T cells increased after adoptive transfer in both challenged and unchallenged recipients. CD8+ T cells of challenged recipients initially retained the stunted IFN-γ production found prior to transfer, and cells from acutely infected mice were never seen to transition to either memory subset at all time points tested, up to 30 days post-primary infection, suggesting a delay in the generation of memory. Here we have identified defects in Brucella-responsive CD8+ T cells that allow chronic persistence of infection. PMID:26416901

Origin and differentiation of human memory CD8 T cells after vaccination.

PubMed

Akondy, Rama S; Fitch, Mark; Edupuganti, Srilatha; Yang, Shu; Kissick, Haydn T; Li, Kelvin W; Youngblood, Ben A; Abdelsamed, Hossam A; McGuire, Donald J; Cohen, Kristen W; Alexe, Gabriela; Nagar, Shashi; McCausland, Megan M; Gupta, Satish; Tata, Pramila; Haining, W Nicholas; McElrath, M Juliana; Zhang, David; Hu, Bin; Greenleaf, William J; Goronzy, Jorg J; Mulligan, Mark J; Hellerstein, Marc; Ahmed, Rafi

2017-12-21

The differentiation of human memory CD8 T cells is not well understood. Here we address this issue using the live yellow fever virus (YFV) vaccine, which induces long-term immunity in humans. We used in vivo deuterium labelling to mark CD8 T cells that proliferated in response to the virus and then assessed cellular turnover and longevity by quantifying deuterium dilution kinetics in YFV-specific CD8 T cells using mass spectrometry. This longitudinal analysis showed that the memory pool originates from CD8 T cells that divided extensively during the first two weeks after infection and is maintained by quiescent cells that divide less than once every year (doubling time of over 450 days). Although these long-lived YFV-specific memory CD8 T cells did not express effector molecules, their epigenetic landscape resembled that of effector CD8 T cells. This open chromatin profile at effector genes was maintained in memory CD8 T cells isolated even a decade after vaccination, indicating that these cells retain an epigenetic fingerprint of their effector history and remain poised to respond rapidly upon re-exposure to the pathogen.

Is magnetite a universal memory molecule?

PubMed

Størmer, Fredrik C

2014-11-01

Human stem cells possess memory, and consequently all living human cells must have a memory system. How memory is stored in cells and organisms is an open question. Magnetite is perhaps the best candidate to be a universal memory molecule. Magnetite may give us a clue, because it is the Earth's most distributed and important magnetic material. It is found in living organisms with no known functions except for involvement in navigation in some organisms. In humans magnetite is found in the brain, heart, liver and spleen. Humans suffer from memory dysfunctions in many cases when iron is out of balance. Anomalous concentrations of magnetite is known to be associated with a neurodegenerative disorder like Alzheimer's disease. Due to the rapid speed and accuracy of our brain, memory and its functions must be governed by quantum mechanics. Copyright © 2014 Elsevier Ltd. All rights reserved.

A dual-docking microfluidic cell migration assay (D2-Chip) for testing neutrophil chemotaxis and the memory effect.

PubMed

Yang, Ke; Wu, Jiandong; Xu, Guoqing; Xie, Dongxue; Peretz-Soroka, Hagit; Santos, Susy; Alexander, Murray; Zhu, Ling; Zhang, Michael; Liu, Yong; Lin, Francis

2017-04-18

Chemotaxis is a classic mechanism for guiding cell migration and an important topic in both fundamental cell biology and health sciences. Neutrophils are a widely used model to study eukaryotic cell migration and neutrophil chemotaxis itself can lead to protective or harmful immune actions to the body. While much has been learnt from past research about how neutrophils effectively navigate through a chemoattractant gradient, many interesting questions remain unclear. For example, while it is tempting to model neutrophil chemotaxis using the well-established biased random walk theory, the experimental proof was challenged by the cell's highly persistent migrating nature. A special experimental design is required to test the key predictions from the random walk model. Another question that has interested the cell migration community for decades concerns the existence of chemotactic memory and its underlying mechanism. Although chemotactic memory has been suggested in various studies, a clear quantitative experimental demonstration will improve our understanding of the migratory memory effect. Motivated by these questions, we developed a microfluidic cell migration assay (so-called dual-docking chip or D 2 -Chip) that can test both the biased random walk model and the memory effect for neutrophil chemotaxis on a single chip enabled by multi-region gradient generation and dual-region cell alignment. Our results provide experimental support for the biased random walk model and chemotactic memory for neutrophil chemotaxis. Quantitative data analyses provide new insights into neutrophil chemotaxis and memory by making connections to entropic disorder, cell morphology and oscillating migratory response.

Killing of targets by effector CD8 T cells in the mouse spleen follows the law of mass action

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ganusov, Vitaly V

2009-01-01

In contrast with antibody-based vaccines, it has been difficult to measure the efficacy of T cell-based vaccines and to correlate the efficacy of CD8 T cell responses with protection again viral infections. In part, this difficulty is due to poor understanding of the in vivo efficacy of CD8 T cells produced by vaccination. Using a: recently developed experimental method of in vivo cytotoxicity we have investigated quantitative aspects of killing of peptide-pulsed targets by effector and memory CD8 T cells, specific to three epitopes of lymphocytic choriomeningitis virus (LCMV), in the mouse spleen. By analyzing data on killing of targetsmore » with varying number of epitope-specific effector and memory CD8 T cells, we find that killing of targets by effectors follows the law of mass-action, that is the death rate of peptide-pulsed targets is proportional to the frequency of CTLs in the spleen. In contrast, killing of targets by memory CD8 T cells does not follow the mass action law because the death rate of targets saturates at high frequencies of memory CD8 T cells. For both effector and memory cells, we also find little support for the killing term that includes the decrease of the death rate of targets with target cell density. Interestingly, our analysis suggests that at low CD8 T cell frequencies, memory CD8 T cells on the per capita basis are more efficient at killing peptide-pulsed targets than effectors, but at high frequencies, effectors are more efficient killers than memory T cells. Comparison of the estimated killing efficacy of effector T cells with the value that is predicted from theoretical physics and based on motility of T cells in lymphoid tissues, suggests that limiting step in the killing of peptide-pulsed targets is delivering the lethal hit and not finding the target. Our results thus form a basis for quantitative understanding of the process of killing of virus-infected cells by T cell responses in tissues and can be used to correlate the phenotype of vaccine-induced memory CD8 T cells with their killing efficacy in vivo.« less

Oct1 and OCA-B are selectively required for CD4 memory T cell function.

PubMed

Shakya, Arvind; Goren, Alon; Shalek, Alex; German, Cody N; Snook, Jeremy; Kuchroo, Vijay K; Yosef, Nir; Chan, Raymond C; Regev, Aviv; Williams, Matthew A; Tantin, Dean

2015-11-16

Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4(+) memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4(+) T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4(+) T cell memory. © 2015 Shakya et al.

Oct1 and OCA-B are selectively required for CD4 memory T cell function

PubMed Central

Shakya, Arvind; Goren, Alon; Shalek, Alex; German, Cody N.; Snook, Jeremy; Kuchroo, Vijay K.; Yosef, Nir; Chan, Raymond C.; Regev, Aviv

2015-01-01

Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4+ memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at the Il2 target locus in resting but previously stimulated CD4+ T cells. OCA-B is also required for the robust reexpression of multiple other genes including Ifng. ChIPseq identifies ∼50 differentially expressed direct Oct1 and OCA-B targets. We identify an underlying mechanism involving OCA-B recruitment of the histone lysine demethylase Jmjd1a to targets such as Il2, Ifng, and Zbtb32. The findings pinpoint Oct1 and OCA-B as central mediators of CD4+ T cell memory. PMID:26481684

B7-H1 limits the entry of effector CD8(+) T cells to the memory pool by upregulating Bim.

PubMed

Gibbons, Rachel M; Liu, Xin; Pulko, Vesna; Harrington, Susan M; Krco, Christopher J; Kwon, Eugene D; Dong, Haidong

2012-10-01

Protective T‑cell immunity against cancer and infections is dependent on the generation of a durable effector and memory T‑cell pool. Studies from cancer and chronic infections reveal that B7-H1 (PD-L1) engagement with its receptor PD-1 promotes apoptosis of effector T cells. It is not clear how B7-H1 regulates T‑cell apoptosis and the subsequent impact of B7-H1 on the generation of memory T cells. In immunized B7-H1-deficient mice, we detected an increased expansion of effector CD8(+) T cells and a delayed T‑cell contraction followed by the emergence of a protective CD8(+) T‑cell memory capable of completely rejecting tumor metastases in the lung. Intracellular staining revealed that antigen-primed CD8(+) T cells in B7-H1-deficient mice express lower levels of the pro-apoptotic molecule Bim. The engagement of activated CD8(+) T cells by a plate-bound B7-H1 fusion protein led to the upregulation of Bim and increased cell death. Assays based on blocking antibodies determined that both PD-1 and CD80 are involved in the B7-H1-mediated regulation of Bim in activated CD8(+) T cells. Our results suggest that B7-H1 may negatively regulate CD8(+) T‑cell memory by enhancing the depletion of effector CD8(+) T cells through the upregulation of Bim. Our findings may provide a new strategy for targeting B7-H1 signaling in effector CD8(+) T cells to achieve protective antitumor memory responses.

Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells.

PubMed

Watanabe, Rei; Gehad, Ahmed; Yang, Chao; Scott, Laura L; Teague, Jessica E; Schlapbach, Christoph; Elco, Christopher P; Huang, Victor; Matos, Tiago R; Kupper, Thomas S; Clark, Rachael A

2015-03-18

The skin of an adult human contains about 20 billion memory T cells. Epithelial barrier tissues are infiltrated by a combination of resident and recirculating T cells in mice, but the relative proportions and functional activities of resident versus recirculating T cells have not been evaluated in human skin. We discriminated resident from recirculating T cells in human-engrafted mice and lymphoma patients using alemtuzumab, a medication that depletes recirculating T cells from skin, and then analyzed these T cell populations in healthy human skin. All nonrecirculating resident memory T cells (TRM) expressed CD69, but most were CD4(+), CD103(-), and located in the dermis, in contrast to studies in mice. Both CD4(+) and CD8(+) CD103(+) TRM were enriched in the epidermis, had potent effector functions, and had a limited proliferative capacity compared to CD103(-) TRM. TRM of both types had more potent effector functions than recirculating T cells. We observed two distinct populations of recirculating T cells, CCR7(+)/L-selectin(+) central memory T cells (TCM) and CCR7(+)/L-selectin(-) T cells, which we term migratory memory T cells (TMM). Circulating skin-tropic TMM were intermediate in cytokine production between TCM and effector memory T cells. In patients with cutaneous T cell lymphoma, malignant TCM and TMM induced distinct inflammatory skin lesions, and TMM were depleted more slowly from skin after alemtuzumab, suggesting that TMM may recirculate more slowly. In summary, human skin is protected by four functionally distinct populations of T cells, two resident and two recirculating, with differing territories of migration and distinct functional activities. Copyright © 2015, American Association for the Advancement of Science.

Altered Memory Circulating T Follicular Helper-B Cell Interaction in Early Acute HIV Infection

PubMed Central

Muir, Roshell; Metcalf, Talibah; Tardif, Virginie; Takata, Hiroshi; Phanuphak, Nittaya; Kroon, Eugene; Colby, Donn J.; Trichavaroj, Rapee; Valcour, Victor; Robb, Merlin L.; Michael, Nelson L.; Ananworanich, Jintanat; Trautmann, Lydie; Haddad, Elias K.

2016-01-01

The RV254 cohort of HIV-infected very early acute (4thG stage 1 and 2) (stage 1/2) and late acute (4thG stage 3) (stage 3) individuals was used to study T helper- B cell responses in acute HIV infection and the impact of early antiretroviral treatment (ART) on T and B cell function. To investigate this, the function of circulating T follicular helper cells (cTfh) from this cohort was examined, and cTfh and memory B cell populations were phenotyped. Impaired cTfh cell function was observed in individuals treated in stage 3 when compared to stage 1/2. The cTfh/B cell cocultures showed lower B cell survival and IgG secretion at stage 3 compared to stage 1/2. This coincided with lower IL-10 and increased RANTES and TNF-α suggesting a role for inflammation in altering cTfh and B cell responses. Elevated plasma viral load in stage 3 was found to correlate with decreased cTfh-mediated B cell IgG production indicating a role for increased viremia in cTfh impairment and dysfunctional humoral response. Phenotypic perturbations were also evident in the mature B cell compartment, most notably a decrease in resting memory B cells in stage 3 compared to stage 1/2, coinciding with higher viremia. Our coculture assay also suggested that intrinsic memory B cell defects could contribute to the impaired response despite at a lower level. Overall, cTfh-mediated B cell responses are significantly altered in stage 3 compared to stage 1/2, coinciding with increased inflammation and a reduction in memory B cells. These data suggest that early ART for acutely HIV infected individuals could prevent immune dysregulation while preserving cTfh function and B cell memory. PMID:27463374

Effect with high density nano dot type storage layer structure on 20 nm planar NAND flash memory characteristics

NASA Astrophysics Data System (ADS)

Sasaki, Takeshi; Muraguchi, Masakazu; Seo, Moon-Sik; Park, Sung-kye; Endoh, Tetsuo

2014-01-01

The merits, concerns and design principle for the future nano dot (ND) type NAND flash memory cell are clarified, by considering the effect of storage layer structure on NAND flash memory characteristics. The characteristics of the ND cell for a NAND flash memory in comparison with the floating gate type (FG) is comprehensively studied through the read, erase, program operation, and the cell to cell interference with device simulation. Although the degradation of the read throughput (0.7% reduction of the cell current) and slower program time (26% smaller programmed threshold voltage shift) with high density (10 × 1012 cm-2) ND NAND are still concerned, the suppress of the cell to cell interference with high density (10 × 1012 cm-2) plays the most important part for scaling and multi-level cell (MLC) operation in comparison with the FG NAND. From these results, the design knowledge is shown to require the control of the number of nano dots rather than the higher nano dot density, from the viewpoint of increasing its memory capacity by MLC operation and suppressing threshold voltage variability caused by the number of dots in the storage layer. Moreover, in order to increase its memory capacity, it is shown the tunnel oxide thickness with ND should be designed thicker (>3 nm) than conventional designed ND cell for programming/erasing with direct tunneling mechanism.

The role of human chorionic gonadotropin in regulation of naïve and memory T cells activity in vitro.

PubMed

Zamorina, S A; Litvinova, L S; Yurova, K A; Khaziakhmatova, O G; Timganova, V P; Bochkova, M S; Khramtsov, P V; Rayev, M B

2018-01-01

The role of human chorionic gonadotropin (hCG) in the regulation of molecular genetics factors determining the functional activity of human naïve and memory T cells in vitro was studied. It was found that hCG (10 and 100IU/ml) inhibited CD28 and CD25 expression on the naïve T cells (CD45RA+) and CD25 expression on the memory T cells (CD45R0+). hCG didn't affect the CD71 proliferation marker expression in total. Nevertheless, hCG reduced the percentage of proliferating memory T cells with simultaneous suppression of CD71 expression on proliferating CD45R0+cells. In parallel, expression of U2af1l4, Gfi1, and hnRNPLL genes, which are Ptprc gene alternative splicing regulators was evaluated. It was established that hCG stimulated the expression of U2af1l4 and hnRNPLL genes, responsible for the assembly of CD45R0 in memory T cells, but reduced the expression of Gfi1 in these cells. In general, hCG promotes the differentiation of memory T cells by increasing of CD45R0 expression, but inhibits proliferation and CD25 expression which reflects their functional activity. Copyright © 2017 Elsevier B.V. All rights reserved.

The Cellular Bases of Antibody Responses during Dengue Virus Infection

PubMed Central

Yam-Puc, Juan Carlos; Cedillo-Barrón, Leticia; Aguilar-Medina, Elsa Maribel; Ramos-Payán, Rosalío; Escobar-Gutiérrez, Alejandro; Flores-Romo, Leopoldo

2016-01-01

Dengue virus (DENV) is one of the most significant human viral pathogens transmitted by mosquitoes and can cause from an asymptomatic disease to mild undifferentiated fever, classical dengue, and severe dengue. Neutralizing memory antibody (Ab) responses are one of the most important mechanisms that counteract reinfections and are therefore the main aim of vaccination. However, it has also been proposed that in dengue, some of these class-switched (IgG) memory Abs might worsen the disease. Although these memory Abs derive from B cells by T-cell-dependent processes, we know rather little about the (acute, chronic, or memory) B cell responses and the complex cellular mechanisms generating these Abs during DENV infections. This review aims to provide an updated and comprehensive perspective of the B cell responses during DENV infection, starting since the very early events such as the cutaneous DENV entrance and the arrival into draining lymph nodes, to the putative B cell activation, proliferation, and germinal centers (GCs) formation (the source of affinity-matured class-switched memory Abs), till the outcome of GC reactions such as the generation of plasmablasts, Ab-secreting plasma cells, and memory B cells. We discuss topics very poorly explored such as the possibility of B cell infection by DENV or even activation-induced B cell death. The current information about the nature of the Ab responses to DENV is also illustrated. PMID:27375618

Nanoscale CuO solid-electrolyte-based conductive-bridging, random-access memory cell with a TiN liner

NASA Astrophysics Data System (ADS)

Lee, Jong-Sun; Kim, Dong-Won; Kim, Hea-Jee; Jin, Soo-Min; Song, Myung-Jin; Kwon, Ki-Hyun; Park, Jea-Gun; Jalalah, Mohammed; Al-Hajry, Ali

2018-01-01

The Conductive-bridge random-access memory (CBRAM) cell is a promising candidate for a terabit-level non-volatile memory due to its remarkable advantages. We present for the first time TiN as a diffusion barrier in CBRAM cells for enhancing their reliability. CuO solid-electrolyte-based CBRAM cells implemented with a 0.1-nm TiN liner demonstrated better non-volatile memory characteristics such as 106 AC write/erase endurance cycles with 100-μs AC pulse width and a long retention time of 7.4-years at 85 °C. In addition, the analysis of Ag diffusion in the CBRAM cell suggests that the morphology of the Ag filaments in the electrolyte can be effectively controlled by tuning the thickness of the TiN liner. These promising results pave the way for faster commercialization of terabit-level non-volatile memories.

Functional heterogeneity of memory B lymphocytes: in vivo analysis of TD-primed B cells responsive to secondary stimulation with TD and TI antigens.

PubMed

Rennick, D M; Morrow, P R; Benjamini, E

1983-08-01

The functional heterogeneity of memory B cells induced by a single determinant, consisting of a decapeptide representing amino acid residues 103-112 of tobacco mosaic virus protein (TMVP), was analyzed. Decapeptide specific antibodies were elicited in mice adoptively transferred with TMVP-immune spleen cells when challenged with TMVP, decapeptide conjugated to succinylated human gamma-globulin (SHGG), or decapeptide conjugated to Brucella abortus (BA). Whereas secondary stimulation by either TMVP or decapeptide-SHGG was dependent on appropriately primed T cells, stimulation by decapeptide-BA was independent of conventional T cell help. Furthermore, memory B cells responsive to TMVP (TD), decapeptide-SHGG (TD), or decapeptide-BA (TI. 1 prototype) were shown to consist of overlapping populations because adoptive recipients of TMVP-primed cells challenged simultaneously with TD and TI decapeptide antigens did not result in a higher antibody response than that elicited by one of the TD antigens injected alone. However, decapeptide-BA consistently induced a smaller antidecapeptide response than either TMVP or decapeptide-SHGG. This suggested that only a fraction of the memory B cell population which was activated by the original priming antigen (thymus-dependent) was also responsive to secondary in vivo stimulation by the priming hapten conjugated to Brucella abortus. Detailed analyses of the antibodies induced in the recipients of TMVP-immune spleen cells after secondary challenge with either TMVP, decapeptide-SHGG, or decapeptide-BA failed to distinguish between the responsive memory B cells; the antidecapeptide antibodies induced by all three immunogens shared the same fine specificities and immunoglobulin isotype composition. These data are viewed as further evidence that subsets of TD-primed B cells, which may display differential sensitivity to cross-stimulation with TD and TI forms of the antigen, represent distinct stages of memory B cell maturation within a common B cell lineage. In support of this conclusion, we establish a developmental relationship between TI and/or TD responsive decapeptide memory B cell in the following communication.

Asymmetric soft-error resistant memory

NASA Technical Reports Server (NTRS)

Buehler, Martin G. (Inventor); Perlman, Marvin (Inventor)

1991-01-01

A memory system is provided, of the type that includes an error-correcting circuit that detects and corrects, that more efficiently utilizes the capacity of a memory formed of groups of binary cells whose states can be inadvertently switched by ionizing radiation. Each memory cell has an asymmetric geometry, so that ionizing radiation causes a significantly greater probability of errors in one state than in the opposite state (e.g., an erroneous switch from '1' to '0' is far more likely than a switch from '0' to'1'. An asymmetric error correcting coding circuit can be used with the asymmetric memory cells, which requires fewer bits than an efficient symmetric error correcting code.

Cutting Edge: Protection by Antiviral Memory CD8 T Cells Requires Rapidly Produced Antigen in Large Amounts.

PubMed

Remakus, Sanda; Ma, Xueying; Tang, Lingjuan; Xu, Ren-Huan; Knudson, Cory; Melo-Silva, Carolina R; Rubio, Daniel; Kuo, Yin-Ming; Andrews, Andrew; Sigal, Luis J

2018-05-15

Numerous attempts to produce antiviral vaccines by harnessing memory CD8 T cells have failed. A barrier to progress is that we do not know what makes an Ag a viable target of protective CD8 T cell memory. We found that in mice susceptible to lethal mousepox (the mouse homolog of human smallpox), a dendritic cell vaccine that induced memory CD8 T cells fully protected mice when the infecting virus produced Ag in large quantities and with rapid kinetics. Protection did not occur when the Ag was produced in low amounts, even with rapid kinetics, and protection was only partial when the Ag was produced in large quantities but with slow kinetics. Hence, the amount and timing of Ag expression appear to be key determinants of memory CD8 T cell antiviral protective immunity. These findings may have important implications for vaccine design. Copyright © 2018 by The American Association of Immunologists, Inc.

Entorhinal Cortical Ocean Cells Encode Specific Contexts and Drive Context-Specific Fear Memory

PubMed Central

Kitamura, Takashi; Sun, Chen; Martin, Jared; Kitch, Lacey J; Schnitzer, Mark J; Tonegawa, Susumu

2016-01-01

Summary Forming distinct representations and memories of multiple contexts and episodes is thought to be a crucial function of the hippocampal-entorhinal cortical network. The hippocampal dentate gyrus (DG) and CA3 are known to contribute to these functions but the role of the entorhinal cortex (EC) is poorly understood. Here, we show that Ocean cells, excitatory stellate neurons in the medial EC layer II projecting into DG and CA3, rapidly form a distinct representation of a novel context and drive context-specific activation of downstream CA3 cells as well as context-specific fear memory. In contrast, Island cells, excitatory pyramidal neurons in the medial EC layer II projecting into CA1, are indifferent to context-specific encoding or memory. On the other hand, Ocean cells are dispensable for temporal association learning, for which Island cells are crucial. Together, the two excitatory medial EC layer II inputs to the hippocampus have complementary roles in episodic memory. PMID:26402611

Cell-Type-Specific Transcriptome Analysis in the Drosophila Mushroom Body Reveals Memory-Related Changes in Gene Expression.

PubMed

Crocker, Amanda; Guan, Xiao-Juan; Murphy, Coleen T; Murthy, Mala

2016-05-17

Learning and memory formation in Drosophila rely on a network of neurons in the mushroom bodies (MBs). Whereas numerous studies have delineated roles for individual cell types within this network in aspects of learning or memory, whether or not these cells can also be distinguished by the genes they express remains unresolved. In addition, the changes in gene expression that accompany long-term memory formation within the MBs have not yet been studied by neuron type. Here, we address both issues by performing RNA sequencing on single cell types (harvested via patch pipets) within the MB. We discover that the expression of genes that encode cell surface receptors is sufficient to identify cell types and that a subset of these genes, required for sensory transduction in peripheral sensory neurons, is not only expressed within individual neurons of the MB in the central brain, but is also critical for memory formation. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Viral infection of implanted meningeal tumors induces antitumor memory T-cells to travel to the brain and eliminate established tumors.

PubMed

Gao, Yanhua; Whitaker-Dowling, Patricia; Barmada, Mamdouha A; Basse, Per H; Bergman, Ira

2015-04-01

Leptomeningeal metastases occur in 2%-5% of patients with breast cancer and have an exceptionally poor prognosis. The blood-brain and blood-meningeal barriers severely inhibit successful chemotherapy. We have developed a straightforward method to induce antitumor memory T-cells using a Her2/neu targeted vesicular stomatitis virus. We sought to determine whether viral infection of meningeal tumor could attract antitumor memory T-cells to eradicate the tumors. Meningeal implants in mice were studied using treatment trials and analyses of immune cells in the tumors. This paper demonstrates that there is a blood-meningeal barrier to bringing therapeutic memory T-cells to meningeal tumors. The barrier can be overcome by viral infection of the tumor. Viral infection of the meningeal tumors followed by memory T-cell transfer resulted in 89% cure of meningeal tumor in 2 different mouse strains. Viral infection produced increased infiltration and proliferation of transferred memory T-cells in the meningeal tumors. Following viral infection, the leukocyte infiltration in meninges and tumor shifted from predominantly macrophages to predominantly T-cells. Finally, this paper shows that successful viral therapy of peritoneal tumors generates memory CD8 T-cells that prevent establishment of tumor in the meninges of these same animals. These results support the hypothesis that a virally based immunization strategy can be used to both prevent and treat meningeal metastases. The meningeal barriers to cancer therapy may be much more permeable to treatment based on cells than treatment based on drugs or molecules. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Analog Nonvolatile Computer Memory Circuits

NASA Technical Reports Server (NTRS)

MacLeod, Todd

2007-01-01

In nonvolatile random-access memory (RAM) circuits of a proposed type, digital data would be stored in analog form in ferroelectric field-effect transistors (FFETs). This type of memory circuit would offer advantages over prior volatile and nonvolatile types: In a conventional complementary metal oxide/semiconductor static RAM, six transistors must be used to store one bit, and storage is volatile in that data are lost when power is turned off. In a conventional dynamic RAM, three transistors must be used to store one bit, and the stored bit must be refreshed every few milliseconds. In contrast, in a RAM according to the proposal, data would be retained when power was turned off, each memory cell would contain only two FFETs, and the cell could store multiple bits (the exact number of bits depending on the specific design). Conventional flash memory circuits afford nonvolatile storage, but they operate at reading and writing times of the order of thousands of conventional computer memory reading and writing times and, hence, are suitable for use only as off-line storage devices. In addition, flash memories cease to function after limited numbers of writing cycles. The proposed memory circuits would not be subject to either of these limitations. Prior developmental nonvolatile ferroelectric memories are limited to one bit per cell, whereas, as stated above, the proposed memories would not be so limited. The design of a memory circuit according to the proposal must reflect the fact that FFET storage is only partly nonvolatile, in that the signal stored in an FFET decays gradually over time. (Retention times of some advanced FFETs exceed ten years.) Instead of storing a single bit of data as either a positively or negatively saturated state in a ferroelectric device, each memory cell according to the proposal would store two values. The two FFETs in each cell would be denoted the storage FFET and the control FFET. The storage FFET would store an analog signal value, between the positive and negative FFET saturation values. This signal value would represent a numerical value of interest corresponding to multiple bits: for example, if the memory circuit were designed to distinguish among 16 different analog values, then each cell could store 4 bits. Simultaneously with writing the signal value in the storage FFET, a negative saturation signal value would be stored in the control FFET. The decay of this control-FFET signal from the saturation value would serve as a model of the decay, for use in regenerating the numerical value of interest from its decaying analog signal value. The memory circuit would include addressing, reading, and writing circuitry that would have features in common with the corresponding parts of other memory circuits, but would also have several distinctive features. The writing circuitry would include a digital-to-analog converter (DAC); the reading circuitry would include an analog-to-digital converter (ADC). For writing a numerical value of interest in a given cell, that cell would be addressed, the saturation value would be written in the control FFET in that cell, and the non-saturation analog value representing the numerical value of interest would be generated by use of the DAC and stored in the storage FFET in that cell. For reading the numerical value of interest stored in a given cell, the cell would be addressed, the ADC would convert the decaying control and storage analog signal values to digital values, and an associated fast digital processing circuit would regenerate the numerical value from digital values.

From sensorimotor learning to memory cells in prefrontal and temporal association cortex: a neurocomputational study of disembodiment.

PubMed

Pulvermüller, Friedemann; Garagnani, Max

2014-08-01

Memory cells, the ultimate neurobiological substrates of working memory, remain active for several seconds and are most commonly found in prefrontal cortex and higher multisensory areas. However, if correlated activity in "embodied" sensorimotor systems underlies the formation of memory traces, why should memory cells emerge in areas distant from their antecedent activations in sensorimotor areas, thus leading to "disembodiment" (movement away from sensorimotor systems) of memory mechanisms? We modelled the formation of memory circuits in six-area neurocomputational architectures, implementing motor and sensory primary, secondary and higher association areas in frontotemporal cortices along with known between-area neuroanatomical connections. Sensorimotor learning driven by Hebbian neuroplasticity led to formation of cell assemblies distributed across the different areas of the network. These action-perception circuits (APCs) ignited fully when stimulated, thus providing a neural basis for long-term memory (LTM) of sensorimotor information linked by learning. Subsequent to ignition, activity vanished rapidly from APC neurons in sensorimotor areas but persisted in those in multimodal prefrontal and temporal areas. Such persistent activity provides a mechanism for working memory for actions, perceptions and symbols, including short-term phonological and semantic storage. Cell assembly ignition and "disembodied" working memory retreat of activity to multimodal areas are documented in the neurocomputational models' activity dynamics, at the level of single cells, circuits, and cortical areas. Memory disembodiment is explained neuromechanistically by APC formation and structural neuroanatomical features of the model networks, especially the central role of multimodal prefrontal and temporal cortices in bridging between sensory and motor areas. These simulations answer the "where" question of cortical working memory in terms of distributed APCs and their inner structure, which is, in part, determined by neuroanatomical structure. As the neurocomputational model provides a mechanistic explanation of how memory-related "disembodied" neuronal activity emerges in "embodied" APCs, it may be key to solving aspects of the embodiment debate and eventually to a better understanding of cognitive brain functions. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Multi-floor cascading ferroelectric nanostructures: multiple data writing-based multi-level non-volatile memory devices

NASA Astrophysics Data System (ADS)

Hyun, Seung; Kwon, Owoong; Lee, Bom-Yi; Seol, Daehee; Park, Beomjin; Lee, Jae Yong; Lee, Ju Hyun; Kim, Yunseok; Kim, Jin Kon

2016-01-01

Multiple data writing-based multi-level non-volatile memory has gained strong attention for next-generation memory devices to quickly accommodate an extremely large number of data bits because it is capable of storing multiple data bits in a single memory cell at once. However, all previously reported devices have failed to store a large number of data bits due to the macroscale cell size and have not allowed fast access to the stored data due to slow single data writing. Here, we introduce a novel three-dimensional multi-floor cascading polymeric ferroelectric nanostructure, successfully operating as an individual cell. In one cell, each floor has its own piezoresponse and the piezoresponse of one floor can be modulated by the bias voltage applied to the other floor, which means simultaneously written data bits in both floors can be identified. This could achieve multi-level memory through a multiple data writing process.Multiple data writing-based multi-level non-volatile memory has gained strong attention for next-generation memory devices to quickly accommodate an extremely large number of data bits because it is capable of storing multiple data bits in a single memory cell at once. However, all previously reported devices have failed to store a large number of data bits due to the macroscale cell size and have not allowed fast access to the stored data due to slow single data writing. Here, we introduce a novel three-dimensional multi-floor cascading polymeric ferroelectric nanostructure, successfully operating as an individual cell. In one cell, each floor has its own piezoresponse and the piezoresponse of one floor can be modulated by the bias voltage applied to the other floor, which means simultaneously written data bits in both floors can be identified. This could achieve multi-level memory through a multiple data writing process. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr07377d

Performance Measurement of a Multi-Level/Analog Ferroelectric Memory Device Design

NASA Technical Reports Server (NTRS)

MacLeod, Todd C.; Phillips, Thomas A.; Ho, Fat D.

2007-01-01

Increasing the memory density and utilizing the unique characteristics of ferroelectric devices is important in making ferroelectric memory devices more desirable to the consumer. This paper describes the characterization of a design that allows multiple levels to be stored in a ferroelectric based memory cell. It can be used to store multiple bits or analog values in a high speed nonvolatile memory. The design utilizes the hysteresis characteristic of ferroelectric transistors to store an analog value in the memory cell. The design also compensates for the decay of the polarization of the ferroelectric material over time. This is done by utilizing a pair of ferroelectric transistors to store the data. One transistor is used a reference to determinethe amount of decay that has occurred since the pair was programmed. The second transistor stores the analog value as a polarization value between zero and saturated. The design allows digital data to be stored as multiple bits in each memory cell. The number of bits per cell that can be stored will vary with the decay rate of the ferroelectric transistors and the repeatability of polarization between transistors. This paper presents measurements of an actual prototype memory cell. This prototype is not a complete implementation of a device, but instead, a prototype of the storage and retrieval portion of an actual device. The performance of this prototype is presented with the projected performance of the overall device. This memory design will be useful because it allows higher memory density, compensates for the environmental and ferroelectric aging processes, allows analog values to be directly stored in memory, compensates for the thermal and radiation environments associated with space operations, and relies only on existing technologies.

Design of a Multi-Level/Analog Ferroelectric Memory Device

NASA Technical Reports Server (NTRS)

MacLeod, Todd C.; Phillips, Thomas A.; Ho, Fat D.

2006-01-01

Increasing the memory density and utilizing the dove1 characteristics of ferroelectric devices is important in making ferroelectric memory devices more desirable to the consumer. This paper describes a design that allows multiple levels to be stored in a ferroelectric based memory cell. It can be used to store multiple bits or analog values in a high speed nonvolatile memory. The design utilizes the hysteresis characteristic of ferroelectric transistors to store an analog value in the memory cell. The design also compensates for the decay of the polarization of the ferroelectric material over time. This is done by utilizing a pair of ferroelectric transistors to store the data. One transistor is used as a reference to determine the amount of decay that has occurred since the pair was programmed. The second transistor stores the analog value as a polarization value between zero and saturated. The design allows digital data to be stored as multiple bits in each memory cell. The number of bits per cell that can be stored will vary with the decay rate of the ferroelectric transistors and the repeatability of polarization between transistors. It is predicted that each memory cell may be able to store 8 bits or more. The design is based on data taken from actual ferroelectric transistors. Although the circuit has not been fabricated, a prototype circuit is now under construction. The design of this circuit is different than multi-level FLASH or silicon transistor circuits. The differences between these types of circuits are described in this paper. This memory design will be useful because it allows higher memory density, compensates for the environmental and ferroelectric aging processes, allows analog values to be directly stored in memory, compensates for the thermal and radiation environments associated with space operations, and relies only on existing technologies.

Cytomegalovirus Reinfections Stimulate CD8 T-Memory Inflation.

PubMed

Trgovcich, Joanne; Kincaid, Michelle; Thomas, Alicia; Griessl, Marion; Zimmerman, Peter; Dwivedi, Varun; Bergdall, Valerie; Klenerman, Paul; Cook, Charles H

2016-01-01

Cytomegalovirus (CMV) has been shown to induce large populations of CD8 T-effector memory cells that unlike central memory persist in large quantities following infection, a phenomenon commonly termed "memory inflation". Although murine models to date have shown very large and persistent CMV-specific T-cell expansions following infection, there is considerable variability in CMV-specific T-memory responses in humans. Historically such memory inflation in humans has been assumed a consequence of reactivation events during the life of the host. Because basic information about CMV infection/re-infection and reactivation in immune competent humans is not available, we used a murine model to test how primary infection, reinfection, and reactivation stimuli influence memory inflation. We show that low titer infections induce "partial" memory inflation of both mCMV specific CD8 T-cells and antibody. We show further that reinfection with different strains can boost partial memory inflation. Finally, we show preliminary results suggesting that a single strong reactivation stimulus does not stimulate memory inflation. Altogether, our results suggest that while high titer primary infections can induce memory inflation, reinfections during the life of a host may be more important than previously appreciated.

Figuring fact from fiction: unbiased polling of memory T cells.

PubMed

Gerlach, Carmen; Loughhead, Scott M; von Andrian, Ulrich H

2015-05-07

Immunization generates several memory T cell subsets that differ in their migratory properties, anatomic distribution, and, hence, accessibility to investigation. In this issue, Steinert et al. demonstrate that what was believed to be a minor memory cell subset in peripheral tissues has been dramatically underestimated. Thus, current models of protective immunity require revision. Copyright © 2015 Elsevier Inc. All rights reserved.

The distinctive germinal center phase of IgE+ B lymphocytes limits their contribution to the classical memory response

USDA-ARS?s Scientific Manuscript database

The mechanisms involved in the maintenance of memory IgE responses are poorly understood, and the role played by germinal center (GC) IgE+ cells in memory responses is particularly unclear. IgE B cell differentiation is characterized by a transient GC phase, a bias towards the plasma cell (PC) fate,...

Abacavir-Reactive Memory T Cells Are Present in Drug Naïve Individuals

PubMed Central

Lucas, Andrew; Lucas, Michaela; Strhyn, Anette; Keane, Niamh M.; McKinnon, Elizabeth; Pavlos, Rebecca; Moran, Ellen M.; Meyer-Pannwitt, Viola; Gaudieri, Silvana; D’Orsogna, Lloyd; Kalams, Spyros; Ostrov, David A.; Buus, Søren; Peters, Bjoern; Mallal, Simon; Phillips, Elizabeth

2015-01-01

Background Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population. Methods To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling. Results Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells. Conclusions We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection. PMID:25674793

Abacavir-reactive memory T cells are present in drug naïve individuals.

PubMed

Lucas, Andrew; Lucas, Michaela; Strhyn, Anette; Keane, Niamh M; McKinnon, Elizabeth; Pavlos, Rebecca; Moran, Ellen M; Meyer-Pannwitt, Viola; Gaudieri, Silvana; D'Orsogna, Lloyd; Kalams, Spyros; Ostrov, David A; Buus, Søren; Peters, Bjoern; Mallal, Simon; Phillips, Elizabeth

2015-01-01

Fifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population. To determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling. Abacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells. We propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.

Manipulating memory CD8 T cell numbers by timed enhancement of IL-2 signals1

PubMed Central

Kim, Marie T.; Kurup, Samarchith P.; Starbeck-Miller, Gabriel R.; Harty, John T.

2016-01-01

Due to the growing burden of tumors and chronic infections, manipulating CD8 T cell responses for clinical use has become an important goal for immunologists. Here, we show that dendritic cell (DC) immunization coupled with relatively early (days 1–3) or late (days 4–6) administration of enhanced IL-2-signals both increase peak effector CD8 T cell numbers, but only early IL-2 signals enhance memory numbers. IL-2 signals delivered at relatively late time points drive terminal differentiation, marked Bim mediated contraction and do not increase memory T cell numbers. In contrast, early IL-2 signals induce effector cell metabolic profiles more conducive to memory formation. Of note, down-regulation of CD80 and CD86 was observed on DCs in vivo following early IL-2 treatment. Mechanistically, early IL-2 treatment enhanced CTLA-4 expression on regulatory T (Treg) cells, and CTLA-4 blockade alongside IL-2 treatment in vivo prevented the decrease in CD80 and CD86, supporting a cell-extrinsic role of CTLA-4 in down-regulating B7-ligand expression on DCs. Finally, DC immunization followed by early IL-2 treatment and αCTLA-4 blockade resulted in lower memory CD8 T cell numbers compared to the DC + early IL-2 treatment group. These data suggest that curtailed signaling through the B7-CD28 co-stimulatory axis during CD8 T cell activation limits terminal differentiation and preserves memory CD8 T cell formation and thus, should be considered in future T cell vaccination strategies. PMID:27439516

Particle sensor array

NASA Technical Reports Server (NTRS)

Buehler, Martin G. (Inventor); Blaes, Brent R. (Inventor); Lieneweg, Udo (Inventor)

1994-01-01

A particle sensor array which in a preferred embodiment comprises a static random access memory having a plurality of ion-sensitive memory cells, each such cell comprising at least one pull-down field effect transistor having a sensitive drain surface area (such as by bloating) and at least one pull-up field effect transistor having a source connected to an offset voltage. The sensitive drain surface area and the offset voltage are selected for memory cell upset by incident ions such as alpha-particles. The static random access memory of the present invention provides a means for selectively biasing the memory cells into the same state in which each of the sensitive drain surface areas is reverse biased and then selectively reducing the reversed bias on these sensitive drain surface areas for increasing the upset sensitivity of the cells to ions. The resulting selectively sensitive memory cells can be used in a number of applications. By way of example, the present invention can be used for measuring the linear energy transfer of ion particles, as well as a device for assessing the resistance of CMOS latches to Cosmic Ray induced single event upsets. The sensor of the present invention can also be used to determine the uniformity of an ion beam.

Chronic Dry Eye Disease is Principally Mediated by Effector Memory Th17 Cells

PubMed Central

Chen, Yihe; Chauhan, Sunil K.; Lee, Hyun Soo; Saban, Daniel R.; Dana, Reza

2013-01-01

Recent experimental and clinical data suggest that there is a link between dry eye disease (DED) and T cell-mediated immunity. However, whether these immune responses are a consequence or cause of ocular surface inflammation remains to be determined. Thus far, only models of acute DED have been used to derive experimental data. This is in contrast to clinical DED which usually presents as a chronic disease. In the present study, using a murine model of chronic DED, it was established that the chronic phase of the disease is accompanied by Th17 responses at the ocular surface, and that a significant memory T cell population can be recovered from chronic DED. This memory response is predominantly mediated by Th17 cells. Moreover, adoptive transfer of this memory T cell population was shown to induce more severe and rapidly progressing DED than did the adoptive transfer of its effector or naïve counterparts. Not only do these results clearly demonstrate that effector memory Th17 cells are primarily responsible for maintaining the chronic and relapsing course of DED, but they also highlight a potentially novel therapeutic strategy for targeting memory immune responses in patients with DED. PMID:23571503

Attrition of memory CD8 T cells during sepsis requires LFA-1.

PubMed

Serbanescu, Mara A; Ramonell, Kimberly M; Hadley, Annette; Margoles, Lindsay M; Mittal, Rohit; Lyons, John D; Liang, Zhe; Coopersmith, Craig M; Ford, Mandy L; McConnell, Kevin W

2016-11-01

CD8 T cell loss and dysfunction have been implicated in the increased susceptibility to opportunistic infections during the later immunosuppressive phase of sepsis, but CD8 T cell activation and attrition in early sepsis remain incompletely understood. With the use of a CLP model, we assessed CD8 T cell activation at 5 consecutive time points and found that activation after sepsis results in a distinct phenotype (CD69 + CD25 int CD62L HI ) independent of cognate antigen recognition and TCR engagement and likely through bystander-mediated cytokine effects. Additionally, we observed that sepsis concurrently results in the preferential depletion of a subset of memory-phenotype CD8 T cells that remain "unactivated" (i.e., fail to up-regulate activation markers) by apoptosis. Unactivated CD44 HI OT-I cells were spared from sepsis-induced attrition, as were memory-phenotype CD8 T cells of mice treated with anti-LFA-1 mAb, 1 h after CLP. Perhaps most importantly, we demonstrate that attrition of memory phenotype cells may have a pathologic significance, as elevated IL-6 levels were associated with decreased numbers of memory-phenotype CD8 T cells in septic mice, and preservation of this subset after administration of anti-LFA-1 mAb conferred improved survival at 7 d. Taken together, these data identify potentially modifiable responses of memory-phenotype CD8 T cells in early sepsis and may be particularly important in the application of immunomodulatory therapies in sepsis. © Society for Leukocyte Biology.

Attrition of memory CD8 T cells during sepsis requires LFA-1

PubMed Central

Serbanescu, Mara A.; Ramonell, Kimberly M.; Hadley, Annette; Margoles, Lindsay M.; Mittal, Rohit; Lyons, John D.; Liang, Zhe; Coopersmith, Craig M.; Ford, Mandy L.; McConnell, Kevin W.

2016-01-01

CD8 T cell loss and dysfunction have been implicated in the increased susceptibility to opportunistic infections during the later immunosuppressive phase of sepsis, but CD8 T cell activation and attrition in early sepsis remain incompletely understood. With the use of a CLP model, we assessed CD8 T cell activation at 5 consecutive time points and found that activation after sepsis results in a distinct phenotype (CD69+CD25intCD62LHI) independent of cognate antigen recognition and TCR engagement and likely through bystander-mediated cytokine effects. Additionally, we observed that sepsis concurrently results in the preferential depletion of a subset of memory-phenotype CD8 T cells that remain “unactivated” (i.e., fail to up-regulate activation markers) by apoptosis. Unactivated CD44HI OT-I cells were spared from sepsis-induced attrition, as were memory-phenotype CD8 T cells of mice treated with anti-LFA-1 mAb, 1 h after CLP. Perhaps most importantly, we demonstrate that attrition of memory phenotype cells may have a pathologic significance, as elevated IL-6 levels were associated with decreased numbers of memory-phenotype CD8 T cells in septic mice, and preservation of this subset after administration of anti-LFA-1 mAb conferred improved survival at 7 d. Taken together, these data identify potentially modifiable responses of memory-phenotype CD8 T cells in early sepsis and may be particularly important in the application of immunomodulatory therapies in sepsis. PMID:27286793

IL-7 promotes long-term in vitro survival of unique long-lived memory subset generated from mucosal effector memory CD4+ T cells in chronic colitis mice.

PubMed

Takahara, Masahiro; Nemoto, Yasuhiro; Oshima, Shigeru; Matsuzawa, Yu; Kanai, Takanori; Okamoto, Ryuichi; Tsuchiya, Kiichiro; Nakamura, Tetsuya; Yamamoto, Kazuhide; Watanabe, Mamoru

2013-01-01

Colitogenic memory CD4(+) T cells are important in the pathogenesis of inflammatory bowel disease (IBD). Although memory stem cells with high survival and self-renewal capacity were recently identified in both mice and humans, it is unclear whether a similar subset is present in chronic colitis mice. We sought to identify and purify a long-lived subset of colitogenic memory CD4(+) T cells, which may be targets for treatment of IBD. A long-lived subset of colitogenic memory CD4(+) T cells was purified using a long-term culture system. The characteristics of these cells were assessed. Interleukin (IL)-7 promoted the in vitro survival for >8 weeks of lamina propria (LP) CD4(+) T cells from colitic SCID mice previously injected with CD4(+)CD45RB(high) T cells. These cells were in a quiescent state and divided a maximum of 5 times in 4 weeks. LP CD4(+) T cells expressed higher levels of Bcl-2, integrin-α4β7, CXCR3 and CD25 after than before culture, as well as secreting high concentrations of IL-2 and low concentrations of IFN-γ and IL-17 in response to intestinal bacterial antigens. LP CD4(+) T cells from colitic mice cultured with IL-7 for 8 weeks induced more severe colitis than LP CD4(+) T cells cultured for 4 weeks. We developed a novel culture system to purify a long-lived, highly pathogenic memory subset from activated LP CD4(+) T cells. IL-7 promoted long-term in vitro survival of this subset in a quiescent state. This subset will be a novel, effective target for the treatment of IBD. Copyright © 2013 Elsevier B.V. All rights reserved.

Impairment of pneumococcal antigen specific isotype-switched Igg memory B-cell immunity in HIV infected Malawian adults.

PubMed

Iwajomo, Oluwadamilola H; Finn, Adam; Ogunniyi, Abiodun D; Williams, Neil A; Heyderman, Robert S

2013-01-01

Pneumococcal disease is associated with a particularly high morbidity and mortality amongst adults in HIV endemic countries. Our previous findings implicating a B-cell defect in HIV-infected children from the same population led us to comprehensively characterize B-cell subsets in minimally symptomatic HIV-infected Malawian adults and investigate the isotype-switched IgG memory B-cell immune response to the pneumococcus. We show that similar to vertically acquired HIV-infected Malawian children, horizontally acquired HIV infection in these adults is associated with IgM memory B-cell (CD19(+) CD27(+) IgM(+) IgD(+)) depletion, B-cell activation and impairment of specific IgG B-cell memory to a range of pneumococcal proteins. Our data suggest that HIV infection affects both T-cell independent and T-cell dependent B-cell maturation, potentially leading to impairment of humoral responses to extracellular pathogens such as the pneumococcus, and thus leaving this population susceptible to invasive disease.

Biodegradable double-targeted PTX-mPEG-PLGA nanoparticles for ultrasound contrast enhanced imaging and antitumor therapy in vitro.

PubMed

Ma, Jing; Shen, Ming; Xu, Chang Song; Sun, Ying; Duan, You Rong; Du, Lian Fang

2016-11-29

A porous-structure nano-scale ultrasound contrast agent (UCA) was made of monomethoxypoly (ethylene glycol)-poly (lactic-co-glycolic acid) (mPEG-PLGA), and modified by double-targeted antibody: anti-carcinoembryonic antigen (CEA) and anti-carbohydrate antigen 19-9 (CA19-9), as a double-targeted nanoparticles (NPs). Anti-tumor drug paclitaxel (PTX) was encapsulated in the double-targeted nanoparticles (NPs). The morphor and release curve were characterized. We verified a certain anticancer effect of PTX-NPs through cytotoxicity experiments. The cell uptake result showed much more NPs may be facilitated to ingress the cells or tissues with ultrasound (US) or ultrasound targeted microbubble destruction (UTMD) transient sonoporation in vitro. Ultrasound contrast-enhanced images in vitro and in vivo were investigated. Compared with SonoVue, the NPs prolonged imaging time in rabbit kidneys and tumor of nude mice, which make it possible to further enhance anti-tumor effects by extending retention time in the tumor region. The novel double-targeted NPs with the function of ultrasound contrast enhanced imaging and anti-tumor therapy can be a promising way in clinic.

Effect of sonically induced deflocculation on the efficiency of ozone mediated partial sludge disintegration for improved production of biogas.

PubMed

Sowmya Packyam, G; Kavitha, S; Adish Kumar, S; Kaliappan, S; Yeom, Ick Tae; Rajesh Banu, J

2015-09-01

In this study, ultrasonication was used for sludge deflocculation, followed by cell disintegration using ozone. The effect of this phase separated sono-ozone pretreatment is evaluated based on extra polymeric substances release, deoxyribonucleic acid (DNA) in the medium, solubilization of intra cellular components and suspended solids (SS) reduction. Ultrasonically induced deflocculation was optimized at an energy dosage of 76.4(log 1.88)kJ/kg TS. During cell disintegration (ozone dosage 0.0011 mgO3/mgSS), chemical oxygen demand solubilization (COD) and SS reduction of sonic mediated ozone pretreated sludge were 25.4% and 17.8% comparatively higher than ozone pretreated sludge, respectively. Further, biogas production potential of control (raw), flocculated (ozone pretreated), and deflocculated (sonic mediated ozone pretreated) sludges were observed to be 0.202, 0.535 and 0.637 L/(gVS), respectively. Thus, the phase separated pretreatment at lower ultrasonic specific energy and low dose ozone proved to enhance the anaerobic biodegradability efficiently. Copyright © 2015 Elsevier B.V. All rights reserved.

Antigen-dependent proliferation and cytokine induction in respiratory syncytial virus-infected cotton rats reflect the presence of effector-memory T cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richter, Bettina W.M.; Onuska, Jaya M.; Niewiesk, Stefan

2005-06-20

Respiratory syncytial virus (RSV) is a major cause of lower airway disease in infants and children. Immunity to RSV is not long lasting, resulting in re-occurring infections throughout life. Effective long-lived immunity results when central-memory T cells that proliferate vigorously and secrete IL-2 are present. In contrast, effector-memory T cells that mainly produce IFN-{gamma}, facilitate virus clearance but are not long lived. To identify the type of memory response induced after RSV-A (Long) infection, we characterized the kinetics of the antigen-specific immune response and identified the types of cytokines induced. RSV-specific lymphocytic proliferation following primary and secondary infection was similar,more » and in both cases responses waned within a short period of time. In addition, mRNA for IFN-{gamma} but not IL-2 was induced in RSV-specific CD4{sup +} T cells. This supports the idea that the presence of effector-memory rather than central-memory T cells contributes to the ineffectiveness of the immune response to RSV.« less

Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis.

PubMed

Perdomo, Carolina; Zedler, Ulrike; Kühl, Anja A; Lozza, Laura; Saikali, Philippe; Sander, Leif E; Vogelzang, Alexis; Kaufmann, Stefan H E; Kupz, Andreas

2016-11-22

Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (T RM ) cells have been implicated in protective immune responses against viral infections, but the role of T RM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and T RM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4 + T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8 + T cells displayed prototypical T RM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies. BCG remains the only licensed vaccine against TB. Parenterally administered BCG has variable efficacy against pulmonary TB, and thus, improved prevention strategies and a more refined understanding of correlates of vaccine protection are required. Induction of memory T cells has been shown to be essential for protective TB vaccines. Mimicking the natural infection route by mucosal vaccination has been known to generate superior protection against TB in animal models; however, the mechanisms of protection have remained elusive. Here we performed an in-depth analysis to dissect the immunological mechanisms associated with superior mucosal protection in the mouse model of TB. We found that mucosal, and not subcutaneous, BCG vaccination generates lung-resident memory T cell populations that confer protection against pulmonary TB. We establish a comprehensive phenotypic characterization of these populations, providing a framework for future vaccine development. Copyright © 2016 Perdomo et al.

Thermally efficient and highly scalable In2Se3 nanowire phase change memory

NASA Astrophysics Data System (ADS)

Jin, Bo; Kang, Daegun; Kim, Jungsik; Meyyappan, M.; Lee, Jeong-Soo

2013-04-01

The electrical characteristics of nonvolatile In2Se3 nanowire phase change memory are reported. Size-dependent memory switching behavior was observed in nanowires of varying diameters and the reduction in set/reset threshold voltage was as low as 3.45 V/6.25 V for a 60 nm nanowire, which is promising for highly scalable nanowire memory applications. Also, size-dependent thermal resistance of In2Se3 nanowire memory cells was estimated with values as high as 5.86×1013 and 1.04×106 K/W for a 60 nm nanowire memory cell in amorphous and crystalline phases, respectively. Such high thermal resistances are beneficial for improvement of thermal efficiency and thus reduction in programming power consumption based on Fourier's law. The evaluation of thermal resistance provides an avenue to develop thermally efficient memory cell architecture.

Origin and fate of lymphocytic choriomeningitis virus-specific CD8+ T cells coexpressing the inhibitory NK cell receptor Ly49G2.

PubMed

Peacock, Craig D; Welsh, Raymond M

2004-07-01

CD8+ T cells that coexpress the inhibitory NK cell receptor, Ly49G2 (G2), are present in immunologically naive C57BL/6 mice but display Ags found on memory T cells. To assess how G2+CD8+ cells relate to bona fide memory cells, we examined the origin and fate of lymphocytic choriomeningitis virus (LCMV)-induced G2+CD8+ cells. During early (day 4) acute LCMV infection, both G2+ and G2-CD8+ T cell subsets underwent an attrition in number and displayed an activation (CD69(high)1B11(high)CD62L(low)) phenotype. By day 8, both subsets synthesized IFN-gamma in response to immunodominant LCMV peptides, though the expansion of G2+ cells was less than that of G2- cells. Adoptive transfer experiments with purified G2- or G2+CD8+ cells from naive mice indicated that the LCMV-specific G2+ subset was derived from a pre-existing G2+ population and not generated from G2- cells responding to LCMV infection. Their participation in the LCMV-specific T cell response increased with age, reflecting an increase in the size of the pre-existing G2+ pool. Following establishment of stable LCMV memory, the proportion of CD8+ cells coexpressing G2 was reduced in comparison to naive controls, presumably due to displacement by G2- LCMV-specific memory cells. LCMV-specific G2+ cells were present in the memory pool, but at low frequencies, and they did not exhibit the typical phenotypic changes of reactivation during secondary challenge. We suggest that G2+CD8+ cells represent a cell lineage distinct from bona fide memory T cells, but that they can participate in an acute virus-specific T cell response.

Intrinsic role of FoxO3a in the development of CD8+ T cell memory

PubMed Central

Tzelepis, Fanny; Joseph, Julie; Haddad, Elias K.; MacLean, Susanne; Dudani, Renu; Agenes, Fabien; Peng, Stanford L.; Sekaly, Rafick-Pierre; Sad, Subash

2013-01-01

CD8+ T cells undergo rapid expansion during infection with intracellular pathogens, which is followed by swift and massive culling of primed CD8+ T cells. The mechanisms that govern the massive contraction and maintenance of primed CD8+ T cells are not clear. We show here that the transcription factor, FoxO3a does not influence antigen-presentation and the consequent expansion of CD8+ T cell response during Listeria monocytogenes (LM) infection, but plays a key role in the maintenance of memory CD8+ T cells. The effector function of primed CD8+ T cells as revealed by cytokine secretion and CD107a degranulation was not influenced by inactivation of FoxO3a. Interestingly, FoxO3a-deficient CD8+ T cells displayed reduced expression of pro-apoptotic molecules BIM and PUMA during the various phases of response, and underwent reduced apoptosis in comparison to WT cells. A higher number of memory precursor effector cells (MPECs) and memory subsets were detectable in FoxO3a-deficient mice compared to WT mice. Furthermore, FoxO3a-deficient memory CD8+ T cells upon transfer into normal or RAG1-deficient mice displayed enhanced survival. These results suggest that FoxO3a acts in a cell intrinsic manner to regulate the survival of primed CD8+ T cells. PMID:23277488

Dopaminergic neurons write and update memories with cell-type-specific rules

PubMed Central

Aso, Yoshinori; Rubin, Gerald M

2016-01-01

Associative learning is thought to involve parallel and distributed mechanisms of memory formation and storage. In Drosophila, the mushroom body (MB) is the major site of associative odor memory formation. Previously we described the anatomy of the adult MB and defined 20 types of dopaminergic neurons (DANs) that each innervate distinct MB compartments (Aso et al., 2014a, 2014b). Here we compare the properties of memories formed by optogenetic activation of individual DAN cell types. We found extensive differences in training requirements for memory formation, decay dynamics, storage capacity and flexibility to learn new associations. Even a single DAN cell type can either write or reduce an aversive memory, or write an appetitive memory, depending on when it is activated relative to odor delivery. Our results show that different learning rules are executed in seemingly parallel memory systems, providing multiple distinct circuit-based strategies to predict future events from past experiences. DOI: http://dx.doi.org/10.7554/eLife.16135.001 PMID:27441388

Rapid allergen-induced interleukin-17 and interferon-γ secretion by skin-resident memory CD8+ T cells.

PubMed

Schmidt, Jonas D; Ahlström, Malin G; Johansen, Jeanne D; Dyring-Andersen, Beatrice; Agerbeck, Christina; Nielsen, Morten M; Poulsen, Steen S; Woetmann, Anders; Ødum, Niels; Thomsen, Allan R; Geisler, Carsten; Bonefeld, Charlotte M

2017-04-01

Skin-resident memory T (T RM ) cells are associated with immunological memory in the skin. Whether immunological memory responses to allergens in the skin are solely localized to previously allergen-exposed sites or are present globally in the skin is not clear. Furthermore, the mechanisms whereby T RM cells induce rapid recall responses need further investigation. To study whether contact allergens induce local and/or global memory, and to determine the mechanisms involved in memory responses in the skin. To address these questions, we analysed responses to contact allergens in mice and humans sensitized to 2,4-dinitrofluorobenzene and nickel, respectively. Challenge responses in both mice and humans were dramatically increased at sites previously exposed to allergens as compared with previously unexposed sites. Importantly, the magnitude of the challenge response correlated with the epidermal accumulation of interleukin (IL)-17A-producing and interferon (IFN)-γ-producing T RM cells. Moreover, IL-17A and IFN-γ enhanced allergen-induced IL-1β production in keratinocytes. We show that sensitization with contact allergens induces a strong, long-lasting local memory and a weaker, temporary global immunological memory response to the allergen that is mediated by IL-17A-producing and IFN-γ-producing CD8 + T RM cells. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

CD22 is required for formation of memory B cell precursors within germinal centers.

PubMed

Chappell, Craig P; Draves, Kevin E; Clark, Edward A

2017-01-01

CD22 is a BCR co-receptor that regulates B cell signaling, proliferation and survival and is required for T cell-independent Ab responses. To investigate the role of CD22 during T cell-dependent (TD) Ab responses and memory B cell formation, we analyzed Ag-specific B cell responses generated by wild-type (WT) or CD22-/- B cells following immunization with a TD Ag. CD22-/- B cells mounted normal early Ab responses yet failed to generate either memory B cells or long-lived plasma cells, whereas WT B cells formed both populations. Surprisingly, B cell expansion and germinal center (GC) differentiation were comparable between WT and CD22-/- B cells. CD22-/- B cells, however, were significantly less capable of generating a population of CXCR4hiCD38hi GC B cells, which we propose represent memory B cell precursors within GCs. These results demonstrate a novel role for CD22 during TD humoral responses evident during primary GC formation and underscore that CD22 functions not only during B cell maturation but also during responses to both TD and T cell-independent antigens.

CD22 is required for formation of memory B cell precursors within germinal centers

PubMed Central

Chappell, Craig P.; Draves, Kevin E.

2017-01-01

CD22 is a BCR co-receptor that regulates B cell signaling, proliferation and survival and is required for T cell-independent Ab responses. To investigate the role of CD22 during T cell-dependent (TD) Ab responses and memory B cell formation, we analyzed Ag-specific B cell responses generated by wild-type (WT) or CD22-/- B cells following immunization with a TD Ag. CD22-/- B cells mounted normal early Ab responses yet failed to generate either memory B cells or long-lived plasma cells, whereas WT B cells formed both populations. Surprisingly, B cell expansion and germinal center (GC) differentiation were comparable between WT and CD22-/- B cells. CD22-/- B cells, however, were significantly less capable of generating a population of CXCR4hiCD38hi GC B cells, which we propose represent memory B cell precursors within GCs. These results demonstrate a novel role for CD22 during TD humoral responses evident during primary GC formation and underscore that CD22 functions not only during B cell maturation but also during responses to both TD and T cell-independent antigens. PMID:28346517

Characteristics of memory B cells elicited by a highly efficacious HPV vaccine in subjects with no pre-existing immunity.

PubMed

Scherer, Erin M; Smith, Robin A; Simonich, Cassandra A; Niyonzima, Nixon; Carter, Joseph J; Galloway, Denise A

2014-10-01

Licensed human papillomavirus (HPV) vaccines provide near complete protection against the types of HPV that most commonly cause anogenital and oropharyngeal cancers (HPV 16 and 18) when administered to individuals naive to these types. These vaccines, like most other prophylactic vaccines, appear to protect by generating antibodies. However, almost nothing is known about the immunological memory that forms following HPV vaccination, which is required for long-term immunity. Here, we have identified and isolated HPV 16-specific memory B cells from female adolescents and young women who received the quadrivalent HPV vaccine in the absence of pre-existing immunity, using fluorescently conjugated HPV 16 pseudoviruses to label antigen receptors on the surface of memory B cells. Antibodies cloned and expressed from these singly sorted HPV 16-pseudovirus labeled memory B cells were predominantly IgG (>IgA>IgM), utilized diverse variable genes, and potently neutralized HPV 16 pseudoviruses in vitro despite possessing only average levels of somatic mutation. These findings suggest that the quadrivalent HPV vaccine provides an excellent model for studying the development of B cell memory; and, in the context of what is known about memory B cells elicited by influenza vaccination/infection, HIV-1 infection, or tetanus toxoid vaccination, indicates that extensive somatic hypermutation is not required to achieve potent vaccine-specific neutralizing antibody responses.

Memory Applications Using Resonant Tunneling Diodes

NASA Astrophysics Data System (ADS)

Shieh, Ming-Huei

Resonant tunneling diodes (RTDs) producing unique folding current-voltage (I-V) characteristics have attracted considerable research attention due to their promising application in signal processing and multi-valued logic. The negative differential resistance of RTDs renders the operating points self-latching and stable. We have proposed a multiple -dimensional multiple-state RTD-based static random-access memory (SRAM) cell in which the number of stable states can significantly be increased to (N + 1)^ m or more for m number of N-peak RTDs connected in series. The proposed cells take advantage of the hysteresis and folding I-V characteristics of RTD. Several cell designs are presented and evaluated. A two-dimensional nine-state memory cell has been implemented and demonstrated by a breadboard circuit using two 2-peak RTDs. The hysteresis phenomenon in a series of RTDs is also further analyzed. The switch model provided in SPICE 3 can be utilized to simulate the hysteretic I-V characteristics of RTDs. A simple macro-circuit is described to model the hysteretic I-V characteristic of RTD for circuit simulation. A new scheme for storing word-wide multiple-bit information very efficiently in a single memory cell using RTDs is proposed. An efficient and inexpensive periphery circuit to read from and write into the cell is also described. Simulation results on the design of a 3-bit memory cell scheme using one-peak RTDs are also presented. Finally, a binary transistor-less memory cell which is only composed of a pair of RTDs and an ordinary rectifier diode is presented and investigated. A simple means for reading and writing information from or into the memory cell is also discussed.

Rescue of CD8+ T cell vaccine memory following sublethal γ irradiation.

PubMed

McFarland, Hugh I; Berkson, Julia D; Lee, Jay P; Elkahloun, Abdel G; Mason, Karen P; Rosenberg, Amy S

2015-07-31

Sublethal γ irradiation eliminates CD8+ T cell mediated memory responses. In this work, we explored how these memory responses could be rescued in the aftermath of such exposure. We utilized two models of CD8+ T cell mediated immunity: a mouse model of Listeria monocytogenes (LM) infection in which CD8+ T cells specific for LM expressed antigens (Listeriolysin O, LLO) can be tracked, and a murine skin graft model in which CD8+ T cells mediate rejection across a MHC class I (D(d)) disparity. In the LM immunized mice, LL0 specific CD8+ T memory cells were lost on irradiation, preserved with rapid revaccination with an attenuated strain 1-3 days post-irradiation (PI), and these mice survived a subsequent wild type LM challenge. A genetic "signature of rescue" identified a group of immune-associated mRNA maintained or upregulated following irradiation and rescue. A number of these factors, including IL-36γ, dectin-2 (Clec4n), and mir101c are upregulated rapidly after exposure of mice to sublethal γ radiation alone and are sustained by early, but not later rescue. Such factors will be evaluated as potential therapeutics to replace individual vaccines for global rescue of CD8+ T memory cell responses following sublethal γ irradiation. The skin allograft model mirrored that of the LM model in that the accelerated D(d) skin allograft rejection response was lost in mice exposed to sublethal γ radiation, but infusion of allogeneic D(d) expressing bone marrow cells 1-4 days PI preserved the CD8+ T memory mediated accelerated rejection response, further suggesting that innate immune responses may not always be essential to rescue of CD8+ memory T cells following γ irradiation. Published by Elsevier Ltd.

Phenotypes and distribution of mucosal memory B-cell populations in the SIV/SHIV Rhesus macaque model

PubMed Central

Demberg, Thorsten; Mohanram, Venkatramanan; Venzon, David; Robert-Guroff, Marjorie

2014-01-01

As vaccine-elicited antibodies have now been associated with HIV protective efficacy, a thorough understanding of mucosal and systemic B-cell development and maturation is needed. We phenotyped mucosal memory B-cells, investigated isotype expression and homing patterns, and defined plasmablasts and plasma cells at three mucosal sites (duodenum, jejunum and rectum) in rhesus macaques, the commonly used animal model for pre-clinical vaccine studies. Unlike humans, macaque mucosal memory B-cells lacked CD27 expression; only two sub-populations were present: naïve (CD21+CD27−) and tissue-like (CD21−CD27−) memory. Similar to humans, IgA was the dominant isotype expressed. The homing markers CXCR4, CCR6, CCR9 and α4β7 were differentially expressed between naïve and tissue-like memory B-cells. Mucosal plasmablasts were identified as CD19+CD20+/−HLA-DR+Ki-67+IRF4+CD138+/− and mucosal plasma cells as CD19+CD20−HLA-DR−Ki-67−IRF4+CD138+. Both populations were CD39+/−CD27−. Plasma cell phenotype was confirmed by spontaneous IgA secretion by ELISpot of positively-selected cells and J-chain expression by real-time PCR. Duodenal, jejunal and rectal samples were similar in B-cell memory phenotype, isotype expression, homing receptors and plasmablast/plasma cell distribution among the three tissues. Thus rectal biopsies adequately monitor B-cell dynamics in the gut mucosa, and provide a critical view of mucosal B-cell events associated with development of vaccine-elicited protective immune responses and SIV/SHIV pathogenesis and disease control. PMID:24814239

Fluorescently labeled dengue viruses as probes to identify antigen-specific memory B cells by multiparametric flow cytometry.

PubMed

Woda, Marcia; Mathew, Anuja

2015-01-01

Low frequencies of memory B cells in the peripheral blood make it challenging to measure the functional and phenotypic characteristics of this antigen experienced subset of B cells without in vitro culture. To date, reagents are lacking to measure ex vivo frequencies of dengue virus (DENV)-specific memory B cells. We wanted to explore the possibility of using fluorescently labeled DENV as probes to detect antigen-specific memory B cells in the peripheral blood of DENV immune individuals. Alexa Fluor dye-labeled DENV yielded viable virus that could be stored at -80°C for long periods of time. Using a careful gating strategy and methods to decrease non-specific binding, we were able to identify a small frequency of B cells from dengue immune individuals that bound labeled DENV. Sorted DENV(+) B cells from immune, but not naïve donors secreted antibodies that bound DENV after in vitro stimulation. Overall, Alexa Fluor dye-labeled DENVs are useful reagents to enable the detection and characterization of memory B cells in DENV immune individuals. Copyright © 2014 Elsevier B.V. All rights reserved.

Generation of cellular immune memory and B-cell immunity is impaired by natural killer cells.

PubMed

Rydyznski, Carolyn; Daniels, Keith A; Karmele, Erik P; Brooks, Taylor R; Mahl, Sarah E; Moran, Michael T; Li, Caimei; Sutiwisesak, Rujapak; Welsh, Raymond M; Waggoner, Stephen N

2015-02-27

The goal of most vaccines is the induction of long-lived memory T and B cells capable of protecting the host from infection by cytotoxic mechanisms, cytokines and high-affinity antibodies. However, efforts to develop vaccines against major human pathogens such as HIV and HCV have not been successful, thereby highlighting the need for novel approaches to circumvent immunoregulatory mechanisms that limit the induction of protective immunity. Here, we show that mouse natural killer (NK) cells inhibit generation of long-lived virus-specific memory T- and B cells as well as virus-specific antibody production after acute infection. Mechanistically, NK cells suppressed CD4 T cells and follicular helper T cells (T(FH)) in a perforin-dependent manner during the first few days of infection, resulting in a weaker germinal centre (GC) response and diminished immune memory. We anticipate that innovative strategies to relieve NK cell-mediated suppression of immunity should facilitate development of efficacious new vaccines targeting difficult-to-prevent infections.

Chronic exposure to trichloroethylene increases DNA methylation of the Ifng promoter in CD4+ T cells.

PubMed

Gilbert, Kathleen M; Blossom, Sarah J; Erickson, Stephen W; Broadfoot, Brannon; West, Kirk; Bai, Shasha; Li, Jingyun; Cooney, Craig A

2016-10-17

CD4 + T cells in female MRL+/+ mice exposed to solvent and water pollutant trichloroethylene (TCE) skew toward effector/memory CD4 + T cells, and demonstrate seemingly non-monotonic alterations in IFN-γ production. In the current study we examined the mechanism for this immunotoxicity using effector/memory and naïve CD4 + T cells isolated every 6 weeks during a 40 week exposure to TCE (0.5mg/ml in drinking water). A time-dependent effect of TCE exposure on both Ifng gene expression and IFN-γ protein production was observed in effector/memory CD4 + T cells, with an increase after 22 weeks of exposure and a decrease after 40 weeks of exposure. No such effect of TCE was observed in naïve CD4 + T cells. A cumulative increase in DNA methylation in the CpG sites of the promoter of the Ifng gene was observed in effector/memory, but not naïve, CD4 + T cells over time. Also unique to the Ifng promoter was an increase in methylation variance in effector/memory compared to naïve CD4 + T cells. Taken together, the CpG sites of the Ifng promoter in effector/memory CD4 + T cells were especially sensitive to the effects of TCE exposure, which may help explain the regulatory effect of the chemical on this gene. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Temporal dynamics of the primary human T cell response to yellow fever virus 17D as it matures from an effector- to a memory-type response.

PubMed

Blom, Kim; Braun, Monika; Ivarsson, Martin A; Gonzalez, Veronica D; Falconer, Karolin; Moll, Markus; Ljunggren, Hans-Gustaf; Michaëlsson, Jakob; Sandberg, Johan K

2013-03-01

The live attenuated yellow fever virus (YFV) 17D vaccine provides a good model to study immune responses to an acute viral infection in humans. We studied the temporal dynamics, composition, and character of the primary human T cell response to YFV. The acute YFV-specific effector CD8 T cell response was broad and complex; it was composed of dominant responses that persisted into the memory population, as well as of transient subdominant responses that were not detected at the memory stage. Furthermore, HLA-A2- and HLA-B7-restricted YFV epitope-specific effector cells predominantly displayed a CD45RA(-)CCR7(-)PD-1(+)CD27(high) phenotype, which transitioned into a CD45RA(+)CCR7(-)PD-1(-)CD27(low) memory population phenotype. The functional profile of the YFV-specific CD8 T cell response changed in composition as it matured from an effector- to a memory-type response, and it tended to become less polyfunctional during the course of this transition. Interestingly, activation of CD4 T cells, as well as FOXP3(+) T regulatory cells, in response to YFV vaccination preceded the kinetics of the CD8 T cell response. The present results contribute to our understanding of how immunodominance patterns develop, as well as the phenotypic and functional characteristics of the primary human T cell response to a viral infection as it evolves and matures into memory.

Switching kinetics of SiC resistive memory for harsh environments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morgan, K. A., E-mail: kam2g11@soton.ac.uk; Huang, R.; Groot, C. H. de

2015-07-15

Cu/a-SiC/Au resistive memory cells are measured using voltage pulses and exhibit the highest R{sub OFF}/R{sub ON} ratio recorded for any resistive memory. The switching kinetics are investigated and fitted to a numerical model, using thermal conductivity and resistivity properties of the dielectric. The SET mechanism of the Cu/a-SiC/Au memory cells is found to be due to ionic motion without joule heating contributions, whereas the RESET mechanism is found to be due to thermally assisted ionic motion. The conductive filament diameter is extracted to be around 4nm. The high thermal conductivity and resistivity for the Cu/a-SiC/Au memory cells result in slowmore » switching but with high thermal reliability and stability, showing potential for use in harsh environments. Radiation properties of SiC memory cells are investigated. No change was seen in DC sweep or pulsed switching nor in conductive mechanisms, up to 2Mrad(Si) using {sup 60}Co gamma irradiation.« less

Memory B lymphocytes determine repertoire oligoclonality early after haematopoietic stem cell transplantation

PubMed Central

OMAZIC, B; LUNDKVIST, I; MATTSSON, J; PERMERT, J; NÄSMAN-BJÖRK, I

2003-01-01

The objective of this study was to investigate if oligoclonality of the Ig repertoire post-haematopoietic stem cell transplantation (HSCT) is restricted to memory B lymphocytes or if it is a general property among B lymphocytes. As a measure of B lymphocyte repertoire diversity, we have analysed size distribution of polymerase chain reaction (PCR) amplified Ig H complementarity determining region 3 (CDR3) in naive and memory B lymphocytes isolated from patients before HSCT and at 3, 6 and 12 months after HSCT as well as from healthy controls. We demonstrate a limited variation of the IgH CDR3 repertoire in the memory B lymphocyte population compared to the naive B cell population. This difference was significant at 3 and 6 months post-HSCT. Compared to healthy controls there is a significant restriction of the memory B lymphocyte repertoire at 3 months after HSCT, but not of the naive B lymphocyte repertoire. Twelve months after HSCT, the IgH CDR3 repertoire in both memory and naive B lymphocytes are as diverse as in healthy controls. Thus, our findings suggest a role for memory B cells in the restriction of the oligoclonal B cell repertoire observed early after HSCT, which may be of importance when considering reimmunization of transplanted patients. PMID:12974769

Aortopexy for the treatment of tracheomalacia in children: review of the literature

PubMed Central

2012-01-01

Abstract Severe tracheomalacia presents a significant challenge for Paediatricians, Intensivists, Respiratory Physicians, Otolaryngologists and Paediatric Surgeons. The treatment of tracheomacia remains controversial, but aortopexy is considered by most to be one of the best options. We conducted a review of the English literature relating to aortopexy. Among 125 papers, 40 have been included in this review. Among 758 patients (62% males) affected with tracheomalacia, 581 underwent aortopexy. Associated co-morbidities were reported in 659 patients. The most frequent association was with oesophageal atresia (44%), vascular ring or large vessel anomalies (18%) and innominate artery compression (16%); in 9% tracheomalacia was idiopathic. The symptoms reported were various, but the most important indication for aortopexy was an acute life-threatening event (ALTE), observed in 43% of patients. The main preoperative investigation was bronchoscopy. Surgical approach was through a left anterior thoracotomy in 72% of patients, while median approach was chosen in 14% and in 1.3% a thoracoscopic aortopexy was performed. At follow-up (median 47 months) more than 80% of the patients improved significantly, but 8% showed no improvement, 4% had a worsening of their symptoms and 6% died. Complications were observed in 15% of patients, in 1% a redo aortopexy was deemed necessary. In our review, we found a lack of general consensus about symptom description and evaluation, indications for surgery, though ALTE and bronchoscopy were considered by all an absolute indication to aortopexy and the gold standard for the diagnosis of tracheomalacia, respectively. Differences were reported also in surgical approaches and technical details, so that the same term “aortopexy” was used to describe different types of procedures. Whatever approach or technique was used, the efficacy of aortopexy was reported as high in the majority of cases (more than 80%). A subgroup of patients particularly delicate is represented by those with associated gastro-esophageal reflux, in whom a fundoplication should be performed. Other treatments of tracheomalacia, particularly tracheal stenting, were associated with a higher rate of failure, severe morbidity and mortality. Non english abstract La tracheomalacia severa rappresenta una sfida per Pediatri, Intensivisti, Pneumologi, Otorinolaringoiatri, Chirurghi Pediatri. Il trattamento della tracheomalacia è tuttora controverso. L’aortopessi è considerata da molti la migliore opzione terapeutica. Abbiamo condotto una revisione della letteratura di lingua inglese su tale argomento. Di 125 lavori, 40 sono stati inclusi nella revisione. Tra 758 pazienti (62% maschi) affetti da tracheomalacia, 581 sono stati sottoposti ad aortopessi tra il 1968 e il 2008. In 659 pazienti alcune comorbidità erano presenti. L’associazione più frequente era con l’atresia esofagea (44%), l’anello vascolare o un’anomalia dei grossi vasi (18%), la compressione da parte dell’arteria innominata (16%); nel 9% la tracheomalacia era idiopatica. I sintomi riportati sono stati variabili, ma l’indicazione più importante all’aortopessi sono stati eventi di ALTE, osservati nel 43% dei pazienti. Lo studio diagnostico preoperatorio principale è stato la broncoscopia. L’approccio chirurgico è avvenuto attraverso una toracotomia anteriore sinistra nel 72% dei pazienti, mentre un approccio mediano è stato scelto nel 14% e nell’1.3% dei casi è stato eseguito un approccio toracoscopico. Al follow-up (mediana di 47 mesi) la maggioranza dei pazienti sono migliorati significativamente, ma l’8% di essi non è migliorato, il 4% è peggiorato e il 6% è morto. Complicazioni sono state riportate nel 15% dei pazienti, nell’1% un nuovo intervento di aortopessi è stato necessario. In questa revisione abbiamo trovato che non c’è un consenso generale sulla valutazione e sulla descrizione dei sintomi, sulle indicazioni chirurgiche ed esami preoperatori, anche se le ALTE e la broncoscopia venivano considerate rispettivamente un’indicazione assoluta all’aortopessi e il “gold standard” diagnostico per la tracheomalacia. Venivano riportate differenze negli approcci chirurgici e nei dettagli tecnici, e lo stesso termine di aortopessi veniva usato per indicare diverse procedure chirurgiche. In ogni caso, indipendentemente dall’approccio o tecnica utilizzati, l’efficacia dell’aortopessi veniva riportata come elevata nella maggioranza dei casi (più dell’80%). Un sottogruppo di pazienti particolarmente delicato è rappresentato da quelli con reflusso gastroesofageo associato, nei quali sarebbe indicata una fundoplicatio. Altri trattamenti della tracheomalacia, quali stent tracheale, sembrano gravati da una maggiore percentuale di insuccessi, morbidità severa e mortalità. PMID:23110796

[The role of endoscopy in gastroenteropancreatic neuroendocrine tumors].

PubMed

Magno, L; Sivero, L; Napolitano, V; Ruggiero, S; Fontanarosa, G; Massa, S

2010-01-01

Versione italiana Riassunto: Il ruolo dell'endoscopia nei tumori neuroendocrini gastroenteropancreatici. L. Magno, L. Sivero, V. Napolitano, S. Ruggiero, G. Fontanarosa, S. Massa I tumori neuroendocrini (NET) gastro-entero-pancreatici (GEP) sono neoplasie rare che originano dalle cellule neuroendocrine del tubo digerente e del pancreas. L'endoscopia digestiva e l'ecoendoscopia rivestono un ruolo importante nella diagnosi, stadiazione e sorveglianza dei pazienti con NET. Inoltre, in casi selezionati, le tecniche endoscopiche operative consentono il trattamento di queste neoplasie in fase precoce. English version Summary: The role of endoscopy in gastroenteropancreatic neuroendocrine tumors. L. Magno, L. Sivero, V. Napolitano, S. Ruggiero, G. Fontanarosa, S. Massa Gastroenteropancreatic (GEP) neuroendocrine tumors (NET) are rare neoplasia arisen from neuroendocrine cells present in the gut mucosa and pancreas. Digestive endoscopy and endoscopic ultrasonography play a relevant role in NET diagnosis, stadiation and surveillance. Moreover, in selected patients, surgical endoscopy allows the tratment of these cancers at an early stage.

Evaluation of profile and functionality of memory T cells in pulmonary tuberculosis.

PubMed

Tonaco, Marcela M; Moreira, Jôsimar D; Nunes, Fernanda F C; Loures, Cristina M G; Souza, Larissa R; Martins, Janaina M; Silva, Henrique R; Porto, Arthur Henrique R; Toledo, Vicente Paulo C P; Miranda, Silvana S; Guimarães, Tânia Mara P D

2017-12-01

The cells T CD4+ T and CD8+ can be subdivided into phenotypes naïve, T of central memory, T of effector memory and effector, according to the expression of surface molecules CD45RO and CD27. The T lymphocytes are cells of long life with capacity of rapid expansion and function, after a new antigenic exposure. In tuberculosis, it was found that specific memory T cells are present, however, gaps remain about the role of such cells in the disease immunology. In this study, the phenotypic profile was analyzed and characterized the functionality of CD4+ T lymphocytes and CD8+ T cells of memory and effector, in response to specific stimuli in vitro, in patients with active pulmonary TB, compared to individuals with latent infection with Mycobacterium tuberculosis the ones treated with pulmonary TB. It was observed that the group of patients with active pulmonary tuberculosis was the one which presented the highest proportion of cells T CD4+ of central memory IFN-ɣ+ e TNF-α+, suggesting that in TB, these T of central memory cells would have a profile of protective response, being an important target of study for the development of more effective vaccines; this group also developed lower proportion of CD8+ T effector lymphocytes than the others, a probable cause of specific and less effective response against the bacillus in these individuals; the ones treated for pulmonary tuberculosis were those who developed higher proportion of T CD4+ of memory central IL-17+ cells, indicating that the stimulation of long duration, with high antigenic load, followed by elimination of the pathogen, contribute to more significant generation of such cells; individuals with latent infection by M. tuberculosis and treated for pulmonary tuberculosis, showed greater response of CD8+ T effector lymphocytes IFN-ɣ+ than the controls, suggesting that these cells, as well as CD4+ T lymphocytes, have crucial role of protection against M. tuberculosis. These findings have contributed to a better understanding of the immunologic changes in M. tuberculosis infection and the development of new strategies for diagnosis and prevention of tuberculosis. Copyright © 2017. Published by Elsevier B.V.

Virus-Specific Immune Memory at Peripheral Sites of Herpes Simplex Virus Type 2 (HSV-2) Infection in Guinea Pigs

PubMed Central

Xia, Jingya; Veselenak, Ronald L.; Gorder, Summer R.; Bourne, Nigel; Milligan, Gregg N.

2014-01-01

Despite its importance in modulating HSV-2 pathogenesis, the nature of tissue-resident immune memory to HSV-2 is not completely understood. We used genital HSV-2 infection of guinea pigs to assess the type and location of HSV-specific memory cells at peripheral sites of HSV-2 infection. HSV-specific antibody-secreting cells were readily detected in the spleen, bone marrow, vagina/cervix, lumbosacral sensory ganglia, and spinal cord of previously-infected animals. Memory B cells were detected primarily in the spleen and to a lesser extent in bone marrow but not in the genital tract or neural tissues suggesting that the HSV-specific antibody-secreting cells present at peripheral sites of HSV-2 infection represented persisting populations of plasma cells. The antibody produced by these cells isolated from neural tissues of infected animals was functionally relevant and included antibodies specific for HSV-2 glycoproteins and HSV-2 neutralizing antibodies. A vigorous IFN-γ-secreting T cell response developed in the spleen as well as the sites of HSV-2 infection in the genital tract, lumbosacral ganglia and spinal cord following acute HSV-2 infection. Additionally, populations of HSV-specific tissue-resident memory T cells were maintained at these sites and were readily detected up to 150 days post HSV-2 infection. Unlike the persisting plasma cells, HSV-specific memory T cells were also detected in uterine tissue and cervicothoracic region of the spinal cord and at low levels in the cervicothoracic ganglia. Both HSV-specific CD4+ and CD8+ resident memory cell subsets were maintained long-term in the genital tract and sensory ganglia/spinal cord following HSV-2 infection. Together these data demonstrate the long-term maintenance of both humoral and cellular arms of the adaptive immune response at the sites of HSV-2 latency and virus shedding and highlight the utility of the guinea pig infection model to investigate tissue-resident memory in the setting of HSV-2 latency and spontaneous reactivation. PMID:25485971

B-cell subset alterations and correlated factors in HIV-1 infection.

PubMed

Pensieroso, Simone; Galli, Laura; Nozza, Silvia; Ruffin, Nicolas; Castagna, Antonella; Tambussi, Giuseppe; Hejdeman, Bo; Misciagna, Donatella; Riva, Agostino; Malnati, Mauro; Chiodi, Francesca; Scarlatti, Gabriella

2013-05-15

During HIV-1 infection, the development, phenotype, and functionality of B cells are impaired. Transitional B cells and aberrant B-cell populations arise in blood, whereas a declined percentage of resting memory B cells is detected. Our study aimed at pinpointing the demographic, immunological, and viral factors driving these pathological findings, and the role of antiretroviral therapy in reverting these alterations. B-cell phenotype and correlating factors were evaluated. Variations in B-cell subsets were evaluated by flow cytometry in HIV-1-infected individuals naive to therapy, elite controllers, and patients treated with antiretroviral drugs (virological control or failure). Multivariable analysis was performed to identify variables independently associated with the B-cell alterations. Significant differences were observed among patients' groups in relation to all B-cell subsets. Resting memory B cells were preserved in patients naive to therapy and elite controllers, but reduced in treated patients. Individuals naive to therapy and experiencing multidrug failure, as well as elite controllers, had significantly higher levels of activated memory B cells compared to healthy controls. In the multivariate analysis, plasma viral load and nadir CD4 T cells independently correlated with major B-cell alterations. Coinfection with hepatitis C but not hepatitis B virus also showed an impact on specific B-cell subsets. Successful protracted antiretroviral treatment led to normalization of all B-cell subsets with exception of resting memory B cells. Our results indicate that viremia and nadir CD4 T cells are important prognostic markers of B-cell perturbations and provide evidence that resting memory B-cell depletion during chronic infection is not reverted upon successful antiretroviral therapy.

Niches for the Long-Term Maintenance of Tissue-Resident Memory T Cells

PubMed Central

Takamura, Shiki

2018-01-01

Tissue-resident memory T cells (TRM cells) are a population of immune cells that reside in the lymphoid and non-lymphoid organs without recirculation through the blood. These important cells occupy and utilize unique anatomical and physiological niches that are distinct from those for other memory T cell populations, such as central memory T cells in the secondary lymphoid organs and effector memory T cells that circulate through the tissues. CD8+ TRM cells typically localize in the epithelial layers of barrier tissues where they are optimally positioned to act as sentinels to trigger antigen-specific protection against reinfection. CD4+ TRM cells typically localize below the epithelial layers, such as below the basement membrane, and cluster in lymphoid structures designed to optimize interactions with antigen-presenting cells upon reinfection. A key feature of TRM populations is their ability to be maintained in barrier tissues for prolonged periods of time. For example, skin CD8+ TRM cells displace epidermal niches originally occupied by γδ T cells, thereby enabling their stable persistence for years. It is also clear that the long-term maintenance of TRM cells in different microenvironments is dependent on multiple tissue-specific survival cues, although the specific details are poorly understood. However, not all TRM persist over the long term. Recently, we identified a new spatial niche for the maintenance of CD8+ TRM cells in the lung, which is created at the site of tissue regeneration after injury [termed repair-associated memory depots (RAMD)]. The short-lived nature of RAMD potentially explains the short lifespans of CD8+ TRM cells in this particular tissue. Clearly, a better understanding of the niche-dependent maintenance of TRM cells will be important for the development of vaccines designed to promote barrier immunity. In this review, we discuss recent advances in our understanding of the properties and nature of tissue-specific niches that maintain TRM cells in different tissues. PMID:29904388

Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells

PubMed Central

Watanabe, Rei; Gehad, Ahmed; Yang, Chao; Campbell, Laura; Teague, Jessica E.; Schlapbach, Christoph; Elco, Christopher; Huang, Victor; Matos, Tiago R.; Kupper, Thomas S.; Clark, Rachael A.

2015-01-01

The skin of an adult human contains approximately 20 billion memory T cells. Epithelial barrier tissues are infiltrated by a combination of resident and recirculating T cells in mice but the relative proportions and functional activities of resident versus recirculating T cells have not been evaluated in human skin. We discriminated resident from recirculating T cells in human engrafted mice and lymphoma patients using alemtuzumab, a medication that depletes recirculating T cells from skin, and then analyzed these T cell populations in healthy human skin. All non-recirculating resident memory T cells (TRM) expressed CD69, but the majority were CD4+, CD103− and located in the dermis, in contrast to studies in mice. Both CD4+ and CD8+ CD103+ TRM were enriched in the epidermis, had potent effector functions and had a limited proliferative capacity compared to CD103− TRM. TRM of both types had more potent effector functions than recirculating T cells. Induction of CD103 on human T cells was enhanced by keratinocyte contact, depended on TGFβ and was independent of T cell keratinocyte adhesive interactions. We observed two distinct populations of recirculating T cells, CCR7+/L-selectin+ central memory T cells (TCM) and CCR7+/L-selectin− T cells, which we term migratory memory T cells (TMM). Circulating skin-tropic TMM were intermediate in cytokine production between TCM and effector memory T cells. In patients with cutaneous T cell lymphoma, malignant TCM and TMM induced distinct inflammatory skin lesions and TMM were depleted more slowly from skin after alemtuzumab, suggesting TMM may recirculate more slowly. In summary, human skin is protected by four functionally distinct populations of T cells, two resident and two recirculating, with differing territories of migration and distinct functional activities. PMID:25787765

Quantum random access memory.

PubMed

Giovannetti, Vittorio; Lloyd, Seth; Maccone, Lorenzo

2008-04-25

A random access memory (RAM) uses n bits to randomly address N=2(n) distinct memory cells. A quantum random access memory (QRAM) uses n qubits to address any quantum superposition of N memory cells. We present an architecture that exponentially reduces the requirements for a memory call: O(logN) switches need be thrown instead of the N used in conventional (classical or quantum) RAM designs. This yields a more robust QRAM algorithm, as it in general requires entanglement among exponentially less gates, and leads to an exponential decrease in the power needed for addressing. A quantum optical implementation is presented.

Dimethyl Fumarate Selectively Reduces Memory T Cells and Shifts the Balance between Th1/Th17 and Th2 in Multiple Sclerosis Patients.

PubMed

Wu, Qi; Wang, Qin; Mao, Guangmei; Dowling, Catherine A; Lundy, Steven K; Mao-Draayer, Yang

2017-04-15

Dimethyl fumarate (DMF; trade name Tecfidera) is an oral formulation of the fumaric acid ester that is Food and Drug Administration approved for treatment of relapsing-remitting multiple sclerosis. To better understand the therapeutic effects of Tecfidera and its rare side effect of progressive multifocal leukoencephalopathy, we conducted cross-sectional and longitudinal studies by immunophenotyping cells from peripheral blood (particularly T lymphocytes) derived from untreated and 4-6 and 18-26 mo Tecfidera-treated stable relapsing-remitting multiple sclerosis patients using multiparametric flow cytometry. The absolute numbers of CD4 and CD8 T cells were significantly decreased and the CD4/CD8 ratio was increased with DMF treatment. The proportions of both effector memory T cells and central memory T cells were reduced, whereas naive T cells increased in treated patients. T cell activation was reduced with DMF treatment, especially among effector memory T cells and effector memory RA T cells. Th subsets Th1 (CXCR3 + ), Th17 (CCR6 + ), and particularly those expressing both CXCR3 and CD161 were reduced most significantly, whereas the anti-inflammatory Th2 subset (CCR3 + ) was increased after DMF treatment. A corresponding increase in IL-4 and decrease in IFN-γ and IL-17-expressing CD4 + T cells were observed in DMF-treated patients. DMF in vitro treatment also led to increased T cell apoptosis and decreased activation, proliferation, reactive oxygen species, and CCR7 expression. Our results suggest that DMF acts on specific memory and effector T cell subsets by limiting their survival, proliferation, activation, and cytokine production. Monitoring these subsets could help to evaluate the efficacy and safety of DMF treatment. Copyright © 2017 by The American Association of Immunologists, Inc.

Genome-wide RNA profiling of long-lasting stem cell-like memory CD8 T cells induced by Yellow Fever vaccination in humans.

PubMed

Fuertes Marraco, Silvia A; Soneson, Charlotte; Delorenzi, Mauro; Speiser, Daniel E

2015-09-01

The live-attenuated Yellow Fever (YF) vaccine YF-17D induces a broad and polyfunctional CD8 T cell response in humans. Recently, we identified a population of stem cell-like memory CD8 T cells induced by YF-17D that persists at stable frequency for at least 25 years after vaccination. The YF-17D is thus a model system of human CD8 T cell biology that furthermore allows to track and study long-lasting and antigen-specific human memory CD8 T cells. Here, we describe in detail the sample characteristics and preparation of a microarray dataset acquired for genome-wide gene expression profiling of long-lasting YF-specific stem cell-like memory CD8 T cells, compared to the reference CD8 T cell differentiation subsets from total CD8 T cells. We also describe the quality controls, annotations and exploratory analyses of the dataset. The microarray data is available from the Gene Expression Omnibus (GEO) public repository with accession number GSE65804.

High affinity IgM(+) memory B cells are generated through a germinal center-dependent pathway.

PubMed

Hara, Yasushi; Tashiro, Yasuyuki; Murakami, Akikazu; Nishimura, Miyuki; Shimizu, Takeyuki; Kubo, Masato; Burrows, Peter D; Azuma, Takachika

2015-12-01

During a T cell-dependent immune response, B cells undergo clonal expansion and selection and the induction of isotype switching and somatic hypermutation (SHM). Although somatically mutated IgM(+) memory B cells have been reported, it has not been established whether they are really high affinity B cells. We tracked (4-hydroxy-3-nitrophenyl) acetyl hapten-specific GC B cells from normal immunized mice based on affinity of their B cell receptor (BCR) and performed BCR sequence analysis. SHM was evident by day 7 postimmunization and increased with time, such that high affinity IgM(+) as well as IgG(+) memory B cells continued to be generated up to day 42. In contrast, class-switch recombination (CSR) was almost completed by day 7 and then the ratio of IgG1(+)/IgM(+) GC B cells remained unchanged. Together these findings suggest that IgM(+) B cells undergo SHM in the GC to generate high affinity IgM(+) memory cells and that this process continues even after CSR is accomplished. Copyright © 2015 Elsevier Ltd. All rights reserved.

Radiation Tests of Highly Scaled, High-Density, Commercial, Nonvolatile NAND Flash Memories - Update 2010

NASA Technical Reports Server (NTRS)

Irom, Farokh; Nguyen, Duc N.

2010-01-01

High-density, commercial, nonvolatile flash memories with NAND architecture are now available from several manufacturers. This report examines SEE effects and TID response in single-level cell (SLC) and multi-level cell (MLC) NAND flash memories manufactured by Micron Technology.

Characterization of naïve, memory and effector T cells in progressive multiple sclerosis.

PubMed

Nielsen, Birgitte Romme; Ratzer, Rikke; Börnsen, Lars; von Essen, Marina Rode; Christensen, Jeppe Romme; Sellebjerg, Finn

2017-09-15

We characterized naïve, central memory (CM), effector memory (EM) and terminally differentiated effector memory (TEMRA) CD4 + and CD8 + T cells and their expression of CD49d and CD26 in peripheral blood in patients with multiple sclerosis (MS) and healthy controls. CD26 + CD28 + CD4 + TEMRA T cells were increased in all subtypes of MS, and CD26 + CD28 + CD8 + TEMRA T cells were increased in relapsing-remitting and secondary progressive MS. Conversely, in progressive MS, CD49d + CM T cells were decreased and natalizumab increased the circulating number of all six subsets but reduced the frequency of most subsets expressing CD49d and CD26. Copyright © 2017 Elsevier B.V. All rights reserved.

Rapid Functional Decline of Activated and Memory Graft-vs-Host-Reactive T Cells Encountering Host Antigens in the Absence of Inflammation

PubMed Central

Li, Hao Wei; Andreola, Giovanna; Carlson, Alicia; Shao, Steven; Lin, Charles; Zhao, Guiling; Sykes, Megan

2015-01-01

Inflammation in the priming host environment has critical effects on the graft-vs-host (GVH) responses mediated by naïve donor T cells. However, it is unclear how a quiescent or inflammatory environment impacts the activity of GVH-reactive primed T and memory cells. We show here that GVH-reactive primed donor T cells generated in irradiated recipients had diminished ability compared to naïve T cells to increase donor chimerism when transferred to quiescent mixed allogeneic chimeras. GVH-reactive primed T cells showed marked loss of cytotoxic function and activation and delayed but not decreased proliferation or accumulation in lymphoid tissues when transferred to quiescent mixed chimeras compared to freshly irradiated secondary recipients. Primed CD4 and CD8 T cells provided mutual help to sustain these functions in both subsets. CD8 help for CD4 cells was largely IFN-γ-dependent. Toll-like receptor (TLR) stimulation following transfer of GVH-reactive primed T cells to mixed chimeras restored their cytotoxic effector function and permitted the generation of more effective T cell memory in association with reduced PD-1 expression on CD4 memory cells. Our data indicate that an inflammatory host environment is required for the maintenance of GVH-reactive primed T cell functions and the generation of memory T cells that can rapidly acquire effector functions. These findings have important implications for GVHD and T cell-mediated immunotherapies. PMID:26085679

Lack of Original Antigenic Sin in Recall CD8+ T Cell Responses

PubMed Central

Zehn, Dietmar; Turner, Michael J.; Lefrançois, Leo; Bevan, Michael J.

2010-01-01

In the real world, mice and men are not immunologically naive, having been exposed to numerous antigenic challenges. Prior infections sometimes negatively impact the response to a subsequent infection. This can occur in serial infections with pathogens sharing cross-reactive Ags. At the T cell level it has been proposed that preformed memory T cells, which cross-react with low avidity to epitopes presented in subsequent infections, dampen the response of high-avidity T cells. We investigated this with a series of related MHC class-I restricted Ags expressed by bacterial and viral pathogens. In all cases, we find that high-avidity CD8+ T cell precursors, either naive or memory, massively expand in secondary cross-reactive infections to dominate the response over low-avidity memory T cells. This holds true even when >10% of the CD8+ T cell compartment consists of memory T cells that cross-react weakly with the rechallenge ligand. Occasionally, memory cells generated by low-avidity stimulation in a primary infection recognize a cross-reactive epitope with high avidity and contribute positively to the response to a second infection. Taken together, our data show that the phenomenon of original antigenic sin does not occur in all heterologous infections. PMID:20439913

Asymmetric cellular memory in bacteria exposed to antibiotics.

PubMed

Mathis, Roland; Ackermann, Martin

2017-03-09

The ability to form a cellular memory and use it for cellular decision-making could help bacteria to cope with recurrent stress conditions. We analyzed whether bacteria would form a cellular memory specifically if past events are predictive of future conditions. We worked with the asymmetrically dividing bacterium Caulobacter crescentus where past events are expected to only be informative for one of the two cells emerging from division, the sessile cell that remains in the same microenvironment and does not migrate. Time-resolved analysis of individual cells revealed that past exposure to low levels of antibiotics increases tolerance to future exposure for the sessile but not for the motile cell. Using computer simulations, we found that such an asymmetry in cellular memory could be an evolutionary response to situations where the two cells emerging from division will experience different future conditions. Our results raise the question whether bacteria can evolve the ability to form and use cellular memory conditionally in situations where it is beneficial.

Epigenetic Networks Regulate the Transcriptional Program in Memory and Terminally Differentiated CD8+ T Cells.

PubMed

Rodriguez, Ramon M; Suarez-Alvarez, Beatriz; Lavín, José L; Mosén-Ansorena, David; Baragaño Raneros, Aroa; Márquez-Kisinousky, Leonardo; Aransay, Ana M; Lopez-Larrea, Carlos

2017-01-15

Epigenetic mechanisms play a critical role during differentiation of T cells by contributing to the formation of stable and heritable transcriptional patterns. To better understand the mechanisms of memory maintenance in CD8 + T cells, we performed genome-wide analysis of DNA methylation, histone marking (acetylated lysine 9 in histone H3 and trimethylated lysine 9 in histone), and gene-expression profiles in naive, effector memory (EM), and terminally differentiated EM (TEMRA) cells. Our results indicate that DNA demethylation and histone acetylation are coordinated to generate the transcriptional program associated with memory cells. Conversely, EM and TEMRA cells share a very similar epigenetic landscape. Nonetheless, the TEMRA transcriptional program predicts an innate immunity phenotype associated with genes never reported in these cells, including several mediators of NK cell activation (VAV3 and LYN) and a large array of NK receptors (e.g., KIR2DL3, KIR2DL4, KIR2DL1, KIR3DL1, KIR2DS5). In addition, we identified up to 161 genes that encode transcriptional regulators, some of unknown function in CD8 + T cells, and that were differentially expressed in the course of differentiation. Overall, these results provide new insights into the regulatory networks involved in memory CD8 + T cell maintenance and T cell terminal differentiation. Copyright © 2017 by The American Association of Immunologists, Inc.

Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection.

PubMed

Glennie, Nelson D; Yeramilli, Venkata A; Beiting, Daniel P; Volk, Susan W; Weaver, Casey T; Scott, Phillip

2015-08-24

Leishmaniasis causes a significant disease burden worldwide. Although Leishmania-infected patients become refractory to reinfection after disease resolution, effective immune protection has not yet been achieved by human vaccines. Although circulating Leishmania-specific T cells are known to play a critical role in immunity, the role of memory T cells present in peripheral tissues has not been explored. Here, we identify a population of skin-resident Leishmania-specific memory CD4+ T cells. These cells produce IFN-γ and remain resident in the skin when transplanted by skin graft onto naive mice. They function to recruit circulating T cells to the skin in a CXCR3-dependent manner, resulting in better control of the parasites. Our findings are the first to demonstrate that CD4+ TRM cells form in response to a parasitic infection, and indicate that optimal protective immunity to Leishmania, and thus the success of a vaccine, may depend on generating both circulating and skin-resident memory T cells. © 2015 Glennie et al.

Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection

PubMed Central

Glennie, Nelson D.; Yeramilli, Venkata A.; Beiting, Daniel P.; Volk, Susan W.; Weaver, Casey T.

2015-01-01

Leishmaniasis causes a significant disease burden worldwide. Although Leishmania-infected patients become refractory to reinfection after disease resolution, effective immune protection has not yet been achieved by human vaccines. Although circulating Leishmania-specific T cells are known to play a critical role in immunity, the role of memory T cells present in peripheral tissues has not been explored. Here, we identify a population of skin-resident Leishmania-specific memory CD4+ T cells. These cells produce IFN-γ and remain resident in the skin when transplanted by skin graft onto naive mice. They function to recruit circulating T cells to the skin in a CXCR3-dependent manner, resulting in better control of the parasites. Our findings are the first to demonstrate that CD4+ TRM cells form in response to a parasitic infection, and indicate that optimal protective immunity to Leishmania, and thus the success of a vaccine, may depend on generating both circulating and skin-resident memory T cells. PMID:26216123

Depletion of CD8 Memory T Cells for Induction of Tolerance of a Previously Transplanted Kidney Allograft

PubMed Central

Koyama, I.; Nadazdin, O.; Boskovic, S.; Ochiai, T.; Smith, R. N.; Sykes, M.; Sogawa, H.; Murakami, T.; Strom, T. B.; Colvin, R. B.; Sachs, D. H.; Benichou, G.; Cosimi, A. B.; Kawai, T.

2013-01-01

Heterologous immunologic memory has been considered a potent barrier to tolerance induction in primates. Induction of such tolerance for a previously transplanted organ may be more difficult, because specific memory cells can be induced and activated by a transplanted organ. In the current study, we attempted to induce tolerance to a previously transplanted kidney allograft in nonhuman primates. The conditioning regimen consisted of low dose total body irradiation, thymic irradiation, antithymocyte globulin, and anti- CD154 antibody followed by a brief course of a calcineurin inhibitor. This regimen had been shown to induce mixed chimerism and allograft tolerance when kidney transplantation (KTx) and donor bone marrow transplantation (DBMT) were simultaneously performed. However, the same regimen failed to induce mixed chimerism when delayed DBMT was performed after KTx. We found that significant levels of memory T cells remained after conditioning, despite effective depletion of naïve T cells. By adding humanized anti-CD8 monoclonal antibody (cM-T807), CD8 memory T cells were effectively depleted and these recipients successfully achieved mixed chimerism and tolerance. The current studies provide ‘proof of principle’ that the mixed chimerism approach can induce renal allograft tolerance, even late after organ transplantation if memory T-cell function is adequately controlled. PMID:17286617

Preserved antibody levels and loss of memory B cells against pneumococcus and tetanus after splenectomy: tailoring better vaccination strategies.

PubMed

Rosado, M Manuela; Gesualdo, Francesco; Marcellini, Valentina; Di Sabatino, Antonio; Corazza, Gino Roberto; Smacchia, Maria Paola; Nobili, Bruno; Baronci, Carlo; Russo, Lidia; Rossi, Francesca; Vito, Rita De; Nicolosi, Luciana; Inserra, Alessandro; Locatelli, Franco; Tozzi, Alberto E; Carsetti, Rita

2013-10-01

Splenectomized patients are exposed to an increased risk of septicemia caused by encapsulated bacteria. Defense against infection is ensured by preformed serum antibodies produced by long-lived plasma cells and by memory B cells that secrete immunoglobulin in response to specific antigenic stimuli. Studying a group of asplenic individuals (57 adults and 21 children) without additional immunologic defects, we found that spleen removal does not alter serum anti-pneumococcal polysaccharide (PnPS) IgG concentration, but reduces the number of PnPS-specific memory B cells, of both IgM and IgG isotypes. The number of specific memory B cells was low in splenectomized adults and children that had received the PnPS vaccine either before or after splenectomy. Seven children were given the 13-valent pneumococcal conjugated vaccine after splenectomy. In this group, the number of PnPS-specific IgG memory B cells was similar to that of eusplenic children, suggesting that pneumococcal conjugated vaccine administered after splenectomy is able to restore the pool of anti-PnPS IgG memory B cells. Our data further elucidate the crucial role of the spleen in the immunological response to infections caused by encapsulated bacteria and suggest that glycoconjugated vaccines may be the most suitable choice to generate IgG-mediated protection in these patients. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Mucosal immunization in macaques upregulates the innate APOBEC 3G anti-viral factor in CD4(+) memory T cells.

PubMed

Wang, Yufei; Bergmeier, Lesley A; Stebbings, Richard; Seidl, Thomas; Whittall, Trevor; Singh, Mahavir; Berry, Neil; Almond, Neil; Lehner, Thomas

2009-02-05

APOBEC3G is an innate intracellular anti-viral factor which deaminates retroviral cytidine to uridine. In vivo studies of APOBEC3G (A3G) were carried out in rhesus macaques, following mucosal immunization with SIV antigens and CCR5 peptides, linked to the 70kDa heat shock protein. A progressive increase in A3G mRNA was elicited in PBMC after each immunization (p<0.0002 to p< or =0.02), which was maintained for at least 17 weeks. Analysis of memory T cells showed a significant increase in A3G mRNA and protein in CD4(+)CCR5(+) memory T cells in circulating (p=0.0001), splenic (p=0.0001), iliac lymph nodes (p=0.002) and rectal (p=0.01) cells of the immunized compared with unimmunized macaques. Mucosal challenge with SIVmac 251 showed a significant increase in A3G mRNA in the CD4(+)CCR5(+) circulating cells (p<0.01) and the draining iliac lymph node cells (p<0.05) in the immunized uninfected macaques, consistent with a protective effect exerted by A3G. The results suggest that mucosal immunization in a non-human primate can induce features of a memory response to an innate anti-viral factor in CCR5(+)CD4(+) memory and CD4(+)CD95(+)CCR7(-) effector memory T cells.

Working Memory in Children With Neurocognitive Effects From Sickle Cell Disease: Contributions of the Central Executive and Processing Speed

PubMed Central

Smith, Kelsey E.; Schatz, Jeffrey

2017-01-01

Children with sickle cell disease (SCD) are at risk for working memory deficits due to multiple disease processes. We assessed working memory abilities and related functions in 32 school-age children with SCD and 85 matched comparison children using Baddeley’s working memory model as a framework. Children with SCD performed worse than controls for working memory, central executive function, and processing/rehearsal speed. Central executive function was found to mediate the relationship between SCD status and working memory, but processing speed did not. Cognitive remediation strategies that focus on central executive processes may be important for remediating working memory deficits in SCD. PMID:27759435

A Positive Correlation between Atypical Memory B Cells and Plasmodium falciparum Transmission Intensity in Cross-Sectional Studies in Peru and Mali

PubMed Central

Weiss, Greta E.; Clark, Eva H.; Li, Shanping; Traore, Boubacar; Kayentao, Kassoum; Ongoiba, Aissata; Hernandez, Jean N.; Doumbo, Ogobara K.; Pierce, Susan K.; Branch, OraLee H.; Crompton, Peter D.

2011-01-01

Background Antibodies that protect against Plasmodium falciparum (Pf) malaria are only acquired after years of repeated infections. The B cell biology that underlies this observation is poorly understood. We previously reported that “atypical” memory B cells are increased in children and adults exposed to intense Pf transmission in Mali, similar to what has been observed in individuals infected with HIV. In this study we examined B cell subsets of Pf -infected adults in Peru and Mali to determine if Pf transmission intensity correlates with atypical memory B cell expansion. Methodology/Principal Findings In this cross-sectional study venous blood was collected from adults in areas of zero (U.S., n = 10), low (Peru, n = 18) and high (Mali, n = 12) Pf transmission. Adults in Peru and Mali were infected with Pf at the time of blood collection. Thawed lymphocytes were analyzed by flow cytometry to quantify B cell subsets, including atypical memory B cells, defined by the cell surface markers CD19+ CD20+ CD21− CD27− CD10−. In Peru, the mean level of atypical memory B cells, as a percent of total B cells, was higher than U.S. adults (Peru mean: 5.4% [95% CI: 3.61–7.28]; U.S. mean: 1.4% [95% CI: 0.92–1.81]; p<0.0001) but lower than Malian adults (Mali mean 13.1% [95% CI: 10.68–15.57]; p = 0.0001). In Peru, individuals self-reporting ≥1 prior malaria episodes had a higher percentage of atypical memory B cells compared to those reporting no prior episodes (≥1 prior episodes mean: 6.6% [95% CI: 4.09–9.11]; no prior episodes mean: 3.1% [95% CI: 1.52–4.73]; p = 0.028). Conclusions/Significance Compared to Pf-naive controls, atypical memory B cells were increased in Peruvian adults exposed to low Pf transmission, and further increased in Malian adults exposed to intense Pf transmission. Understanding the origin, function and antigen specificity of atypical memory B cells in the context of Pf infection could contribute to our understanding of naturally-acquired malaria immunity. PMID:21264245

Induction of long term mucosal immunological memory in humans by an oral inactivated multivalent enterotoxigenic Escherichia coli vaccine.

PubMed

Lundgren, Anna; Jertborn, Marianne; Svennerholm, Ann-Mari

2016-06-08

We have evaluated the capacity of an oral multivalent enterotoxigenic Escherichia coli (ETEC) vaccine (MEV) to induce mucosal immunological memory. MEV consists of four inactivated E. coli strains over-expressing the major colonization factors (CFs) CFA/I, CS3, CS5 and CS6 and the LTB-related toxoid LCTBA. Memory responses were analyzed by comparing the magnitudes and kinetics of intestine-derived antibody-secreting cell responses to a single dose of MEV in three groups of adult Swedish volunteers (n=16-19 subjects per group) in a Phase I trial: non-immunized controls (I) and subjects who in a previous Phase I trial 13-23 months earlier had received two biweekly doses of MEV (II) or MEV+double mutant LT (dmLT) adjuvant (III). Responses against CFs and LTB were analyzed in antibodies in lymphocyte secretions (ALS) of blood mononuclear cells collected before (day 0) and 4/5 and 7 days after immunization. Specific circulating memory B cells present at the time of the single dose vaccination were also studied to determine if such cells may reflect mucosal memory. Considerably higher and significantly more frequent IgA ALS responses against all CFs and LTB were induced by the single vaccine dose in the previously immunized than in non-immunized volunteers. Furthermore, peak IgA ALS responses against all antigens were observed on days 4/5 in most of the previously immunized subjects whereas only a few previously non-vaccinated individuals responded before day 7. Priming with adjuvant did not influence memory responses. Circulating vaccine specific IgA memory B cells were not detected, whereas anti-toxin IgG memory B cells were identified 13-23 months after priming vaccination. We conclude that MEV induces functional mucosal immunological memory which remains at least 1-2 years. Furthermore, our results support that analysis of antibody-secreting cell responses after booster vaccination may be a useful approach to evaluate longstanding mucosal immunological memory in humans. ISRCTN27096290. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Radiation Tests of Highly scaled, High-Density, Commercial, Nonvolatile NAND Flash Memories--Update 2011

NASA Technical Reports Server (NTRS)

Irom, Farokh; Nguyen, Duc N.

2011-01-01

High-density, commercial, nonvolatile flash memories with NAND architecture are now available from several manufacturers. This report examines SEE effects and TID response in single-level cell (SLC) 32Gb and multi-level cell (MLC) 64Gb NAND flash memories manufactured by Micron Technology.

Bioelectric memory: modeling resting potential bistability in amphibian embryos and mammalian cells.

PubMed

Law, Robert; Levin, Michael

2015-10-15

Bioelectric gradients among all cells, not just within excitable nerve and muscle, play instructive roles in developmental and regenerative pattern formation. Plasma membrane resting potential gradients regulate cell behaviors by regulating downstream transcriptional and epigenetic events. Unlike neurons, which fire rapidly and typically return to the same polarized state, developmental bioelectric signaling involves many cell types stably maintaining various levels of resting potential during morphogenetic events. It is important to begin to quantitatively model the stability of bioelectric states in cells, to understand computation and pattern maintenance during regeneration and remodeling. To facilitate the analysis of endogenous bioelectric signaling and the exploitation of voltage-based cellular controls in synthetic bioengineering applications, we sought to understand the conditions under which somatic cells can stably maintain distinct resting potential values (a type of state memory). Using the Channelpedia ion channel database, we generated an array of amphibian oocyte and mammalian membrane models for voltage evolution. These models were analyzed and searched, by simulation, for a simple dynamical property, multistability, which forms a type of voltage memory. We find that typical mammalian models and amphibian oocyte models exhibit bistability when expressing different ion channel subsets, with either persistent sodium or inward-rectifying potassium, respectively, playing a facilitative role in bistable memory formation. We illustrate this difference using fast sodium channel dynamics for which a comprehensive theory exists, where the same model exhibits bistability under mammalian conditions but not amphibian conditions. In amphibians, potassium channels from the Kv1.x and Kv2.x families tend to disrupt this bistable memory formation. We also identify some common principles under which physiological memory emerges, which suggest specific strategies for implementing memories in bioengineering contexts. Our results reveal conditions under which cells can stably maintain one of several resting voltage potential values. These models suggest testable predictions for experiments in developmental bioelectricity, and illustrate how cells can be used as versatile physiological memory elements in synthetic biology, and unconventional computation contexts.

Vaccination Expands Antigen-Specific CD4+ Memory T Cells and Mobilizes Bystander Central Memory T Cells

PubMed Central

Li Causi, Eleonora; Parikh, Suraj C.; Chudley, Lindsey; Layfield, David M.; Ottensmeier, Christian H.; Stevenson, Freda K.; Di Genova, Gianfranco

2015-01-01

CD4+ T helper memory (Thmem) cells influence both natural and vaccine-boosted immunity, but mechanisms for their maintenance remain unclear. Pro-survival signals from the common gamma-chain cytokines, in particular IL-7, appear important. Previously we showed in healthy volunteers that a booster vaccination with tetanus toxoid (TT) expanded peripheral blood TT-specific Thmem cells as expected, but was accompanied by parallel increase of Thmem cells specific for two unrelated and non cross-reactive common recall antigens. Here, in a new cohort of healthy human subjects, we compare blood vaccine-specific and bystander Thmem cells in terms of differentiation stage, function, activation and proliferative status. Both responses peaked 1 week post-vaccination. Vaccine-specific cytokine-producing Thmem cells were predominantly effector memory, whereas bystander cells were mainly of central memory phenotype. Importantly, TT-specific Thmem cells were activated (CD38High HLA-DR+), cycling or recently divided (Ki-67+), and apparently vulnerable to death (IL-7RαLow and Bcl-2 Low). In contrast, bystander Thmem cells were resting (CD38Low HLA-DR- Ki-67-) with high expression of IL-7Rα and Bcl-2. These findings allow a clear distinction between vaccine-specific and bystander Thmem cells, suggesting the latter do not derive from recent proliferation but from cells mobilized from as yet undefined reservoirs. Furthermore, they reveal the interdependent dynamics of specific and bystander T-cell responses which will inform assessments of responses to vaccines. PMID:26332995

Total Recall: Can We Reshape T Cell Memory by Lymphoablation?

PubMed

Nicosia, M; Valujskikh, A

2017-07-01

Despite recent advances in immunosuppression, donor-reactive memory T cells remain a serious threat to successful organ transplantation. To alleviate damaging effects of preexisting immunologic memory, lymphoablative induction therapies are used as part of standard care in sensitized recipients. However, accumulating evidence suggests that memory T cells have advantages over their naive counterparts in surviving depletion and expanding under lymphopenic conditions. This may at least partially explain the inability of existing lymphoablative strategies to improve long-term allograft outcome in sensitized recipients, despite the well-documented decrease in the frequency of early acute rejection episodes. This minireview summarizes the insights gained from both experimental and clinical transplantation as to the effects of existing lymphoablative strategies on memory T cells and discusses the latest research developments aimed at improving the efficacy and safety of lymphoablation. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Multi-floor cascading ferroelectric nanostructures: multiple data writing-based multi-level non-volatile memory devices.

PubMed

Hyun, Seung; Kwon, Owoong; Lee, Bom-Yi; Seol, Daehee; Park, Beomjin; Lee, Jae Yong; Lee, Ju Hyun; Kim, Yunseok; Kim, Jin Kon

2016-01-21

Multiple data writing-based multi-level non-volatile memory has gained strong attention for next-generation memory devices to quickly accommodate an extremely large number of data bits because it is capable of storing multiple data bits in a single memory cell at once. However, all previously reported devices have failed to store a large number of data bits due to the macroscale cell size and have not allowed fast access to the stored data due to slow single data writing. Here, we introduce a novel three-dimensional multi-floor cascading polymeric ferroelectric nanostructure, successfully operating as an individual cell. In one cell, each floor has its own piezoresponse and the piezoresponse of one floor can be modulated by the bias voltage applied to the other floor, which means simultaneously written data bits in both floors can be identified. This could achieve multi-level memory through a multiple data writing process.

Memory Engram Cells Have Come of Age.

PubMed

Tonegawa, Susumu; Liu, Xu; Ramirez, Steve; Redondo, Roger

2015-09-02

The idea that memory is stored in the brain as physical alterations goes back at least as far as Plato, but further conceptualization of this idea had to wait until the 20(th) century when two guiding theories were presented: the "engram theory" of Richard Semon and Donald Hebb's "synaptic plasticity theory." While a large number of studies have been conducted since, each supporting some aspect of each of these theories, until recently integrative evidence for the existence of engram cells and circuits as defined by the theories was lacking. In the past few years, the combination of transgenics, optogenetics, and other technologies has allowed neuroscientists to begin identifying memory engram cells by detecting specific populations of cells activated during specific learning epochs and by engineering them not only to evoke recall of the original memory, but also to alter the content of the memory. Copyright © 2015 Elsevier Inc. All rights reserved.

Central Memory CD4+ T Cells Are Responsible for the Recombinant Bacillus Calmette-Guérin ΔureC::hly Vaccine's Superior Protection Against Tuberculosis

PubMed Central

Vogelzang, Alexis; Perdomo, Carolina; Zedler, Ulrike; Kuhlmann, Stefanie; Hurwitz, Robert; Gengenbacher, Martin; Kaufmann, Stefan H. E.

2014-01-01

Bacillus Calmette-Guérin (BCG) has been used for vaccination against tuberculosis for nearly a century. Here, we analyze immunity induced by a live tuberculosis vaccine candidate, recombinant BCG ΔureC::hly vaccine (rBCG), with proven preclinical and clinical safety and immunogenicity. We pursue in-depth analysis of the endogenous mycobacteria-specific CD4+ T-cell population, comparing the more efficacious rBCG with canonical BCG to determine which T-cell memory responses are prerequisites for superior protection against tuberculosis. rBCG induced higher numbers and proportions of antigen-specific memory CD4+ T cells than BCG, with a CXCR5+CCR7+ phenotype and low expression of the effector transcription factors T-bet and Bcl-6. We found that the superior protection of rBCG, compared with BCG, correlated with higher proportions and numbers of these central memory T cells and of T follicular helper cells associated with specific antibody responses. Adoptive transfer of mycobacteria-specific central memory T cells validated their critical role in protection against pulmonary tuberculosis. PMID:24943726

IFN-Gamma-Dependent and Independent Mechanisms of CD4⁺ Memory T Cell-Mediated Protection from Listeria Infection.

PubMed

Meek, Stephanie M; Williams, Matthew A

2018-02-13

While CD8⁺ memory T cells can promote long-lived protection from secondary exposure to intracellular pathogens, less is known regarding the direct protective mechanisms of CD4⁺ T cells. We utilized a prime/boost model in which mice are initially exposed to an acutely infecting strain of lymphocytic choriomeningitis virus (LCMV), followed by a heterologous rechallenge with Listeria monocytogenes recombinantly expressing the MHC Class II-restricted LCMV epitope, GP 61-80 (Lm-gp61). We found that heterologous Lm-gp61 rechallenge resulted in robust activation of CD4⁺ memory T cells and that they were required for rapid bacterial clearance. We further assessed the relative roles of TNF and IFNγ in the direct anti-bacterial function of CD4⁺ memory T cells. We found that disruption of TNF resulted in a complete loss of protection mediated by CD4⁺ memory T cells, whereas disruption of IFNγ signaling to macrophages results in only a partial loss of protection. The protective effect mediated by CD4⁺ T cells corresponded to the rapid accumulation of pro-inflammatory macrophages in the spleen and an altered inflammatory environment in vivo. Overall, we conclude that protection mediated by CD4⁺ memory T cells from heterologous Listeria challenge is most directly dependent on TNF, whereas IFNγ only plays a minor role.

Age and CD161 Expression Contribute to Inter-Individual Variation in Interleukin-23 Response in CD8+ Memory Human T Cells

PubMed Central

Abraham, Clara; Cho, Judy H.

2013-01-01

The interleukin-23 (IL-23) pathway plays a critical role in the pathogenesis of multiple chronic inflammatory disorders, however, inter-individual variability in IL-23-induced signal transduction in circulating human lymphocytes has not been well-defined. In this study, we observed marked, reproducible inter-individual differences in IL-23 responsiveness (measured by STAT3 phosphorylation) in peripheral blood CD8+CD45RO+ memory T and CD3+CD56+ NKT cells. Age, but not gender, was a significant (Pearson’s correlation coefficient, r = −0.37, p = 0.001) source of variability observed in CD8+CD45RO+ memory T cells, with IL-23 responsiveness gradually decreasing with increasing age. Relative to cells from individuals demonstrating low responsiveness to IL-23 stimulation, CD8+CD45RO+ memory T cells from individuals demonstrating high responsiveness to IL-23 stimulation showed increased gene expression for IL-23 receptor (IL-23R), RORC (RORγt) and CD161 (KLRB1), whereas RORA (RORα) and STAT3 expression were equivalent. Similar to CD4+ memory T cells, IL-23 responsiveness is confined to the CD161+ subset in CD8+CD45RO+ memory T cells, suggesting a similar CD161+ precursor as has been reported for CD4+ Th17 cells. We observed a very strong positive correlation between IL-23 responsiveness and the fraction of CD161+, CD8+CD45RO+ memory T cells (r = 0.80, p<0.001). Moreover, the fraction of CD161+, CD8+CD45RO+ memory T cells gradually decreases with aging (r = −0.34, p = 0.05). Our data define the inter-individual differences in IL-23 responsiveness in peripheral blood lymphocytes from the general population. Variable expression of CD161, IL-23R and RORC affects IL-23 responsiveness and contributes to the inter-individual susceptibility to IL-23-mediated defenses and inflammatory processes. PMID:23469228

Neem leaf glycoprotein generates superior tumor specific central memory CD8+ T cells than cyclophosphamide that averts post-surgery solid sarcoma recurrence.

PubMed

Ghosh, Sarbari; Sarkar, Madhurima; Ghosh, Tithi; Guha, Ipsita; Bhuniya, Avishek; Saha, Akata; Dasgupta, Shayani; Barik, Subhasis; Bose, Anamika; Baral, Rathindranath

2017-08-03

The success of cancer vaccines is limited as most of them induce corrupted CD8 + T cell memory populations. We reported earlier that a natural immunomodulator, neem leaf glycoprotein (NLGP), therapeutically restricts tumor growth in a CD8 + T cell-dependent manner. Here, our objective is to study whether memory CD8 + T cell population is generated in sarcoma hosts after therapeutic NLGP treatment and their role in prevention of post-surgery tumor recurrence, in comparison to the immunostimulatory metronomic cyclophosphamide (CTX) treatment. We found that therapeutic NLGP and CTX treatment generates central memory CD8 + T (TCM) cells with characteristic CD44 + CD62L high CCR7 high IL-2 high phenotypes. But these TCM cells are functionally impaired to prevent re-appearance of tumors along with compromised proliferative, IL-2 secretive and cytotoxic status. This might be due to the presence of tumor load, even a small one in the host, which serves as a persistent source of tumor antigens thereby corrupting the TCM cells so generated. Surgical removal of the persisting tumors from the host restored the functional characteristics of memory CD8 + T cells, preventing tumor recurrence after surgery till end of the experiment. Moreover, we observed that generation of superior TCM cells in NLGP treated surgically removed tumor hosts is related to the activation of Wnt signalling in memory CD8 + T cells with concomitant inhibition of GSK-3β and stabilisation of β-catenin, which ultimately activates transcription of Wnt target genes, like, eomesodermin, a signature molecule of CD8 + TCM cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

Apoptosis Susceptibility Prolongs the Lack of Memory B Cells in Acute Leukemic Patients After Allogeneic Hematopoietic Stem Cell Transplantation.

PubMed

Mensen, Angela; Oh, Youngseong; Becker, Sonya C; Hemmati, Philipp G; Jehn, Christian; Westermann, Jörg; Szyska, Martin; Göldner, Henning; Dörken, Bernd; Scheibenbogen, Carmen; Arnold, Renate; Na, Il-Kang

2015-11-01

Long-term survival after allogeneic hematopoietic stem cell transplantation requires intact immunosurveillance, which is hampered by lymphoid organ damage associated with conditioning therapy, graft-versus-host disease, and immunosuppression. Our study aimed to identify the mechanisms contributing to sustained low memory B cell numbers after transplantation. Peripheral B and T cell subset recovery and functional marker expression were investigated in 35 acute leukemic patients up to 1 year after transplantation. Apoptosis of B cells after CD40/TLR-9, CD40/BCR, and CD40/BCR/TLR-9-dependent stimulation and drug efflux capacity were analyzed. One half of the patients suffered from infections after day 180. All patients had strongly diminished CD27(+) memory B cells despite already normalized total B cell numbers and fully recovered CD27(-)IgD(-) memory B cells, putatively of extra-follicular origin. Circulating memory follicular helper T cells were reduced in the majority of patients as well. Naïve B cells exhibited a decreased expression of CXCR5, which mediates follicular B cell entry. Additionally, a lower HLA-DR expression was found on naïve B cells, impairing antigen presentation. Upon CD40/TLR-9-dependent activation, B cells underwent significantly increased apoptosis paralleled by an aberrant up-regulation of Fas-L on activated T cells and Fas on resting B cells. Significantly increased B cell apoptosis was also observed after CD40/BCR and CD40/BCR/TLR-9-dependent activation. Drug efflux capacity of naïve B cells was diminished in cyclosporin A-treated patients, additionally contributing to an apoptosis-prone phenotype. We conclude that B cell survival and migration and T cell communication defects are contributing candidates for an impaired germinal center formation of memory B cells after allogeneic hematopoietic stem cell transplantation. Follow-up studies should evaluate effectiveness of revaccinations on the cellular level and should address the long-term sequelae of B cell defects after transplantation. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Verification of immune response optimality through cybernetic modeling.

PubMed

Batt, B C; Kompala, D S

1990-02-09

An immune response cascade that is T cell independent begins with the stimulation of virgin lymphocytes by antigen to differentiate into large lymphocytes. These immune cells can either replicate themselves or differentiate into plasma cells or memory cells. Plasma cells produce antibody at a specific rate up to two orders of magnitude greater than large lymphocytes. However, plasma cells have short life-spans and cannot replicate. Memory cells produce only surface antibody, but in the event of a subsequent infection by the same antigen, memory cells revert rapidly to large lymphocytes. Immunologic memory is maintained throughout the organism's lifetime. Many immunologists believe that the optimal response strategy calls for large lymphocytes to replicate first, then differentiate into plasma cells and when the antigen has been nearly eliminated, they form memory cells. A mathematical model incorporating the concept of cybernetics has been developed to study the optimality of the immune response. Derived from the matching law of microeconomics, cybernetic variables control the allocation of large lymphocytes to maximize the instantaneous antibody production rate at any time during the response in order to most efficiently inactivate the antigen. A mouse is selected as the model organism and bacteria as the replicating antigen. In addition to verifying the optimal switching strategy, results showing how the immune response is affected by antigen growth rate, initial antigen concentration, and the number of antibodies required to eliminate an antigen are included.

Enhancement of CD8+ T-cell memory by removal of a vaccinia virus nuclear factor-κB inhibitor

PubMed Central

Ren, Hongwei; Ferguson, Brian J; de Motes, Carlos Maluquer; Sumner, Rebecca P; Harman, Laura E R; Smith, Geoffrey L

2015-01-01

Factors influencing T-cell responses are important for vaccine development but are incompletely understood. Here, vaccinia virus (VACV) protein N1 is shown to impair the development of both effector and memory CD8+ T cells and this correlates with its inhibition of nuclear factor-κB (NF-κB) activation. Infection with VACVs that either have the N1L gene deleted (vΔN1) or contain a I6E mutation (vN1.I6E) that abrogates its inhibition of NF-κB resulted in increased central and memory CD8+ T-cell populations, increased CD8+ T-cell cytotoxicity and lower virus titres after challenge. Furthermore, CD8+ memory T-cell function was increased following infection with vN1.I6E, with more interferon-γ production and greater protection against VACV infection following passive transfer to naive mice, compared with CD8+ T cells from mice infected with wild-type virus (vN1.WT). This demonstrates the importance of NF-κB activation within infected cells for long-term CD8+ T-cell memory and vaccine efficacy. Further, it provides a rationale for deleting N1 from VACV vectors to enhance CD8+ T-cell immunogenicity, while simultaneously reducing virulence to improve vaccine safety. PMID:25382035

Kinetics of B cell responses to Plasmodium falciparum erythrocyte membrane protein 1 in Ghanaian women naturally exposed to malaria parasites.

PubMed

Ampomah, Paulina; Stevenson, Liz; Ofori, Michael F; Barfod, Lea; Hviid, Lars

2014-06-01

Naturally acquired protective immunity to Plasmodium falciparum malaria takes years to develop. It relies mainly on Abs, particularly IgG specific for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins on the infected erythrocyte surface. It is only partially understood why acquisition of clinical protection takes years to develop, but it probably involves a range of immune-evasive parasite features, not least of which are PfEMP1 polymorphism and clonal variation. Parasite-induced subversion of immunological memory and expansion of "atypical" memory B cells may also contribute. In this first, to our knowledge, longitudinal study of its kind, we measured B cell subset composition, as well as PfEMP1-specific Ab levels and memory B cell frequencies, in Ghanaian women followed from early pregnancy up to 1 y after delivery. Cell phenotypes and Ag-specific B cell function were assessed three times during and after pregnancy. Levels of IgG specific for pregnancy-restricted, VAR2CSA-type PfEMP1 increased markedly during pregnancy and declined after delivery, whereas IgG levels specific for two PfEMP1 proteins not restricted to pregnancy did not. Changes in VAR2CSA-specific memory B cell frequencies showed typical primary memory induction among primigravidae and recall expansion among multigravidae, followed by contraction postpartum in all. No systematic changes in the frequencies of memory B cells specific for the two other PfEMP1 proteins were identified. The B cell subset analysis confirmed earlier reports of high atypical memory B cell frequencies among residents of P. falciparum-endemic areas, and indicated an additional effect of pregnancy. Our study provides new knowledge regarding immunity to P. falciparum malaria and underpins efforts to develop PfEMP1-based vaccines against this disease. Copyright © 2014 by The American Association of Immunologists, Inc.

HIV dynamics linked to memory CD4+ T cell homeostasis.

PubMed

Murray, John M; Zaunders, John; Emery, Sean; Cooper, David A; Hey-Nguyen, William J; Koelsch, Kersten K; Kelleher, Anthony D

2017-01-01

The dynamics of latent HIV is linked to infection and clearance of resting memory CD4+ T cells. Infection also resides within activated, non-dividing memory cells and can be impacted by antigen-driven and homeostatic proliferation despite suppressive antiretroviral therapy (ART). We investigated whether plasma viral level (pVL) and HIV DNA dynamics could be explained by HIV's impact on memory CD4+ T cell homeostasis. Median total, 2-LTR and integrated HIV DNA levels per μL of peripheral blood, for 8 primary (PHI) and 8 chronic HIV infected (CHI) individuals enrolled on a raltegravir (RAL) based regimen, exhibited greatest changes over the 1st year of ART. Dynamics slowed over the following 2 years so that total HIV DNA levels were equivalent to reported values for individuals after 10 years of ART. The mathematical model reproduced the multiphasic dynamics of pVL, and levels of total, 2-LTR and integrated HIV DNA in both PHI and CHI over 3 years of ART. Under these simulations, residual viremia originated from reactivated latently infected cells where most of these cells arose from clonal expansion within the resting phenotype. Since virion production from clonally expanded cells will not be affected by antiretroviral drugs, simulations of ART intensification had little impact on pVL. HIV DNA decay over the first year of ART followed the loss of activated memory cells (120 day half-life) while the 5.9 year half-life of total HIV DNA after this point mirrored the slower decay of resting memory cells. Simulations had difficulty reproducing the fast early HIV DNA dynamics, including 2-LTR levels peaking at week 12, and the later slow loss of total and 2-LTR HIV DNA, suggesting some ongoing infection. In summary, our modelling indicates that much of the dynamical behavior of HIV can be explained by its impact on memory CD4+ T cell homeostasis.

Use of ultrasonography to identify late-stage maturity in rainbow trout Oncorhynchus mykiss

USDA-ARS?s Scientific Manuscript database

Morphometric measurements by ultrasonography has been used to determine gonad and follicle size in many species of fish for purposes of identifying sex and estimating stage of maturation. We have been using a portable ultrasound system (SonoSite MicroMaxx, L25e/13-6 MHz transducer) to identify fem...

Central radio galaxies in groups: cavities, bubbles and the history of AGN heating

NASA Astrophysics Data System (ADS)

Giacintucci, S.; Venturi, T.; Raychaudhury, S.; Vrtilek, J.

2008-10-01

E' noto che le regioni centrali degli ammassi e gruppi di galassie costituiscono un ambiente in cui gas caldo e plasma radioemittente proveniente dalle galassie dominanti interagiscono tra loro. In particolare, si pensa che la radioemissione dell'AGN centrale ed i suoi possibili cicli di attivita', siano strettamente legati alla presenza di cavita' e "bubbles" nel gas intergalattico. Si presentera' lo status di un progetto osservativo effettuato con il Giant Metrewave Radio Telescope (GMRT, India) su di un campione di 18 gruppi di galassie, osservati a tre frequenze radio (235 MHz, 325 MHz e 610 MHz). Lo studio della morfologia radio degli AGN centrali e la relativa analisi spettrale permettono di ottenere stime sull'eta' di questi oggetti, e sulla loro energia totale, che a loro volta sono in relazione con le proprieta' X dei gruppi stessi. Per tutti gli oggetti del campione sono disponibili osservazioni Chandra di proprieta'. Per due oggetti del campione, 4C+24.36 (al centro di AWM04) e NGC741 (al centro di RSOG17) verra' presentato uno studio dettagliato.

DFT studies on the mechanism of the reaction of C2H5S with NO2

NASA Astrophysics Data System (ADS)

Tang, Yi-Zhen; Sun, Hao; Pan, Ya-Ru; Pan, Xiu-Mei; Wang, Rong-Shun

The mechanisms for the reaction of C2H5S with NO2 are investigated at the QCISD(T)/6-311++G(d, p)//B3LYP/6-311++G(d, p) level on both single and triple potential energy surfaces. The geometries, vibrational frequencies and zero-point energy (ZPE) corrections of all stationary points involved in the title reaction are calculated at the B3LYP/6-311++G(d, p) level. The results show that the reaction is more predominant on the single potential energy surface, while it is negligible on the triple potential energy surface. Without barrier height in the whole process, the major channel is R ? C2H5SONO (IM1 and IM2) ? P1 (C2H5SO+NO). With much heat released in the formation of C2H5SNO2 (IM3) and the transition state involved in the subsequent step more stable than reactants, P4 (CH3CHS + t-HONO) is subdominant product energetically.

Microbubbles in macrocysts - Contrast-enhanced ultrasound assisted sclerosant therapy of a congenital macrocystic lymphangioma: a case report.

PubMed

Menendez-Castro, Carlos; Zapke, Maren; Fahlbusch, Fabian; von Goessel, Heiko; Rascher, Wolfgang; Jüngert, Jörg

2017-07-06

Congenital cystic lymphangiomas are benign malformations due to a developmental disorder of lymphatic vessels. Besides surgical excision, sclerosant therapy of these lesions by intracavitary injection of OK-432 (Picibanil®), a lyophilized mixture of group A Streptococcus pyogenes, is a common therapeutical option. For an appropriate application of OK-432, a detailed knowledge about the structure and composition of the congenital cystic lymphangioma is essential. SonoVue® is a commercially available contrast agent commonly used in sonography by intravenous and intracavitary application. Here we report the case of 2 month old male patient with a large thoracic congenital cystic lymphangioma. Preinterventional imaging of the malformation was performed by contrast-enhanced ultrasound after intracavitary application of SonoVue® immediately followed by a successful sclerotherapy with OK-432. Contrast agent-enhanced ultrasound imaging offers a valuable option to preinterventionally clarify the anatomic specifications of a congenital cystic lymphangioma in more detail than by single conventional sonography. By the exact knowledge about the composition and especially about the intercystic communications of the lymphangioma sclerosant therapy becomes safer and more efficient.

[Trattamento del disturbo da uso di alcol da un punto di vista psicologico].

PubMed

Coriale, Giovanna; Fiorentino, Daniela; De Rosa, Francesca; Solombrino, Simona; Scalese, Bruna; Ciccarelli, Rosaria; Attilia, Fabio; Vitali, Mario; Musetti, Alessia; Fiore, Marco; Ceccanti, Mauro

2018-01-01

RIASSUNTO. L'elaborazione del piano di trattamento rappresenta un momento molto delicato e complesso del processo terapeutico del disturbo da abuso di alcol (DUA). È la fase in cui le informazioni raccolte da un'équipe di professionisti (medici, psicologi e assistenti sociali) (modello bio-psico-sociale del DUA) vengono messe insieme per decidere il percorso terapeutico più adatto. Per quanto riguarda la parte psicologica, è di notevole importanza scegliere un trattamento clinico in grado di ridurre al minimo la mancata adesione al trattamento e, per i soggetti che rimangono in trattamento, di garantirne l'efficacia. Se da una parte, le tecniche psicoanalitiche e comportamentali hanno fornito le basi della terapia psicologica dell'alcolismo, dall'altra, gli approcci basati sull'evidenza scientifica sono stati elaborati a partire dai principi del colloquio motivazionale e della terapia cognitivo-comportamentale. In questo articolo viene fornita una panoramica dei trattamenti che sono risultati più efficaci nel trattare il DUA e delle modalità temporali più adeguate per monitorare l'efficacia del trattamento.

Phenotype and specificity of T cells in primary human cytomegalovirus infection during pregnancy: IL-7Rpos long-term memory phenotype is associated with protection from vertical transmission.

PubMed

Mele, Federico; Fornara, Chiara; Jarrossay, David; Furione, Milena; Arossa, Alessia; Spinillo, Arsenio; Lanzavecchia, Antonio; Gerna, Giuseppe; Sallusto, Federica; Lilleri, Daniele

2017-01-01

Congenital human cytomegalovirus (HCMV) infection is the major cause of birth defects and a precise definition of the HCMV-specific T-cell response in primary infection may help define reliable correlates of immune protection during pregnancy. In this study, a high throughput method was used to define the frequency of CD4+ and CD8+ T cells specific for four HCMV proteins in the naïve compartment of seronegative subjects and the effector/memory compartments of subjects with primary/remote HCMV infection. The naïve repertoire displayed comparable frequencies of T cells that were reactive with HCMV structural (pp65, gB and the pentamer gHgLpUL128L) and non-structural (IE-1) proteins. Whereas, following natural infection, the majority of effector/memory CD4+ and CD8+ T cells recognized either gB or IE-1, respectively, and pp65. The pattern of T cell reactivity was comparable at early and late stages of infection and in pregnant women with primary HCMV infection transmitting or not transmitting the virus to the fetus. At an early stage of primary infection, about 50% of HCMV-reactive CD4+ T cells were long-term IL-7Rpos memory cells, while 6-12 months later, the frequency of these cells increased to 70%, approaching 100% in remote infections. In contrast, only 10-20% of HCMV-specific CD8+ T cells were long-term memory cells up to 12 months after infection onset, thereafter increasing to 70% in remote infections. Interestingly, a significantly higher frequency of HCMV-specific CD4+ T cells with a long-term IL-7Rpos memory phenotype was observed in non-transmitting compared to transmitting women. These findings indicate that immunodominance in HCMV infection is not predetermined in the naïve compartment, but is the result of virus-host interactions and suggest that prompt control of HCMV infection in pregnancy is associated with the rapid development of long-term IL-7Rpos memory HCMV-specific CD4+ T cells and a low risk of virus transmission to the fetus.

Naïve and memory CD8 T cell pool homeostasis in advanced aging: impact of age and of antigen-specific responses to cytomegalovirus.

PubMed

Vescovini, Rosanna; Fagnoni, Francesco Fausto; Telera, Anna Rita; Bucci, Laura; Pedrazzoni, Mario; Magalini, Francesca; Stella, Adriano; Pasin, Federico; Medici, Maria Cristina; Calderaro, Adriana; Volpi, Riccardo; Monti, Daniela; Franceschi, Claudio; Nikolich-Žugich, Janko; Sansoni, Paolo

2014-04-01

Alterations in the circulating CD8+ T cell pool, with a loss of naïve and accumulation of effector/effector memory cells, are pronounced in older adults. However, homeostatic forces that dictate such changes remain incompletely understood. This observational cross-sectional study explored the basis for variability of CD8+ T cell number and composition of its main subsets: naïve, central memory and effector memory T cells, in 131 cytomegalovirus (CMV) seropositive subjects aged over 60 years. We found great heterogeneity of CD8+ T cell numbers, which was mainly due to variability of the CD8 + CD28- T cell subset regardless of age. Analysis, by multiple regression, of distinct factors revealed that age was a predictor for the loss in absolute number of naïve T cells, but was not associated with changes in central or effector memory CD8+ T cell subsets. By contrast, the size of CD8+ T cells specific to pp65 and IE-1 antigens of CMV, predicted CD28 - CD8+ T cell, antigen-experienced CD8+ T cell, and even total CD8+ T cell numbers, but not naïve CD8+ T cell loss. These results indicate a clear dichotomy between the homeostasis of naïve and antigen-experienced subsets of CD8+ T cells which are independently affected, in human later life, by age and antigen-specific responses to CMV, respectively.

Distribution of Peripheral Memory T Follicular Helper Cells in Patients with Schistosomiasis Japonica

PubMed Central

Chen, Xiaojun; Li, Wei; Zhang, Yang; Song, Xian; Xu, Lei; Xu, Zhipeng; Zhou, Sha; Zhu, Jifeng; Jin, Xin; Liu, Feng; Chen, Gengxin; Su, Chuan

2015-01-01

Background Schistosomiasis is a helminthic disease that affects more than 200 million people. An effective vaccine would be a major step towards eliminating the disease. Studies suggest that T follicular helper (Tfh) cells provide help to B cells to generate the long-term humoral immunity, which would be a crucial component of successful vaccines. Thus, understanding the biological characteristics of Tfh cells in patients with schistosomiasis, which has never been explored, is essential for vaccine design. Methodology/Principal Findings In this study, we investigated the biological characteristics of peripheral memory Tfh cells in schistosomiasis patients by flow cytometry. Our data showed that the frequencies of total and activated peripheral memory Tfh cells in patients were significantly increased during Schistosoma japonicum infection. Moreover, Tfh2 cells, which were reported to be a specific subpopulation to facilitate the generation of protective antibodies, were increased more greatly than other subpopulations of total peripheral memory Tfh cells in patients with schistosomiasis japonica. More importantly, our result showed significant correlations of the percentage of Tfh2 cells with both the frequency of plasma cells and the level of IgG antibody. In addition, our results showed that the percentage of T follicular regulatory (Tfr) cells was also increased in patients with schistosomiasis. Conclusions/Significance Our report is the first characterization of peripheral memory Tfh cells in schistosomasis patients, which not only provides potential targets to improve immune response to vaccination, but also is important for the development of vaccination strategies to control schistosomiasis. PMID:26284362

Memory strategy training in children with cerebral infarcts related to sickle cell disease.

PubMed

Yerys, Benjamin E; White, Desirée A; Salorio, Cynthia F; McKinstry, Robert; Moinuddin, Asif; DeBaun, Michael

2003-06-01

Cerebral infarcts occur in approximately 30% of children with sickle cell disease (SCD), but little information exists regarding remediation of associated cognitive deficits. The authors examined the benefits of training children with infarcts to use memory strategies. Six children with SCD-related infarcts received academic tutoring; three of these children received additional training in memory strategies (silent rehearsal to facilitate short-term memory and semantic organization to facilitate long-term memory). The performance of children receiving strategy training appeared to improve more than that of children receiving only tutoring. Memory in children with SCD-related infarcts may be enhanced through strategy training.

Inception of a false memory by optogenetic manipulation of a hippocampal memory engram.

PubMed

Liu, Xu; Ramirez, Steve; Tonegawa, Susumu

2014-01-05

Memories can be easily distorted, and a lack of relevant animal models has largely hindered our understanding of false-memory formation. Here, we first identified a population of cells in the dentate gyrus (DG) of the hippocampus that bear the engrams for a specific context; these cells were naturally activated during the encoding phase of fear conditioning and their artificial reactivation using optogenetics in an unrelated context was sufficient for inducing the fear memory specific to the conditioned context. In a further study, DG or CA1 neurons activated by exposure to a particular context were labelled with channelrhodopsin-2 (ChR2). These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context in which a foot shock was never delivered. The recall of this false memory was context specific, activated similar downstream regions engaged during natural fear-memory recall, and was also capable of driving an active fear response. Together, our data demonstrate that by substituting a natural conditioned stimulus with optogenetically reactivated DG cells that bear contextual memory engrams, it is possible to incept an internally and behaviourally represented false fear memory.

Inception of a false memory by optogenetic manipulation of a hippocampal memory engram

PubMed Central

Liu, Xu; Ramirez, Steve; Tonegawa, Susumu

2014-01-01

Memories can be easily distorted, and a lack of relevant animal models has largely hindered our understanding of false-memory formation. Here, we first identified a population of cells in the dentate gyrus (DG) of the hippocampus that bear the engrams for a specific context; these cells were naturally activated during the encoding phase of fear conditioning and their artificial reactivation using optogenetics in an unrelated context was sufficient for inducing the fear memory specific to the conditioned context. In a further study, DG or CA1 neurons activated by exposure to a particular context were labelled with channelrhodopsin-2 (ChR2). These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context in which a foot shock was never delivered. The recall of this false memory was context specific, activated similar downstream regions engaged during natural fear-memory recall, and was also capable of driving an active fear response. Together, our data demonstrate that by substituting a natural conditioned stimulus with optogenetically reactivated DG cells that bear contextual memory engrams, it is possible to incept an internally and behaviourally represented false fear memory. PMID:24298144

Gut memories do not fade: epigenetic regulation of lasting gut homing receptor expression in CD4+ memory T cells.

PubMed

Szilagyi, B A; Triebus, J; Kressler, C; de Almeida, M; Tierling, S; Durek, P; Mardahl, M; Szilagyi, A; Floess, S; Huehn, J; Syrbe, U; Walter, J; Polansky, J K; Hamann, A

2017-11-01

The concept of a "topographical memory" in lymphocytes implies a stable expression of homing receptors mediating trafficking of lymphocytes back to the tissue of initial activation. However, a significant plasticity of the gut-homing receptor α 4 β 7 was found in CD8 + T cells, questioning the concept. We now demonstrate that α 4 β 7 expression in murine CD4 + memory T cells is, in contrast, imprinted and remains stable in the absence of the inducing factor retinoic acid (RA) or other stimuli from mucosal environments. Repetitive rounds of RA treatment enhanced the stability of de novo induced α 4 β 7 . A novel enhancer element in the murine Itga4 locus was identified that showed, correlating to stability, selective DNA demethylation in mucosa-seeking memory cells and methylation-dependent transcriptional activity in a reporter gene assay. This implies that epigenetic mechanisms contribute to the stabilization of α 4 β 7 expression. Analogous DNA methylation patterns could be observed in the human ITGA4 locus, suggesting that its epigenetic regulation is conserved between mice and men. These data prove that mucosa-specific homing mediated by α 4 β 7 is imprinted in CD4 + memory T cells, reinstating the validity of the concept of "topographical memory" for mucosal tissues, and imply a critical role of epigenetic mechanisms.

SPATIAL MEMORY IMPAIRMENT AND HIPPOCAMPAL CELL LOSS INDUCED BY OKADAIC ACID (EXPERIMENTAL STUDY).

PubMed

Chighladze, M; Dashniani, M; Beselia, G; Kruashvili, L; Naneishvili, T

2016-01-01

In the present study, we evaluated and compared effect of intracerebroventricular (ICV) and intrahippocampal bilateral microinjection of okadaic acid (OA) on spatial memory function assessed in one day water maze paradigm and hippocampal structure in rats. Rats were divided in following groups: Control(icv) - rats injected with ICV and aCSF; Control(hipp) - rats injected intrahippocampally with aCSF; OAicv - rats injected with ICV and OA; OAhipp - rats injected intrahippocampally with OA. Nissl staining of hippocampal sections showed that the pyramidal cell loss in OAhipp group is significantly higher than that in the OAicv. The results of behavioral experiments showed that ICV or intrahippocampal bilateral microinjection of OA did not affect learning process and short-term spatial memory but induced impairment in spatial long-term memory assessed in probe test performance 24 h after training. OA-induced spatial memory impairment may be attributed to the hippocampal cell death. Based on these results OA induced memory deficit and hippocampal cell loss in rat may be considered as a potential animal model for preclinical evaluation of antidementic drug activity.

[Evaluation of mercury exposure in populations living near the industrial Augusta Bay (Sicily Region, Southern Italy)].

PubMed

Bonsignore, Maria; Andolfi, Nunzia; Quinci, Enza Maria; Madeddu, Anselmo; Tisano, Francesco; Ingallinella, Vincenzo; Castorina, Maria; Sprovieri, Mario

2016-01-01

OBIETTIVI: valutare e quantificare l'esposizione umana al mercurio (Hg) ed esplorare i fattori chiave che influenzano la contaminazione nelle popolazioni residenti in prossimità della Rada di Augusta, un'area a elevato rischio ambientale a causa degli effetti degli sversamenti incontrollati di Hg da parte di uno dei più grandi impianti cloro-soda d'Europa. DISEGNO: un campione di residenti nei comuni di Augusta, Priolo e Melilli (Sicilia orientale) è stato selezionato per lo studio di biomonitoraggio umano. Un questionario dettagliato è stato somministrato a ogni partecipante per raccogliere informazioni anagrafiche sulle abitudini di vita e alimentari. I livelli di Hg in sangue e capelli, usati come traccianti di esposizione a metilmercurio, sono stati messi in relazione al consumo di pesce locale. Il contenuto di Hg nelle urine è stato utilizzato per esplorare eventuali esposizioni atmosferiche a Hg inorganico. Una regressione lineare multivariata è stata applicata con l'obiettivo di esplorare i fattori che influenzano l'esposizione umana al Hg. L'approccio tossicocinetico è stato impiegato al fine di calcolare la dose settimanale provvisoria tollerabile ( provisional tolerable weekly intake, PTWI) e di predire le concentrazioni di Hg attese nel sangue degli individui con una dieta alimentare basata esclusivamente su pesce locale. 224 individui residenti nei comuni di Augusta, Melilli e Priolo. RISULTATI: eccessi di Hg sono stati misurati nel sangue e nei capelli del campione considerato. I più alti livelli sono stati rilevati ad Augusta, dove anche il consumo di pesce locale risulta maggiore. I valori di dose settimanale tollerabile provvisoria (PTWI) calcolati eccedono, nella maggior parte dei casi, le raccomandazioni internazionali, specialmente nei residenti ad Augusta. CONCLUSIONI: gli elevati livelli di Hg registrati nei campioni di sangue e capelli derivano, con ogni probabilità, dal consumo di pesce locale. Rispetto ad Augusta, gli individui di Priolo e Melilli subiscono un impatto più limitato. L'esposizione a Hg inorganico può essere considerata trascurabile.

Light sensitivity of a one transistor-one capacitor memory cell when used as a micromirror actuator in projector applications

NASA Astrophysics Data System (ADS)

Huffman, James Douglas

2001-11-01

The most important issue facing the future business success of the Digital Micromirror Device or DMD™ produced by Texas Instruments is the cost of the actual device. As the business and consumer markets call for higher resolution displays, the array size will have to be increased to incorporate more pixels. The manufacturing costs associated with building these higher resolution displays follow an exponential relation with the number of pixels due to yield loss and reduced number of chips per silicon wafer. Each pixel is actuated by electrostatics that are provided by a memory cell that is built in the underlying silicon substrate. One way to decrease cost of the wafer is to change the memory cell architecture from a static random access configuration or SRAM to a dynamic random access configuration or DRAM. This change has the benefits of having fewer components per area and a lower metal density. This reduction in the component count and metal density has a dramatic effect on the yield of the memory array by reducing the particle sensitivity of the underlying cell. The main drawback to using a DRAM configuration in a display application is the light sensitivity of a charge storage device built in the silicon substrate. As the photons pass through the mechanical micromirrors and illuminate the DRAM cell, the effective electrostatic potential of the memory element used for the mirror actuation is reduced. This dissertation outlines the issues associated with the light sensitivity of a DRAM memory cell as the actuation element for a micromirror. The concept of charge depletion on a silicon capacitor due to recombination of photogenerated carriers is explored and experimentally verified. The effects of the reduced potential on the capacitor on the micromirror are also explored. Optical modeling is used to determine the incoming photon flux to determine the benefits of adding a charge recombination region as part of the DRAM memory cell. Several options are explored to reduce the effect of the incoming photons on the potential of the memory cell. The results will show that a 1T1C memory cell with N-type recombination regions and maximum light shielding is sufficient for a projector application.

Interleukin (IL)-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts1

PubMed Central

Iida, Shoichi; Tsuda, Hidetoshi; Tanaka, Toshiaki; Kish, Danielle D.; Abe, Toyofumi; Su, Charles A.; Abe, Ryo; Tanabe, Kazunari; Valujskikh, Anna; Baldwin, William M.; Fairchild, Robert L.

2016-01-01

Reperfusion of organ allografts induces a potent inflammatory response that directs rapid memory T cell, neutrophil and macrophage graft infiltration and their activation to express functions mediating graft tissue injury. The role of cardiac allograft IL-1 receptor signaling in this early inflammation and the downstream primary alloimmune response was investigated. When compared to complete MHC-mismatched wild type cardiac allografts, IL-1R−/− allografts had marked decreases in endogenous memory CD8 T cell and neutrophil infiltration and expression of proinflammatory mediators at early times after transplant whereas endogenous memory CD4 T cell and macrophage infiltration was not decreased. IL-1R−/− allograft recipients also had marked decreases in de novo donor-reactive CD8, but not CD4, T cell development to IFN-γ-producing cells. CD8 T cell-mediated rejection of IL-1R−/− cardiac allografts took 3 weeks longer than wild type allografts. Cardiac allografts from reciprocal bone marrow reconstituted IL-1R−/−/wild type chimeric donors indicated that IL-1R signaling on graft non-hematopoietic-derived, but not bone marrow-derived, cells is required for the potent donor-reactive memory and primary CD8 T cell alloimmune responses observed in response to wild type allografts. These studies implicate IL-1R-mediated signals by allograft parenchymal cells in generating the stimuli provoking development and elicitation of optimal alloimmune responses to the grafts. PMID:26856697

Identification and optogenetic manipulation of memory engrams in the hippocampus

PubMed Central

Ramirez, Steve; Tonegawa, Susumu; Liu, Xu

2014-01-01

With the accumulation of our knowledge about how memories are formed, consolidated, retrieved, and updated, neuroscience is now reaching a point where discrete memories can be identified and manipulated at rapid timescales. Here, we start with historical studies that lead to the modern memory engram theory. Then, we will review recent advances in memory engram research that combine transgenic and optogenetic approaches to reveal the underlying neuronal substrates sufficient for activating mnemonic processes. We will focus on three concepts: (1) isolating memory engrams at the level of single cells to tag them for subsequent manipulation; (2) testing the sufficiency of these engrams for memory recall by artificially activating them; and (3) presenting new stimuli during the artificial activation of these engrams to induce an association between the two to form a false memory. We propose that hippocampal cells that show activity-dependent changes during learning construct a cellular basis for contextual memory engrams. PMID:24478647

Altered hippocampal replay is associated with memory impairment in mice heterozygous for the Scn2a gene.

PubMed

Middleton, Steven J; Kneller, Emily M; Chen, Shuo; Ogiwara, Ikuo; Montal, Mauricio; Yamakawa, Kazuhiro; McHugh, Thomas J

2018-06-04

An accumulating body of experimental evidence has implicated hippocampal replay occurring within sharp wave ripples (SPW-Rs) as crucial for learning and memory in healthy subjects. This raises speculation that neurological disorders impairing memory disrupt either SPW-Rs or their underlying neuronal activity. We report that mice heterozygous for the gene Scn2a, a site of frequent de novo mutations in humans with intellectual disability, displayed impaired spatial memory. While we observed no changes during encoding, to either single place cells or cell assemblies, we identified abnormalities restricted to SPW-R episodes that manifest as decreased cell assembly reactivation strengths and truncated hippocampal replay sequences. Our results suggest that alterations to hippocampal replay content may underlie disease-associated memory deficits.

Switched Memory B Cells Are Increased in Oligoarticular and Polyarticular Juvenile Idiopathic Arthritis and Their Change Over Time Is Related to Response to Tumor Necrosis Factor Inhibitors.

PubMed

Marasco, Emiliano; Aquilani, Angela; Cascioli, Simona; Moneta, Gian Marco; Caiello, Ivan; Farroni, Chiara; Giorda, Ezio; D'Oria, Valentina; Marafon, Denise Pires; Magni-Manzoni, Silvia; Carsetti, Rita; De Benedetti, Fabrizio

2018-04-01

To investigate whether abnormalities in B cell subsets in patients with juvenile idiopathic arthritis (JIA) correlate with clinical features and response to treatment. A total of 109 patients diagnosed as having oligoarticular JIA or polyarticular JIA were enrolled in the study. B cell subsets in peripheral blood and synovial fluid were analyzed by flow cytometry. Switched memory B cells were significantly increased in patients compared to age-matched healthy controls (P < 0.0001). When patients were divided according to age at onset of JIA, in patients with early-onset disease (presenting before age 6 years) the expansion in switched memory B cells was more pronounced than that in patients with late-onset disease and persisted throughout the disease course. In longitudinal studies, during methotrexate (MTX) treatment, regardless of the presence or absence of active disease, the number of switched memory B cells increased significantly (median change from baseline 36% [interquartile range {IQR} 15, 66]). During treatment with MTX plus tumor necrosis factor inhibitors (TNFi), in patients maintaining disease remission, the increase in switched memory B cells was significantly lower than that in patients who experienced active disease (median change from baseline 4% [IQR -6, 32] versus 41% [IQR 11, 73]; P = 0.004). The yearly rate of increases in switched memory B cells was 1.5% in healthy controls, 1.2% in patients who maintained remission during treatment with MTX plus TNFi, 4.7% in patients who experienced active disease during treatment with MTX plus TNFi, and ~4% in patients treated with MTX alone. Switched memory B cells expand during the disease course at a faster rate in JIA patients than in healthy children. This increase is more evident in patients with early-onset JIA. TNFi treatment inhibits this increase in patients who achieve and maintain remission, but not in those with active disease. © 2018, American College of Rheumatology.

Early programming and late-acting checkpoints governing the development of CD4 T cell memory.

PubMed

Dhume, Kunal; McKinstry, K Kai

2018-04-27

CD4 T cells contribute to protection against pathogens through numerous mechanisms. Incorporating the goal of memory CD4 T cell generation into vaccine strategies thus offers a powerful approach to improve their efficacy, especially in situations where humoral responses alone cannot confer long-term immunity. These threats include viruses such as influenza that mutate coat proteins to avoid neutralizing antibodies, but that are targeted by T cells that recognize more conserved protein epitopes shared by different strains. A major barrier in the design of such vaccines is that the mechanisms controlling the efficiency with which memory cells form remain incompletely understood. Here, we discuss recent insights into fate decisions controlling memory generation. We focus on the importance of three general cues: interleukin-2, antigen, and costimulatory interactions. It is increasingly clear that these signals have a powerful influence on the capacity of CD4 T cells to form memory during two distinct phases of the immune response. First, through 'programming' that occurs during initial priming, and second, through 'checkpoints' that operate later during the effector stage. These findings indicate that novel vaccine strategies must seek to optimize cognate interactions, during which interleukin-2-, antigen, and costimulation-dependent signals are tightly linked, well beyond initial antigen encounter to induce robust memory CD4 T cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Content addressable memory project

NASA Technical Reports Server (NTRS)

Hall, Josh; Levy, Saul; Smith, D.; Wei, S.; Miyake, K.; Murdocca, M.

1991-01-01

The progress on the Rutgers CAM (Content Addressable Memory) Project is described. The overall design of the system is completed at the architectural level and described. The machine is composed of two kinds of cells: (1) the CAM cells which include both memory and processor, and support local processing within each cell; and (2) the tree cells, which have smaller instruction set, and provide global processing over the CAM cells. A parameterized design of the basic CAM cell is completed. Progress was made on the final specification of the CPS. The machine architecture was driven by the design of algorithms whose requirements are reflected in the resulted instruction set(s). A few of these algorithms are described.

Sleep, quality of life and mood of nursing professionals of pediatric intensive care units.

PubMed

Guerra, Priscilla Caetano; Oliveira, Nilton Ferraro; Terreri, Maria Teresa de Sande E Lemos Ramos Ascensão; Len, Claudio Arnaldo

2016-04-01

To assess sleep, quality of life and mood of nursing professionals of pediatric intensive care units. Quantitative, cross-sectional and descriptive study. Professionals grouped by morning, afternoon and evening shifts were assessed by means of the instruments: Morningness-Eveningness Questionnaire; Pittsburgh Sleep Quality Index; Epworth Sleepiness Scale; Generic questionnaire for the assessment of quality of life (SF-36); Beck Depression Inventory; Beck Anxiety Inventory; State-Trait Anxiety Inventory. Sample consisted of 168 professionals, with prevalence of neutral typology (57.49%). There was no statistical significance regarding sleep, despite scores showing a poor quality of sleep and excessive daytime sleepiness for the three shifts. Quality of life did not reveal any statistical significance, but in the field "social role functioning" of the evening shift, a lower score was observed (p<0.007). There was no statistical significance regarding levels of anxiety and depression. The results suggest that these professionals may present sleeping problems, but they do not have lower scores of quality of life or mood disorders. Likely explanations for these findings may include an adaptation to their work type over time and the fact that working with children is rewarding. Avaliar sono, qualidade de vida e humor em profissionais de enfermagem em Unidades de Terapia Intensiva Infantil. Estudo quantitativo, transversal e descritivo. Profissionais agrupados por turnos matutino, vespertino e noturno foram avaliados pelos instrumentos: Questionário de identificação Matutinidade-Vespertinidade; Índice de qualidade do sono de Pittsburgh; Escala de sonolência Epworth; Questionário genérico de avaliação de qualidade de vida - SF-36; Inventário de depressão de Beck; Inventário de ansiedade de Beck; Inventário de ansiedade Traço-Estado. Amostra composta por 168 profissionais, predominando tipologia neutra, 57,49%. Não houve significância estatística quanto ao sono, apesar dos escores mostrarem qualidade ruim e sonolência diurna excessiva para os três turnos. A qualidade de vida não denotou diferença estatística, mas no domínio "aspecto social" do turno noturno, observou-se escore pior (p<0,007). Não houve significância estatística nos níveis de ansiedade e depressão. Os resultados sugerem que estes profissionais podem apresentar problemas no sono, entretanto não apresentam escores mais baixos de qualidade de vida ou transtornos do humor. Possíveis explicações para estes achados são que haja uma adaptação ao regime de trabalho ao longo do tempo e que trabalhar com crianças seja recompensador.

Acute effects of sono-activated photocatalytic titanium dioxide nanoparticles on oral squamous cell carcinoma.

PubMed

Moosavi Nejad, S; Takahashi, Hiromasa; Hosseini, Hamid; Watanabe, Akiko; Endo, Hitomi; Narihira, Kyoichi; Kikuta, Toshihiro; Tachibana, Katsuro

2016-09-01

Sonodynamic therapy (SDT) is a new treatment modality using ultrasound to activate certain chemical sensitizers for cancer therapy. In this study, effects of high intensity focused ultrasound (HIFU) combined with photocatalytic titanium dioxide (TiO2) nanoparticles on human oral squamous cell line HSC-2 were investigated. Viability of HSC-2 cells after 0, 0.1, 1, or 3s of HIFU irradiation with 20, 32, 55 and 73Wcm(-2) intensities in the presence or absence of TiO2 was measured immediately after the exposures in vitro. Immediate effects of HIFU (3s, 73Wcm(-2)) combined with TiO2 on solid tumors were also examined by histological study. Cytotoxic effect of HIFU+TiO2in vitro was significantly higher than that of TiO2 or HIFU alone with the tendency to increase for higher HIFU intensity, duration, and TiO2 concentration in the suspension. In vivo results showed significant necrosis and tissue damage in HIFU and HIFU+TiO2 treated samples. However, penetration of TiO2 nanoparticles into the cell cytoplasm was only observed in HIFU+TiO2 treated tissues. In this study, our findings provide a rational basis for the development of an effective HIFU based sonodynamic activation method. This approach offers an attractive non-invasive therapy technique for oral cancer in future. Copyright © 2016 Elsevier B.V. All rights reserved.

The correlational research among serum CXCL13 levels, circulating plasmablasts and memory B cells in patients with systemic lupus erythematosus: A STROBE-compliant article.

PubMed

Fang, Chenglong; Luo, Tingting; Lin, Ling

2017-12-01

We investigated whether serum CXC ligand 13 protein (CXCL13) levels correlate with the circulating plasmablasts and memory B-cells alteration in systemic lupus erythematosus (SLE) patients. The diagnostic use of CXCL13 concentrations in active lupus was also analyzed.A total of 36 SLE patients and 18 healthy controls were included. Serum CXCL13 levels were examined by enzyme-linked immunosorbent assay. The frequency and absolute count of circulating plasmablasts and memory B cells were analyzed by flow cytometry. Receiver operating characteristic curves (ROC curves) were generated to analyze the utility of serum CXCL13 level and plasmablasts frequency as tools for the recognition of active SLE.Elevation of serum CXCL13 levels, higher plasmablasts frequency, and reduction of memory B-cells count were observed in SLE patients, compared with healthy controls. Interestingly, correlational analyses showed not only significantly positive association between CXCL13 levels and SLE Disease Activity Index (SLEDAI) or plasmablasts frequency, but an inverse correlation between CXCL13 concentration and memory B-cell count. ROC curves showed that serum CXCL13 level and plasmablasts frequency were practical in identifying active disease from overall SLE patients, with considerable accuracy.Serum CXCL13 levels correlate with the alteration of plasmablasts and memory B cells in SLE. CXCL13 may be used as a practical tool in judgment of active SLE.

Progressive CD4+ central–memory T cell decline results in CD4+ effector–memory insufficiency and overt disease in chronic SIV infection

PubMed Central

Okoye, Afam; Meier-Schellersheim, Martin; Brenchley, Jason M.; Hagen, Shoko I.; Walker, Joshua M.; Rohankhedkar, Mukta; Lum, Richard; Edgar, John B.; Planer, Shannon L.; Legasse, Alfred; Sylwester, Andrew W.; Piatak, Michael; Lifson, Jeffrey D.; Maino, Vernon C.; Sodora, Donald L.; Douek, Daniel C.; Axthelm, Michael K.; Grossman, Zvi; Picker, Louis J.

2007-01-01

Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4+ CCR5+ effector–memory T (TEM) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4+ memory T cell proliferation appears to prevent collapse of effector site CD4+ TEM cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4+ TEM cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4+ TEM cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4+ TEM cells from central–memory T (TCM) cell precursors. The instability of effector site CD4+ TEM cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5− CD4+ TCM cells. These data suggest that although CD4+ TEM cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4+ TCM cells. PMID:17724130

Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection.

PubMed

Okoye, Afam; Meier-Schellersheim, Martin; Brenchley, Jason M; Hagen, Shoko I; Walker, Joshua M; Rohankhedkar, Mukta; Lum, Richard; Edgar, John B; Planer, Shannon L; Legasse, Alfred; Sylwester, Andrew W; Piatak, Michael; Lifson, Jeffrey D; Maino, Vernon C; Sodora, Donald L; Douek, Daniel C; Axthelm, Michael K; Grossman, Zvi; Picker, Louis J

2007-09-03

Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4(+) CCR5(+) effector-memory T (T(EM)) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4(+) memory T cell proliferation appears to prevent collapse of effector site CD4(+) T(EM) cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4(+) T(EM) cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors. The instability of effector site CD4(+) T(EM) cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5(-) CD4(+) T(CM) cells. These data suggest that although CD4(+) T(EM) cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4(+) T(CM) cells.

Blocking Glycolytic Metabolism Increases Memory T Cells and Antitumor Function | Center for Cancer Research

Cancer.gov

CD8+ T cells are a major component of the cellular immune response, which is necessary to control a variety of bacterial and viral infections. CD8+ T cells also play a major role in the cell-mediated antitumor immune response. After encountering antigen, naïve CD8+ T cells undergo an extensive period of proliferation and expansion, and differentiate into effector cells and distinct memory T cell subsets. Preclinical studies using adoptive transfer of purified CD8+ T cells have shown that the ability of T cells to proliferate and survive for a long time after transfer is associated with effective antitumor and antiviral responses. Understanding how the formation of long-lived memory T cell subsets is controlled may enable development of more potent immunotherapies against cancer and infectious diseases.

T Cell Receptor-Major Histocompatibility Complex Interaction Strength Defines Trafficking and CD103+ Memory Status of CD8 T Cells in the Brain.

PubMed

Sanecka, Anna; Yoshida, Nagisa; Kolawole, Elizabeth Motunrayo; Patel, Harshil; Evavold, Brian D; Frickel, Eva-Maria

2018-01-01

T cell receptor-major histocompatibility complex (TCR-MHC) affinities span a wide range in a polyclonal T cell response, yet it is undefined how affinity shapes long-term properties of CD8 T cells during chronic infection with persistent antigen. Here, we investigate how the affinity of the TCR-MHC interaction shapes the phenotype of memory CD8 T cells in the chronically Toxoplasma gondii- infected brain. We employed CD8 T cells from three lines of transnuclear (TN) mice that harbor in their endogenous loci different T cell receptors specific for the same Toxoplasma antigenic epitope ROP7. The three TN CD8 T cell clones span a wide range of affinities to MHCI-ROP7. These three CD8 T cell clones have a distinct and fixed hierarchy in terms of effector function in response to the antigen measured as proliferation capacity, trafficking, T cell maintenance, and memory formation. In particular, the T cell clone of lowest affinity does not home to the brain. The two higher affinity T cell clones show differences in establishing resident-like memory populations (CD103 + ) in the brain with the higher affinity clone persisting longer in the host during chronic infection. Transcriptional profiling of naïve and activated ROP7-specific CD8 T cells revealed that Klf2 encoding a transcription factor that is known to be a negative marker for T cell trafficking is upregulated in the activated lowest affinity ROP7 clone. Our data thus suggest that TCR-MHC affinity dictates memory CD8 T cell fate at the site of infection.

Strategic priming with multiple antigens can yield memory cell phenotypes optimized for infection with Mycobacterium tuberculosis: A computational study

DOE PAGES

Ziraldo, Cordelia; Gong, Chang; Kirschner, Denise E.; ...

2016-01-06

Lack of an effective vaccine results in 9 million new cases of tuberculosis (TB) every year and 1.8 million deaths worldwide. While many infants are vaccinated at birth with BCG (an attenuated M. bovis), this does not prevent infection or development of TB after childhood. Immune responses necessary for prevention of infection or disease are still unknown, making development of effective vaccines against TB challenging. Several new vaccines are ready for human clinical trials, but these trials are difficult and expensive; especially challenging is determining the appropriate cellular response necessary for protection. The magnitude of an immune response is likelymore » key to generating a successful vaccine. Characteristics such as numbers of central memory (CM) and effector memory (EM) T cells responsive to a diverse set of epitopes are also correlated with protection. Promising vaccines against TB contain mycobacterial subunit antigens (Ag) present during both active and latent infection. We hypothesize that protection against different key immunodominant antigens could require a vaccine that produces different levels of EM and CM for each Ag-specific memory population. We created a computational model to explore EM and CM values, and their ratio, within what we term Memory Design Space. Our model captures events involved in T cell priming within lymph nodes and tracks their circulation through blood to peripheral tissues. We used the model to test whether multiple Ag-specific memory cell populations could be generated with distinct locations within Memory Design Space at a specific time point post vaccination. Boosting can further shift memory populations to memory cell ratios unreachable by initial priming events. By strategically varying antigen load, properties of cellular interactions within the LN, and delivery parameters (e.g., number of boosts) of multi-subunit vaccines, we can generate multiple Ag-specific memory populations that cover a wide range of Memory Design Space. As a result, given a set of desired characteristics for Ag-specific memory populations, we can use our model as a tool to predict vaccine formulations that will generate those populations.« less

Strategic priming with multiple antigens can yield memory cell phenotypes optimized for infection with Mycobacterium tuberculosis: A computational study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ziraldo, Cordelia; Gong, Chang; Kirschner, Denise E.

Lack of an effective vaccine results in 9 million new cases of tuberculosis (TB) every year and 1.8 million deaths worldwide. While many infants are vaccinated at birth with BCG (an attenuated M. bovis), this does not prevent infection or development of TB after childhood. Immune responses necessary for prevention of infection or disease are still unknown, making development of effective vaccines against TB challenging. Several new vaccines are ready for human clinical trials, but these trials are difficult and expensive; especially challenging is determining the appropriate cellular response necessary for protection. The magnitude of an immune response is likelymore » key to generating a successful vaccine. Characteristics such as numbers of central memory (CM) and effector memory (EM) T cells responsive to a diverse set of epitopes are also correlated with protection. Promising vaccines against TB contain mycobacterial subunit antigens (Ag) present during both active and latent infection. We hypothesize that protection against different key immunodominant antigens could require a vaccine that produces different levels of EM and CM for each Ag-specific memory population. We created a computational model to explore EM and CM values, and their ratio, within what we term Memory Design Space. Our model captures events involved in T cell priming within lymph nodes and tracks their circulation through blood to peripheral tissues. We used the model to test whether multiple Ag-specific memory cell populations could be generated with distinct locations within Memory Design Space at a specific time point post vaccination. Boosting can further shift memory populations to memory cell ratios unreachable by initial priming events. By strategically varying antigen load, properties of cellular interactions within the LN, and delivery parameters (e.g., number of boosts) of multi-subunit vaccines, we can generate multiple Ag-specific memory populations that cover a wide range of Memory Design Space. As a result, given a set of desired characteristics for Ag-specific memory populations, we can use our model as a tool to predict vaccine formulations that will generate those populations.« less

Memory CD8+ T cells are sufficient to alleviate impaired host resistance to influenza A virus infection caused by neonatal oxygen supplementation.

PubMed

Giannandrea, Matthew; Yee, Min; O'Reilly, Michael A; Lawrence, B Paige

2012-09-01

Supplemental oxygen administered to preterm infants is an important clinical intervention, but it is associated with life-long changes in lung development and increased sensitivity to respiratory viral infections. The precise immunological changes caused by neonatal oxygen treatment remain poorly understood. We previously reported that adult mice exposed to supplemental oxygen as neonates display persistent pulmonary inflammation and enhanced mortality after a sublethal influenza A virus infection. These changes suggest that neonatal hyperoxia impairs the cytotoxic CD8(+) T cell response required to clear the virus. In this study, we show that although host resistance to several different strains of influenza A virus is reduced by neonatal hyperoxia, this treatment does not impair viral clearance, nor does it alter the magnitude of the virus-specific CD8(+) T cell response to primary infection. Moreover, memory T cells are sufficient to ameliorate the increased morbidity and mortality and alleviate the excessive lung damage observed in mice exposed to high oxygen levels as neonates, and we attribute this sufficiency principally to virus-specific memory CD8(+) T cells. Thus, we show that neonatal hyperoxia reduces host resistance to influenza virus infection without diminishing the function of cytotoxic T lymphocytes or the generation of virus-specific memory T cells and that CD8(+) memory T cells are sufficient to provide protection from negative consequences of this important life-saving intervention. Our findings suggest that vaccines that generate robust T cell memory may be efficacious at reducing the increased sensitivity to respiratory viral infections in people born prematurely.

Beneficial Effects of cART Initiated during Primary and Chronic HIV-1 Infection on Immunoglobulin-Expression of Memory B-Cell Subsets

PubMed Central

Pensieroso, Simone; Tolazzi, Monica; Chiappetta, Stefania; Nozza, Silvia; Lazzarin, Adriano; Tambussi, Giuseppe; Scarlatti, Gabriella

2015-01-01

Introduction During HIV-1 infection the B-cell compartment undergoes profound changes towards terminal differentiation, which are only partially restored by antiretroviral therapy (cART). Materials and Methods To investigate the impact of infection as early as during primary HIV-1 infection (PHI) we assessed distribution of B-cell subsets in 19 PHI and 25 chronic HIV-1-infected (CHI) individuals before and during 48 weeks of cART as compared to healthy controls (n = 23). We also analysed Immunoglobulin-expression of memory B-cell subsets to identify alterations in Immunoglobulin-maturation. Results Determination of B-cell subsets at baseline showed that total and Naive B-cells were decreased whereas Activated Memory (AM), Tissue-like Memory (TLM) B-cells and Plasma cells were increased in both PHI and CHI patients. After 4 weeks of cART total B-cells increased, while AM, TLM B-cells and Plasma cells decreased, although without reaching normal levels in either group of individuals. This trend was maintained until week 48, though only total B-cells normalized in both PHI and CHI. Resting Memory (RM) B-cells were preserved since baseline. This subset remained stable in CHI, while was expanded by an early initiation of cART during PHI. Untreated CHI patients showed IgM-overexpression at the expenses of switched (IgM-IgD-) phenotypes of the memory subsets. Interestingly, in PHI patients a significant alteration of Immunoglobulin-expression was evident at BL in TLM cells, and after 4 weeks, despite treatment, in AM and RM subsets. After 48 weeks of therapy, Immunoglobulin-expression of AM and RM almost normalized, but remained perturbed in TLM cells in both groups. Conclusions In conclusion, aberrant activated and exhausted B-cell phenotypes rose already during PHI, while most of the alterations in Ig-expression seen in CHI appeared later, despite 4 weeks of effective cART. After 48 weeks of cART B-cell subsets distribution improved although without full normalization, while Immunoglobulin-expression normalized among AM and RM, remaining perturbed in TLM B-cells of PHI and CHI. PMID:26474181

Beneficial Effects of cART Initiated during Primary and Chronic HIV-1 Infection on Immunoglobulin-Expression of Memory B-Cell Subsets.

PubMed

Pogliaghi, Manuela; Ripa, Marco; Pensieroso, Simone; Tolazzi, Monica; Chiappetta, Stefania; Nozza, Silvia; Lazzarin, Adriano; Tambussi, Giuseppe; Scarlatti, Gabriella

2015-01-01

During HIV-1 infection the B-cell compartment undergoes profound changes towards terminal differentiation, which are only partially restored by antiretroviral therapy (cART). To investigate the impact of infection as early as during primary HIV-1 infection (PHI) we assessed distribution of B-cell subsets in 19 PHI and 25 chronic HIV-1-infected (CHI) individuals before and during 48 weeks of cART as compared to healthy controls (n = 23). We also analysed Immunoglobulin-expression of memory B-cell subsets to identify alterations in Immunoglobulin-maturation. Determination of B-cell subsets at baseline showed that total and Naive B-cells were decreased whereas Activated Memory (AM), Tissue-like Memory (TLM) B-cells and Plasma cells were increased in both PHI and CHI patients. After 4 weeks of cART total B-cells increased, while AM, TLM B-cells and Plasma cells decreased, although without reaching normal levels in either group of individuals. This trend was maintained until week 48, though only total B-cells normalized in both PHI and CHI. Resting Memory (RM) B-cells were preserved since baseline. This subset remained stable in CHI, while was expanded by an early initiation of cART during PHI. Untreated CHI patients showed IgM-overexpression at the expenses of switched (IgM-IgD-) phenotypes of the memory subsets. Interestingly, in PHI patients a significant alteration of Immunoglobulin-expression was evident at BL in TLM cells, and after 4 weeks, despite treatment, in AM and RM subsets. After 48 weeks of therapy, Immunoglobulin-expression of AM and RM almost normalized, but remained perturbed in TLM cells in both groups. In conclusion, aberrant activated and exhausted B-cell phenotypes rose already during PHI, while most of the alterations in Ig-expression seen in CHI appeared later, despite 4 weeks of effective cART. After 48 weeks of cART B-cell subsets distribution improved although without full normalization, while Immunoglobulin-expression normalized among AM and RM, remaining perturbed in TLM B-cells of PHI and CHI.

Dynamics of T cell, antigen-presenting cell, and pathogen interactions during recall responses in the lymph node.

PubMed

Chtanova, Tatyana; Han, Seong-Ji; Schaeffer, Marie; van Dooren, Giel G; Herzmark, Paul; Striepen, Boris; Robey, Ellen A

2009-08-21

Memory T cells circulate through lymph nodes where they are poised to respond rapidly upon re-exposure to a pathogen; however, the dynamics of memory T cell, antigen-presenting cell, and pathogen interactions during recall responses are largely unknown. We used a mouse model of infection with the intracellular protozoan parasite, Toxoplasma gondii, in conjunction with two-photon microscopy, to address this question. After challenge, memory T cells migrated more rapidly than naive T cells, relocalized toward the subcapsular sinus (SCS) near invaded macrophages, and engaged in prolonged interactions with infected cells. Parasite invasion of T cells occurred by direct transfer of the parasite from the target cell into the T cell and corresponded to an antigen-specific increase in the rate of T cell invasion. Our results provide insight into cellular interactions during recall responses and suggest a mechanism of pathogen subversion of the immune response.

Biocompatibility of nanoactuators: stem cell growth on laser-generated nickel-titanium shape memory alloy nanoparticles

NASA Astrophysics Data System (ADS)

Barcikowski, Stephan; Hahn, Anne; Guggenheim, Merlin; Reimers, Kerstin; Ostendorf, Andreas

2010-06-01

Nanoactuators made from nanoparticulate NiTi shape memory alloy show potential in the mechanical stimulation of bone tissue formation from stem cells. We demonstrate the fabrication of Ni, Ti, and NiTi shape memory alloy nanoparticles and their biocompatibility to human adipose-derived stem cells. The stoichiometry and phase transformation property of the bulk alloy is preserved during attrition by femtosecond laser ablation in liquid, giving access to colloidal nanoactuators. No adverse effect on cell growth and attachment is observed in proliferation assay and environmental electron scanning microscopy, making this material attractive for mechanical stimulation of stem cells.

Effector and memory CD8+ T cell differentiation: toward a molecular understanding of fate determination.

PubMed

Belz, Gabrielle T; Kallies, Axel

2010-06-01

CD8(+) T cells play a key role in protecting the body against invading microorganisms. Their capacity to control infection relies on the development of peripheral effector and memory T cells. Much of our current knowledge has been gained by tracking alterations of the phenotype of CD8(+) T cells but the molecular understanding of the events that underpin the emergence of heterogeneous effector and memory CD8(+) T cells in response to infection has remained limited. This review focuses on the recent progress in our understanding of the molecular wiring of this differentiation process. Copyright 2010 Elsevier Ltd. All rights reserved.

Mitochondria-Endoplasmic Reticulum Contact Sites Function as Immunometabolic Hubs that Orchestrate the Rapid Recall Response of Memory CD8+ T Cells.

PubMed

Bantug, Glenn R; Fischer, Marco; Grählert, Jasmin; Balmer, Maria L; Unterstab, Gunhild; Develioglu, Leyla; Steiner, Rebekah; Zhang, Lianjun; Costa, Ana S H; Gubser, Patrick M; Burgener, Anne-Valérie; Sauder, Ursula; Löliger, Jordan; Belle, Réka; Dimeloe, Sarah; Lötscher, Jonas; Jauch, Annaïse; Recher, Mike; Hönger, Gideon; Hall, Michael N; Romero, Pedro; Frezza, Christian; Hess, Christoph

2018-03-20

Glycolysis is linked to the rapid response of memory CD8 + T cells, but the molecular and subcellular structural elements enabling enhanced glucose metabolism in nascent activated memory CD8 + T cells are unknown. We found that rapid activation of protein kinase B (PKB or AKT) by mammalian target of rapamycin complex 2 (mTORC2) led to inhibition of glycogen synthase kinase 3β (GSK3β) at mitochondria-endoplasmic reticulum (ER) junctions. This enabled recruitment of hexokinase I (HK-I) to the voltage-dependent anion channel (VDAC) on mitochondria. Binding of HK-I to VDAC promoted respiration by facilitating metabolite flux into mitochondria. Glucose tracing pinpointed pyruvate oxidation in mitochondria, which was the metabolic requirement for rapid generation of interferon-γ (IFN-γ) in memory T cells. Subcellular organization of mTORC2-AKT-GSK3β at mitochondria-ER contact sites, promoting HK-I recruitment to VDAC, thus underpins the metabolic reprogramming needed for memory CD8 + T cells to rapidly acquire effector function. Copyright © 2018 Elsevier Inc. All rights reserved.

The Chemokine Receptor CXCR6 Is Required for the Maintenance of Liver Memory CD8+ T Cells Specific for Infectious Pathogens

PubMed Central

Tse, Sze-Wah; Radtke, Andrea J.; Espinosa, Diego A.; Cockburn, Ian A.; Zavala, Fidel

2014-01-01

It is well established that immunization with attenuated malaria sporozoites induces CD8+ T cells that eliminate parasite-infected hepatocytes. Liver memory CD8+ T cells induced by immunization with parasites undergo a unique differentiation program and have enhanced expression of CXCR6. Following immunization with malaria parasites, CXCR6-deficient memory CD8+ T cells recovered from the liver display altered cell-surface expression markers as compared to their wild-type counterparts, but they exhibit normal cytokine secretion and expression of cytotoxic mediators on a per-cell basis. Most importantly, CXCR6-deficient CD8+ T cells migrate to the liver normally after immunization with Plasmodium sporozoites or vaccinia virus, but a few weeks later their numbers severely decrease in this organ, losing their capacity to inhibit malaria parasite development in the liver. These studies are the first to show that CXCR6 is critical for the development and maintenance of protective memory CD8+ T cells in the liver. PMID:24823625

ZBTB32 restricts the duration of memory B cell recall responses1

PubMed Central

Jash, Arijita; Wang, Yinan; Weisel, Florian J.; Scharer, Christopher D.; Boss, Jeremy M.; Shlomchik, Mark J.; Bhattacharya, Deepta

2016-01-01

Memory B cell responses are more rapid and of greater magnitude than are primary antibody responses. The mechanisms by which these secondary responses are eventually attenuated remain unknown. We demonstrate that the transcription factor ZBTB32 limits the rapidity and duration of antibody recall responses. ZBTB32 is highly expressed by mouse and human memory B cells, but not by their naïve counterparts. Zbtb32−/− mice mount normal primary antibody responses to T-dependent antigens. However, Zbtb32−/− memory B cell-mediated recall responses occur more rapidly and persist longer than do control responses. Microarray analyses demonstrate that Zbtb32−/− secondary bone marrow plasma cells display elevated expression of genes that promote cell cycle progression and mitochondrial function relative to wild-type controls. BrdU labeling and adoptive transfer experiments confirm more rapid production and a cell-intrinsic survival advantage of Zbtb32−/− secondary plasma cells relative to wild-type counterparts. ZBTB32 is therefore a novel negative regulator of antibody recall responses. PMID:27357154

Multi-port, optically addressed RAM

NASA Technical Reports Server (NTRS)

Johnston, Alan R. (Inventor); Nixon, Robert H. (Inventor); Bergman, Larry A. (Inventor); Esener, Sadik (Inventor)

1989-01-01

A random access memory addressing system utilizing optical links between memory and the read/write logic circuits comprises addressing circuits including a plurality of light signal sources, a plurality of optical gates including optical detectors associated with the memory cells, and a holographic optical element adapted to reflect and direct the light signals to the desired memory cell locations. More particularly, it is a multi-port, binary computer memory for interfacing with a plurality of computers. There are a plurality of storage cells for containing bits of binary information, the storage cells being disposed at the intersections of a plurality of row conductors and a plurality of column conductors. There is interfacing logic for receiving information from the computers directing access to ones of the storage cells. There are first light sources associated with the interfacing logic for transmitting a first light beam with the access information modulated thereon. First light detectors are associated with the storage cells for receiving the first light beam, for generating an electrical signal containing the access information, and for conducting the electrical signal to the one of the storage cells to which it is directed. There are holographic optical elements for reflecting the first light beam from the first light sources to the first light detectors.

ILC2 memory: Recollection of previous activation.

PubMed

Martinez-Gonzalez, Itziar; Ghaedi, Maryam; Steer, Catherine A; Mathä, Laura; Vivier, Eric; Takei, Fumio

2018-05-01

Immunological memory, traditionally thought to belong to T and B cells, has now been extended to innate lymphocytes, including NK cells and ILC2s, myeloid cells such as macrophages, also termed "trained immunity" and more recently to epithelial stem cells. In this review, we discuss the mechanisms underlying memory generation on ILC2s and speculate about their potential role in human allergic diseases, such as asthma. Moreover, we examine the relevance of the spontaneous ILC2 activation in the lung during the neonatal period in order to efficiently respond to stimuli later in life. These "training" of neonatal ILC2s may have an impact on the generation of memory ILC2s in the adulthood. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hippocampal place cell dysfunction and the effects of muscarinic M1 receptor agonism in a rat model of Alzheimer's disease.

PubMed

Galloway, Claire R; Ravipati, Kaushik; Singh, Suyashi; Lebois, Evan P; Cohen, Robert M; Levey, Allan I; Manns, Joseph R

2018-05-09

Alzheimer's disease (AD) is a neurodegenerative disease that disproportionately impacts memory and the hippocampus. However, it is unclear how AD pathology influences the activity of surviving neurons in the hippocampus to contribute to the memory symptoms in AD. One well-understood connection between spatial memory and neuronal activity in healthy brains is the activity of place cells, neurons in the hippocampus that fire preferentially in a specific location of a given environment (the place field of the place cell). In the present study, place cells were recorded from the hippocampus in a recently-developed rat model of AD (Tg-F344 AD) at an age (12-20 months) at which the AD rats showed marked spatial memory deficits. Place cells in the CA2 and CA3 pyramidal regions of the hippocampus in AD rats showed sharply reduced spatial fidelity relative to wild-type (WT) rats. In contrast, spiking activity of place cells recorded in region CA1 in AD rats showed good spatial fidelity that was similar to CA1 place cells in WT rats. Oral administration of the M 1 muscarinic acetylcholine receptor agonist VU0364572 impacted place cell firing rates in CA1 and CA2/3 hippocampal regions but did not improve the spatial fidelity of CA2/3 hippocampal place cells in AD rats. The results indicated that, to the extent the spatial memory impairment in AD rats was attributable to hippocampal dysfunction, the memory impairment was more attributable to dysfunction in hippocampal regions CA2 and CA3 rather than CA1. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy

PubMed Central

Powell, Daniel J.; Dudley, Mark E.; Robbins, Paul F.; Rosenberg, Steven A.

2007-01-01

In humans, the pathways of memory T-cell differentiation remain poorly defined. Recently, adoptive cell transfer (ACT) of tumor-reactive T lymphocytes to metastatic melanoma patients after nonmyeloablative chemotherapy has resulted in persistence of functional, tumor-reactive lymphocytes, regression of disease, and induction of melanocyte-directed autoimmunity in some responding patients. In the current study, longitudinal phenotypic analysis was performed on melanoma antigen–specific CD8+ T cells during their transition from in vitro cultured effector cells to long-term persistent memory cells following ACT to 6 responding patients. Tumor-reactive T cells used for therapy were generally late-stage effector cells with a CD27Lo CD28Lo CD45RA− CD62 ligand− (CD62L−) CC chemokine receptor 7− (CCR7−) interleukin-7 receptor αLo (IL-7RαLo) phenotype. After transfer, rapid up-regulation and continued expression of IL-7Rα in vivo suggested an important role for IL-7R in immediate and long-term T-cell survival. Although the tumor antigen–specific T-cell population contracted between 1 and 4 weeks after transfer, stable numbers of CD27+ CD28+ tumor-reactive T cells were maintained, demonstrating their contribution to the development of long-term, melanoma-reactive memory CD8+ T cells in vivo. At 2 months after transfer, melanoma-reactive T cells persisted at high levels and displayed an effector memory phenotype, including a CD27+ CD28+ CD62L− CCR7− profile, which may explain in part their ability to mediate tumor destruction. PMID:15345595

The Source for Learning & Memory Strategies.

ERIC Educational Resources Information Center

Richards, Regina G.

This book is a comprehensive guide to learning and memory strategies for all students and especially those with learning problems. Chapter 1, on memory and the brain, explains brain cells, the cortex, function of the cerebral lobes, and other brain structures. Chapter 2 examines the memory process and discusses sensory memory, short-term memory,…

Curtailed T-cell activation curbs effector differentiation and generates CD8+ T cells with a naturally-occurring memory stem cell phenotype.

PubMed

Zanon, Veronica; Pilipow, Karolina; Scamardella, Eloise; De Paoli, Federica; De Simone, Gabriele; Price, David A; Martinez Usatorre, Amaia; Romero, Pedro; Mavilio, Domenico; Roberto, Alessandra; Lugli, Enrico

2017-09-01

Human T memory stem (T SCM ) cells with superior persistence capacity and effector functions are emerging as important players in the maintenance of long-lived T-cell memory and are thus considered an attractive population to be used in adoptive transfer-based immunotherapy of cancer. However, the molecular signals regulating their generation remain poorly defined. Here we show that curtailed T-cell receptor stimulation curbs human effector CD8 + T-cell differentiation and allows the generation of CD45RO - CD45RA + CCR7 + CD27 + CD95 + -phenotype cells from highly purified naïve T-cell precursors, resembling naturally-occurring human T SCM . These cells proliferate extensively in vitro and in vivo, express low amounts of effector-associated genes and transcription factors and undergo considerable self-renewal in response to IL-15 while retaining effector differentiation potential. Such a phenotype is associated with a lower number of mitochondria compared to highly-activated effector T cells committed to terminal differentiation. These results shed light on the molecular signals that are required to generate long-lived memory T cells with potential application in adoptive cell transfer immunotherapy. © 2017 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co.KGaA, Weinheim.

Multi-layered epigenetic mechanisms contribute to transcriptional memory in T lymphocytes.

PubMed

Dunn, Jennifer; McCuaig, Robert; Tu, Wen Juan; Hardy, Kristine; Rao, Sudha

2015-05-06

Immunological memory is the ability of the immune system to respond more rapidly and effectively to previously encountered pathogens, a key feature of adaptive immunity. The capacity of memory T cells to "remember" previous cellular responses to specific antigens ultimately resides in their unique patterns of gene expression. Following re-exposure to an antigen, previously activated genes are transcribed more rapidly and robustly in memory T cells compared to their naïve counterparts. The ability for cells to remember past transcriptional responses is termed "adaptive transcriptional memory". Recent global epigenome studies suggest that epigenetic mechanisms are central to establishing and maintaining transcriptional memory, with elegant studies in model organisms providing tantalizing insights into the epigenetic programs that contribute to adaptive immunity. These epigenetic mechanisms are diverse, and include not only classical acetylation and methylation events, but also exciting and less well-known mechanisms involving histone structure, upstream signalling pathways, and nuclear localisation of genomic regions. Current global health challenges in areas such as tuberculosis and influenza demand not only more effective and safer vaccines, but also vaccines for a wider range of health priorities, including HIV, cancer, and emerging pathogens such as Ebola. Understanding the multi-layered epigenetic mechanisms that underpin the rapid recall responses of memory T cells following reactivation is a critical component of this development pathway.

Differential requirements of CD4(+) T-cell signals for effector cytotoxic T-lymphocyte (CTL) priming and functional memory CTL development at higher CD8(+) T-cell precursor frequency.

PubMed

Umeshappa, Channakeshava S; Nanjundappa, Roopa H; Xie, Yufeng; Freywald, Andrew; Xu, Qingyong; Xiang, Jim

2013-04-01

Increased CD8(+) T-cell precursor frequency (PF) precludes the requirement of CD4(+) helper T (Th) cells for primary CD8(+) cytotoxic T-lymphocyte (CTL) responses. However, the key questions of whether unhelped CTLs generated at higher PF are functional effectors, and whether unhelped CTLs can differentiate into functional memory cells at higher PF are unclear. In this study, ovalbumin (OVA) -pulsed dendritic cells (DC(OVA)) derived from C57BL/6, CD40 knockout (CD40(-/-)) or CD40 ligand knockout (CD40L(-/-)) mice were used to immunize C57BL/6, Ia(b-/-), CD40(-/-) or CD40L(-/-) mice, whose PF was previously increased with transfer of 1 × 10(6) CD8(+) T cells derived from OVA-specific T-cell receptor (TCR) transgenic OTI, OTI(CD40(-/-)) or OTI(CD40L(-/-)) mice. All the immunized mice were then assessed for effector and memory CTL responses. Following DC immunization, relatively comparable CTL priming occurred without CD4(+) T-cell help and Th-provided CD40/CD40L signalling. In addition, the unhelped CTLs were functional effectors capable of inducing therapeutic immunity against established OVA-expressing tumours. In contrast, the functional memory development of CTLs was severely impaired in the absence of CD4(+) T-cell help and CD40/CD40L signalling. Finally, unhelped memory CTLs failed to protect mice against lethal tumour challenge. Taken together, these results demonstrate that CD4(+) T-cell help at higher PF, is not required for effector CTL priming, but is required for functional memory CTL development against cancer. Our data may impact the development of novel preventive and therapeutic approaches in cancer patients with compromised CD4(+) T-cell functions. © 2012 Blackwell Publishing Ltd.

Identification of Pertussis-Specific Effector Memory T Cells in Preschool Children

PubMed Central

Schure, Rose-Minke; Öztürk, Kemal; Berbers, Guy; Sanders, Elisabeth; van Twillert, Inonge; Carollo, Maria; Mascart, Françoise; Ausiello, Clara M.; van Els, Cecile A. C. M.; Smits, Kaat; Buisman, Anne-Marie

2015-01-01

Whooping cough remains a problem despite vaccination, and worldwide resurgence of pertussis is evident. Since cellular immunity plays a role in long-term protection against pertussis, we studied pertussis-specific T-cell responses. Around the time of the preschool acellular pertussis (aP) booster dose at 4 years of age, T-cell memory responses were compared in children who were primed during infancy with either a whole-cell pertussis (wP) or an aP vaccine. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with pertussis vaccine antigens for 5 days. T cells were characterized by flow-based analysis of carboxyfluorescein succinimidyl ester (CFSE) dilution and CD4, CD3, CD45RA, CCR7, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α) expression. Before the aP preschool booster vaccination, both the proliferated pertussis toxin (PT)-specific CD4+ and CD8+ T-cell fractions (CFSEdim) were higher in aP- than in wP-primed children. Post-booster vaccination, more pertussis-specific CD4+ effector memory cells (CD45RA− CCR7−) were induced in aP-primed children than in those primed with wP. The booster vaccination did not appear to significantly affect the T-cell memory subsets and functionality in aP-primed or wP-primed children. Although the percentages of Th1 cytokine-producing cells were alike in aP- and wP-primed children pre-booster vaccination, aP-primed children produced more Th1 cytokines due to higher numbers of proliferated pertussis-specific effector memory cells. At present, infant vaccinations with four aP vaccines in the first year of life result in pertussis-specific CD4+ and CD8+ effector memory T-cell responses that persist in children until 4 years of age and are higher than those in wP-primed children. The booster at 4 years of age is therefore questionable; this may be postponed to 6 years of age. PMID:25787136

MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells

NASA Astrophysics Data System (ADS)

Li, Chen Xi; Talele, Nilesh P.; Boo, Stellar; Koehler, Anne; Knee-Walden, Ericka; Balestrini, Jenna L.; Speight, Pam; Kapus, Andras; Hinz, Boris

2017-03-01

Expansion on stiff culture substrates activates pro-fibrotic cell programs that are retained by mechanical memory. Here, we show that priming on physiologically soft silicone substrates suppresses fibrogenesis and desensitizes mesenchymal stem cells (MSCs) against subsequent mechanical activation in vitro and in vivo, and identify the microRNA miR-21 as a long-term memory keeper of the fibrogenic program in MSCs. During stiff priming, miR-21 levels were gradually increased by continued regulation through the acutely mechanosensitive myocardin-related transcription factor-A (MRTF-A/MLK-1) and remained high over 2 weeks after removal of the mechanical stimulus. Knocking down miR-21 once by the end of the stiff-priming period was sufficient to erase the mechanical memory and sensitize MSCs to subsequent exposure to soft substrates. Soft priming and erasing mechanical memory following cell culture expansion protects MSCs from fibrogenesis in the host wound environment and increases the chances for success of MSC therapy in tissue-repair applications.

The effect of patterning options on embedded memory cells in logic technologies at iN10 and iN7

NASA Astrophysics Data System (ADS)

Appeltans, Raf; Weckx, Pieter; Raghavan, Praveen; Kim, Ryoung-Han; Kar, Gouri Sankar; Furnémont, Arnaud; Van der Perre, Liesbet; Dehaene, Wim

2017-03-01

Static Random Access Memory (SRAM) cells are used together with logic standard cells as the benchmark to develop the process flow for new logic technologies. In order to achieve successful integration of Spin-Transfer Torque Magnetic Random Access Memory (STT-MRAM) as area efficient higher level embedded cache, it also needs to be included as a benchmark. The simple cell structure of STT-MRAM brings extra patterning challenges to achieve high density. The two memory types are compared in terms of minimum area and critical design rules in both the iN10 and iN7 node, with an extra focus on patterning options in iN7. Both the use of Self-Aligned Quadruple Patterning (SAQP) mandrel and spacer engineering, as well as multi-level via's are explored. These patterning options result in large area gains for the STT-MRAM cell and moreover determine which cell variant is the smallest.

Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells.

PubMed

Nishida, Atsushi; Nagahama, Kiyotaka; Imaeda, Hirotsugu; Ogawa, Atsuhiro; Lau, Cindy W; Kobayashi, Taku; Hisamatsu, Tadakazu; Preffer, Frederic I; Mizoguchi, Emiko; Ikeuchi, Hiroki; Hibi, Toshifumi; Fukuda, Minoru; Andoh, Akira; Blumberg, Richard S; Mizoguchi, Atsushi

2012-12-17

Immune responses are modified by a diverse and abundant repertoire of carbohydrate structures on the cell surface, which is known as the glycome. In this study, we propose that a unique glycome that can be identified through the binding of galectin-4 is created on local, but not systemic, memory CD4+ T cells under diverse intestinal inflammatory conditions, but not in the healthy state. The colitis-associated glycome (CAG) represents an immature core 1-expressing O-glycan. Development of CAG may be mediated by down-regulation of the expression of core-2 β1,6-N-acetylglucosaminyltransferase (C2GnT) 1, a key enzyme responsible for the production of core-2 O-glycan branch through addition of N-acetylglucosamine (GlcNAc) to a core-1 O-glycan structure. Mechanistically, the CAG seems to contribute to super raft formation associated with the immunological synapse on colonic memory CD4+ T cells and to the consequent stabilization of protein kinase C θ activation, resulting in the stimulation of memory CD4+ T cell expansion in the inflamed intestine. Functionally, CAG-mediated CD4+ T cell expansion contributes to the exacerbation of T cell-mediated experimental intestinal inflammations. Therefore, the CAG may be an attractive therapeutic target to specifically suppress the expansion of effector memory CD4+ T cells in intestinal inflammation such as that seen in inflammatory bowel disease.

Effector and central memory T helper 2 cells respond differently to peptide immunotherapy

PubMed Central

Mackenzie, Karen J.; Nowakowska, Dominika J.; Leech, Melanie D.; McFarlane, Amanda J.; Wilson, Claire; Fitch, Paul M.; O’Connor, Richard A.; Howie, Sarah E. M.; Schwarze, Jürgen; Anderton, Stephen M.

2014-01-01

Peptide immunotherapy (PIT) offers realistic prospects for the treatment of allergic diseases, including allergic asthma. Much is understood of the behavior of naive T cells in response to PIT. However, treatment of patients with ongoing allergic disease requires detailed understanding of the responses of allergen-experienced T cells. CD62L expression by allergen-experienced T cells corresponds to effector/effector memory (CD62Llo) and central memory (CD62Lhi) subsets, which vary with allergen exposure (e.g., during, or out with, pollen season). The efficacy of PIT on different T helper 2 (Th2) cell memory populations is unknown. We developed a murine model of PIT in allergic airway inflammation (AAI) driven by adoptively transferred, traceable ovalbumin-experienced Th2 cells. PIT effectively suppressed AAI driven by unfractionated Th2 cells. Selective transfer of CD62Lhi and CD62Llo Th2 cells revealed that these two populations behaved differently from one another and from previously characterized (early deletional) responses of naive CD4+ T cells to PIT. Most notably, allergen-reactive CD62Llo Th2 cells were long-lived within the lung after PIT, before allergen challenge, in contrast to CD62Lhi Th2 cells. Despite this, PIT was most potent against CD62Llo Th2 cells in protecting from AAI, impairing their ability to produce Th2 cytokines, whereas this capacity was heightened in PIT-treated CD62Lhi Th2 cells. We conclude that Th2 cells do not undergo an early deletional form of tolerance after PIT. Moreover, memory Th2 subsets respond differently to PIT. These findings have implications for the clinical translation of PIT in different allergic scenarios. PMID:24516158

The anti-tumor role of NK cells in vivo pre-activated and re-stimulated by interleukins in acute lymphoblastic leukemia

PubMed Central

Jin, Fengyan; Lin, Hai; Gao, Sujun; Hu, Zheng; Zuo, Song; Sun, Liguang; Jin, Chunhui; Li, Wei; Yang, Yanping

2016-01-01

Although natural killer cells (NK cells) were traditionally classified as members of the innate immune system, NK cells have recently been found also to be an important player in the adaptive immune systems. In this context, in vitro activation of NK cells by cytokines leads to generation of NK cells with memory-like properties characterized by increased interferon-γ (IFNγ) production. However, it remains to be defined whether these memory-like NK cells exist in vivo after cytokine activation. Furthermore, it is also unclear whether such memory-like NK cells induced in vivo by cytokines could have effective anti-leukemia response. To address these issues, we used an in vivo pre-activation and re-stimulation system that was able to produce NK cells with increased IFNγ secretion. It was found that after in vivo pre-activation and re-stimulation with interleukins (ILs), NK cells retained a state to produce increased amount of IFNγ. Of note, whereas this intrinsic capacity of enhanced IFNγ production after in vivo IL pre-activation and re-stimulation could be transferred to the next generation of NK cells and was associated with prolonged survival of the mice with acute lymphoid leukemia. Moreover, the anti-leukemia activity of these memory-like NK cells was associated with IFNγ production and up-regulation of NK cells activation receptor-NK Group 2 member D (NKG2D). Together, these findings argue strongly that in vivo IL pre-activation and re-stimulation is capable to induce memory-like NK cells as observed previously in vitro, which are effective against acute lymphoblastic leukemia, likely via NKG2D-dependent IFNγ production, in intact animals. PMID:27816971

The anti-tumor role of NK cells in vivo pre-activated and re-stimulated by interleukins in acute lymphoblastic leukemia.

PubMed

Jin, Fengyan; Lin, Hai; Gao, Sujun; Hu, Zheng; Zuo, Song; Sun, Liguang; Jin, Chunhui; Li, Wei; Yang, Yanping

2016-11-29

Although natural killer cells (NK cells) were traditionally classified as members of the innate immune system, NK cells have recently been found also to be an important player in the adaptive immune systems. In this context, in vitro activation of NK cells by cytokines leads to generation of NK cells with memory-like properties characterized by increased interferon-γ (IFNγ) production. However, it remains to be defined whether these memory-like NK cells exist in vivo after cytokine activation. Furthermore, it is also unclear whether such memory-like NK cells induced in vivo by cytokines could have effective anti-leukemia response. To address these issues, we used an in vivo pre-activation and re-stimulation system that was able to produce NK cells with increased IFNγ secretion. It was found that after in vivo pre-activation and re-stimulation with interleukins (ILs), NK cells retained a state to produce increased amount of IFNγ. Of note, whereas this intrinsic capacity of enhanced IFNγ production after in vivo IL pre-activation and re-stimulation could be transferred to the next generation of NK cells and was associated with prolonged survival of the mice with acute lymphoid leukemia. Moreover, the anti-leukemia activity of these memory-like NK cells was associated with IFNγ production and up-regulation of NK cells activation receptor-NK Group 2 member D (NKG2D). Together, these findings argue strongly that in vivo IL pre-activation and re-stimulation is capable to induce memory-like NK cells as observed previously in vitro, which are effective against acute lymphoblastic leukemia, likely via NKG2D-dependent IFNγ production, in intact animals.

Direct anti-inflammatory effects of granulocyte colony-stimulating factor (G-CSF) on activation and functional properties of human T cell subpopulations in vitro.

PubMed

Malashchenko, Vladimir Vladimirovich; Meniailo, Maxsim Evgenievich; Shmarov, Viacheslav Anatolievich; Gazatova, Natalia Dinislamovna; Melashchenko, Olga Borisovna; Goncharov, Andrei Gennadievich; Seledtsova, Galina Victorovna; Seledtsov, Victor Ivanovich

2018-03-01

We investigated the direct effects of human granulocyte colony-stimulating factor (G-CSF) on functionality of human T-cell subsets. CD3 + T-lymphocytes were isolated from blood of healthy donors by positive magnetic separation. T cell activation with particles conjugated with antibodies (Abs) to human CD3, CD28 and CD2 molecules increased the proportion of cells expressing G-CSF receptor (G-CSFR, CD114) in all T cell subpopulations studied (CD45RA + /CD197 + naive T cells, CD45RA - /CD197 + central memory T cells, CD45RA - /CD197 - effector memory T cells and CD45RA + /CD197 - terminally differentiated effector T cells). Upon T-cell activation in vitro, G-CSF (10.0 ng/ml) significantly and specifically enhanced the proportion of CD114 + T cells in central memory CD4 + T cell compartment. A dilution series of G-CSF (range, 0.1-10.0 ng/ml) was tested, with no effect on the expression of CD25 (interleukin-2 receptor α-chain) on activated T cells. Meanwhile, G-CSF treatment enhanced the proportion of CD38 + T cells in CD4 + naïve T cell, effector memory T cell and terminally differentiated effector T cell subsets, as well as in CD4 - central memory T cells and terminally differentiated effector T cells. G-CSF did not affect IL-2 production by T cells; relatively low concentrations of G-CSF down-regulated INF-γ production, while high concentrations of this cytokine up-regulated IL-4 production in activated T cells. The data obtained suggests that G-CSF could play a significant role both in preventing the development of excessive and potentially damaging inflammatory reactivity, and in constraining the expansion of potentially cytodestructive T cells. Copyright © 2018 Elsevier Inc. All rights reserved.

HematoPorphyrin Monomethyl Ether polymer contrast agent for ultrasound/photoacoustic dual-modality imaging-guided synergistic high intensity focused ultrasound (HIFU) therapy

NASA Astrophysics Data System (ADS)

Yan, Sijing; Lu, Min; Ding, Xiaoya; Chen, Fei; He, Xuemei; Xu, Chunyan; Zhou, Hang; Wang, Qi; Hao, Lan; Zou, Jianzhong

2016-08-01

This study is to prepare a hematoporphyrin monomethyl ether (HMME)-loaded poly(lactic-co-glycolic acid) (PLGA) microcapsules (HMME/PLGA), which could not only function as efficient contrast agent for ultrasound (US)/photoacoustic (PA) imaging, but also as a synergistic agent for high intensity focused ultrasound (HIFU) ablation. Sonosensitizer HMME nanoparticles were integrated into PLGA microcapsules with the double emulsion evaporation method. After characterization, the cell-killing and cell proliferation-inhibiting effects of HMME/PLGA microcapsules on ovarian cancer SKOV3 cells were assessed. The US/PA imaging-enhancing effects and synergistic effects on HIFU were evaluated both in vitro and in vivo. HMME/PLGA microcapsules were highly dispersed with well-defined spherical morphology (357 ± 0.72 nm in diameter, PDI = 0.932). Encapsulation efficiency and drug-loading efficiency were 58.33 ± 0.95% and 4.73 ± 0.15%, respectively. The HMME/PLGA microcapsules remarkably killed the SKOV3 cells and inhibited the cell proliferation, significantly enhanced the US/PA imaging results and greatly enhanced the HIFU ablation effects on ovarian cancer in nude mice by the HMME-mediated sono-dynamic chemistry therapy (SDT). HMME/PLGA microcapsules represent a potential multifunctional contrast agent for HIFU diagnosis and treatment, which might provide a novel strategy for the highly efficient imaging-guided non-invasive HIFU synergistic therapy for cancers by SDT in clinic.

HematoPorphyrin Monomethyl Ether polymer contrast agent for ultrasound/photoacoustic dual-modality imaging-guided synergistic high intensity focused ultrasound (HIFU) therapy

PubMed Central

Yan, Sijing; LU, Min; Ding, Xiaoya; Chen, Fei; He, Xuemei; Xu, Chunyan; Zhou, Hang; Wang, Qi; Hao, Lan; Zou, Jianzhong

2016-01-01

This study is to prepare a hematoporphyrin monomethyl ether (HMME)-loaded poly(lactic-co-glycolic acid) (PLGA) microcapsules (HMME/PLGA), which could not only function as efficient contrast agent for ultrasound (US)/photoacoustic (PA) imaging, but also as a synergistic agent for high intensity focused ultrasound (HIFU) ablation. Sonosensitizer HMME nanoparticles were integrated into PLGA microcapsules with the double emulsion evaporation method. After characterization, the cell-killing and cell proliferation-inhibiting effects of HMME/PLGA microcapsules on ovarian cancer SKOV3 cells were assessed. The US/PA imaging-enhancing effects and synergistic effects on HIFU were evaluated both in vitro and in vivo. HMME/PLGA microcapsules were highly dispersed with well-defined spherical morphology (357 ± 0.72 nm in diameter, PDI = 0.932). Encapsulation efficiency and drug-loading efficiency were 58.33 ± 0.95% and 4.73 ± 0.15%, respectively. The HMME/PLGA microcapsules remarkably killed the SKOV3 cells and inhibited the cell proliferation, significantly enhanced the US/PA imaging results and greatly enhanced the HIFU ablation effects on ovarian cancer in nude mice by the HMME-mediated sono-dynamic chemistry therapy (SDT). HMME/PLGA microcapsules represent a potential multifunctional contrast agent for HIFU diagnosis and treatment, which might provide a novel strategy for the highly efficient imaging-guided non-invasive HIFU synergistic therapy for cancers by SDT in clinic. PMID:27535093

HematoPorphyrin Monomethyl Ether polymer contrast agent for ultrasound/photoacoustic dual-modality imaging-guided synergistic high intensity focused ultrasound (HIFU) therapy.

PubMed

Yan, Sijing; Lu, Min; Ding, Xiaoya; Chen, Fei; He, Xuemei; Xu, Chunyan; Zhou, Hang; Wang, Qi; Hao, Lan; Zou, Jianzhong

2016-08-18

This study is to prepare a hematoporphyrin monomethyl ether (HMME)-loaded poly(lactic-co-glycolic acid) (PLGA) microcapsules (HMME/PLGA), which could not only function as efficient contrast agent for ultrasound (US)/photoacoustic (PA) imaging, but also as a synergistic agent for high intensity focused ultrasound (HIFU) ablation. Sonosensitizer HMME nanoparticles were integrated into PLGA microcapsules with the double emulsion evaporation method. After characterization, the cell-killing and cell proliferation-inhibiting effects of HMME/PLGA microcapsules on ovarian cancer SKOV3 cells were assessed. The US/PA imaging-enhancing effects and synergistic effects on HIFU were evaluated both in vitro and in vivo. HMME/PLGA microcapsules were highly dispersed with well-defined spherical morphology (357 ± 0.72 nm in diameter, PDI = 0.932). Encapsulation efficiency and drug-loading efficiency were 58.33 ± 0.95% and 4.73 ± 0.15%, respectively. The HMME/PLGA microcapsules remarkably killed the SKOV3 cells and inhibited the cell proliferation, significantly enhanced the US/PA imaging results and greatly enhanced the HIFU ablation effects on ovarian cancer in nude mice by the HMME-mediated sono-dynamic chemistry therapy (SDT). HMME/PLGA microcapsules represent a potential multifunctional contrast agent for HIFU diagnosis and treatment, which might provide a novel strategy for the highly efficient imaging-guided non-invasive HIFU synergistic therapy for cancers by SDT in clinic.

Redirection to the bone marrow improves T cell persistence and antitumor functions.

PubMed

Khan, Anjum B; Carpenter, Ben; Santos E Sousa, Pedro; Pospori, Constandina; Khorshed, Reema; Griffin, James; Velica, Pedro; Zech, Mathias; Ghorashian, Sara; Forrest, Calum; Thomas, Sharyn; Gonzalez Anton, Sara; Ahmadi, Maryam; Holler, Angelika; Flutter, Barry; Ramirez-Ortiz, Zaida; Means, Terry K; Bennett, Clare L; Stauss, Hans; Morris, Emma; Lo Celso, Cristina; Chakraverty, Ronjon

2018-05-01

A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15-dependent homeostatic expansion and promoted the differentiation of memory precursor-like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.

A novel ternary content addressable memory design based on resistive random access memory with high intensity and low search energy

NASA Astrophysics Data System (ADS)

Han, Runze; Shen, Wensheng; Huang, Peng; Zhou, Zheng; Liu, Lifeng; Liu, Xiaoyan; Kang, Jinfeng

2018-04-01

A novel ternary content addressable memory (TCAM) design based on resistive random access memory (RRAM) is presented. Each TCAM cell consists of two parallel RRAM to both store and search for ternary data. The cell size of the proposed design is 8F2, enable a ∼60× cell area reduction compared with the conventional static random access memory (SRAM) based implementation. Simulation results also show that the search delay and energy consumption of the proposed design at the 64-bit word search are 2 ps and 0.18 fJ/bit/search respectively at 22 nm technology node, where significant improvements are achieved compared to previous works. The desired characteristics of RRAM for implementation of the high performance TCAM search chip are also discussed.

Multi-range force sensors utilizing shape memory alloys

DOEpatents

Varma, Venugopal K.

2003-04-15

The present invention provides a multi-range force sensor comprising a load cell made of a shape memory alloy, a strain sensing system, a temperature modulating system, and a temperature monitoring system. The ability of the force sensor to measure contact forces in multiple ranges is effected by the change in temperature of the shape memory alloy. The heating and cooling system functions to place the shape memory alloy of the load cell in either a low temperature, low strength phase for measuring small contact forces, or a high temperature, high strength phase for measuring large contact forces. Once the load cell is in the desired phase, the strain sensing system is utilized to obtain the applied contact force. The temperature monitoring system is utilized to ensure that the shape memory alloy is in one phase or the other.

Extraction of the gate capacitance coupling coefficient in floating gate non-volatile memories: Statistical study of the effect of mismatching between floating gate memory and reference transistor in dummy cell extraction methods

NASA Astrophysics Data System (ADS)

Rafhay, Quentin; Beug, M. Florian; Duane, Russell

2007-04-01

This paper presents an experimental comparison of dummy cell extraction methods of the gate capacitance coupling coefficient for floating gate non-volatile memory structures from different geometries and technologies. These results show the significant influence of mismatching floating gate devices and reference transistors on the extraction of the gate capacitance coupling coefficient. In addition, it demonstrates the accuracy of the new bulk bias dummy cell extraction method and the importance of the β function, introduced recently in [Duane R, Beug F, Mathewson A. Novel capacitance coupling coefficient measurement methodology for floating gate non-volatile memory devices. IEEE Electr Dev Lett 2005;26(7):507-9], to determine matching pairs of floating gate memory and reference transistor.