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1

Elevated mitochondrial superoxide disrupts normal T-cell development to impair adaptive immune responses to an influenza challenge  

PubMed Central

Reactive oxygen species (ROS) are critical in a broad spectrum of cellular processes including signaling, tumor progression, and innate immunity. The essential nature of ROS signaling in the immune systems of Drosophila and zebrafish has been demonstrated; however, the role of ROS, if any, in mammalian adaptive immune system development and function remains unknown. The current work provides the first clear demonstration that thymus specific elevation of mitochondrial superoxide (O2·?) disrupts normal T-cell development to impair function of the mammalian adaptive immune system. To assess the effect of elevated mitochondrial superoxide in the developing thymus, we used a T-cell specific knockout of manganese superoxide dismutase (i.e. SOD2) and have thus established a murine model to examine the role of mitochondrial superoxide in T-cell development. Conditional loss of SOD2 led to increased superoxide, apoptosis, and developmental defects in the T-cell population resulting in immunodeficiency and susceptibility to influenza A virus (IAV), H1N1. This phenotype was rescued with mitochondrially targeted superoxide scavenging drugs. These new findings demonstrate that loss of regulated levels of mitochondrial superoxide lead to aberrant T-cell development and function, and further suggest that manipulations of mitochondrial superoxide levels may significantly alter clinical outcomes resulting from viral infection. PMID:21130157

Case, Adam J.; McGill, Jodi L.; Tygrett, Lorraine T.; Shirasawa, Takuji; Spitz, Douglas R.; Waldschmidt, Thomas J.; Legge, Kevin L.; Domann, Frederick E.

2010-01-01

2

Rapid Copper Acquisition by Developing Murine Mesothelioma: Decreasing Bioavailable Copper Slows Tumor Growth, Normalizes Vessels and Promotes T Cell Infiltration  

PubMed Central

Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4+ T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes. PMID:24013775

Crowe, Andrew; Jackaman, Connie; Beddoes, Katie M.; Ricciardo, Belinda; Nelson, Delia J.

2013-01-01

3

Rapid copper acquisition by developing murine mesothelioma: decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration.  

PubMed

Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4(+) T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes. PMID:24013775

Crowe, Andrew; Jackaman, Connie; Beddoes, Katie M; Ricciardo, Belinda; Nelson, Delia J

2013-01-01

4

Extracellular adenosine regulates naive T cell development and peripheral maintenance  

PubMed Central

Adenosine produced as a byproduct of metabolic activity is present in all tissues and produces dose-dependent suppression of TCR signaling. Naive T cell maintenance depends on inhibition of TCR signals by environmental sensors, which are yet to be fully defined. We produced mice with a floxed adenosine A2A receptor (A2AR) gene, Adora2a, and show that either global A2AR deletion or cre-mediated T cell deletion elicits a decline in the number of naive but not memory T cells. A2AR signaling maintains naive T cells in a quiescent state by inhibiting TCR-induced activation of the phosphatidylinositide 3-kinase (PI3K)–AKT pathway, thereby reducing IL-7R? down-regulation and naive T cell apoptosis. Patterns of IL-7R? expression on T cells in chimeric mice reconstituted with Adora2a+/+ and Adora2a?/? bone marrow cells suggest that decreased IL-7R? in naive T cells is a cell-intrinsic consequence of Adora2a deletion. In addition, A2AR expression increases in early thymic T cell development and contributes to progression of double-negative thymic precursors to single-positive thymocytes with increased IL-7R? expression. Therefore, A2AR signaling regulates T cell development and maintenance to sustain normal numbers of naive T cells in the periphery. PMID:24145516

Cekic, Caglar; Sag, Duygu; Day, Yuan-Ji

2013-01-01

5

T cell development: better living through chromatin  

Microsoft Academic Search

T lymphocyte development is directed by a gene-expression program that occurs in the complex nucleoprotein environment of chromatin. This review examines basic principles of chromatin regulation and evaluates ongoing progress toward understanding how the chromatin template is manipulated to control gene expression and gene recombination in developing thymocytes. Special attention is devoted to the loci encoding T cell receptors ?

Michael S Krangel

2007-01-01

6

Encephalitogenic potential of myelin basic protein-specific T cells isolated from normal rhesus macaques.  

PubMed Central

Myelin basic protein (MBP)-specific T cells are implicated in the pathogenesis of multiple sclerosis and are targets of selective immunotherapies. However, autoantigen-specific T cells can also be isolated from healthy individuals. Their functional potential is unknown and obviously cannot be tested in humans. We approached this question in a closely related primate species, the rhesus monkey. CD4+ T cell lines specific for MBP were isolated from normal rhesus monkeys using the same primary limiting dilution technique that is now widely used to generate human autoreactive T cell clones in vitro. Three different epitopes were recognized by three rhesus T cell lines isolated from three different monkeys. Upon activation, all lines produced interferon-gamma, interleukin-2, tumor necrosis factor-alpha, and granulocyte/macrophage colony-stimulating factor but neither interleukin-4 nor transforming growth factor-beta. The MBP-specific T cells were injected intravenously without adjuvant into the nonirradiated autologous monkey. One of the three rhesus monkeys developed an encephalomyelitis with a pleocytosis in the spinal fluid and perivascular infiltrates in the leptomeninges, spinal nerve roots and cerebral cortex. The data demonstrate that the normal immune repertoire of a primate species contains MBP-specific CD4+ T cells that are able to induce an autoimmune encephalomyelitis upon transfer into the nonirradiated autologous recipient. Images Figure 3 PMID:9033260

MeinL, E.; Hoch, R. M.; Dornmair, K.; de Waal Malefyt, R.; Bontrop, R. E.; Jonker, M.; Lassmann, H.; Hohlfeld, R.; Wekerle, H.; 't Hart, B. A.

1997-01-01

7

Bad Can Act as a Key Regulator of ?T Cell Apoptosis and T Cell Development  

PubMed Central

Bad is a distant relative of Bcl-2 and acts to promote cell death. Here, we show that Bad expression levels are greatly increased in thymocytes during apoptosis. We generated bad transgenic mice to study the action of upregulated Bad expression on T cell apoptosis. The T cells from these mice are highly sensitive to apoptotic stimuli, including anti-CD95. The numbers of T cells are greatly depleted and the processes of T cell development and selection are perturbed. We show that the proapoptotic function of Bad in primary T cells is regulated by Akt kinase and that Bad overexpression enhances both cell cycle progression and interleukin 2 production after T cell activation. These data suggest that Bad can act as a key regulator of T cell apoptosis and that this is a consequence of its upregulation after exposure to death stimuli. PMID:9927519

Mok, Chen-Lang; Gil-Gómez, Gabriel; Williams, Owen; Coles, Mark; Taga, Samir; Tolaini, Mauro; Norton, Trisha; Kioussis, Dimitris; Brady, Hugh J.M.

1999-01-01

8

Tracking migration during human T cell development.  

PubMed

Specialized microenvironments within the thymus are comprised of unique cell types with distinct roles in directing the development of a diverse, functional, and self-tolerant T cell repertoire. As they differentiate, thymocytes transit through a number of developmental intermediates that are associated with unique localization and migration patterns. For example, during one particular developmental transition, immature thymocytes more than double in speed as they become mature T cells that are among the fastest cells in the body. This transition is associated with dramatic changes in the expression of chemokine receptors and their antagonists, cell adhesion molecules, and cytoskeletal components to direct the maturing thymocyte population from the cortex to medulla. Here we discuss the dynamic changes in behavior that occur throughout thymocyte development, and provide an overview of the cell-intrinsic and extrinsic mechanisms that regulate human thymocyte migration. PMID:24682469

Halkias, Joanna; Melichar, Heather J; Taylor, Kayleigh T; Robey, Ellen A

2014-08-01

9

Transcriptional control of T-cell development.  

PubMed

T lymphocytes, which are central players in orchestrating immune responses, consist of several subtypes with distinct functions. The thymus is an organ where hematopoietic progenitors undergo sequential developmental processes to give rise to this variety of T-cell subsets with diverse antigen specificity. In the periphery, naive T cells further differentiate into effector cells upon encountering antigens. There are several developmental checkpoints during T-cell development, where regulation by a combination of transcription factors imprints specific functional properties on precursors. The transcription factors E2A, GATA-binding protein 3 (Gata3) and RUNT-related transcription factor (Runx) are involved at various stages in the differentiation of double-negative thymocytes and in ?-selection, as are transcription factors from the Notch signaling pathway; other transcription factors such as B-cell lymphoma/leukemia 11b (Bcl11b), myeloblastosis viral oncogene homolog (Myb) and inhibitor of DNA binding 3 (Id3) are involved at specific stages. Differentiation of T cells into helper versus cytotoxic cells involves not only antagonistic interplay between Runx and T(h) inducing POZ-Kruppel factor (ThPOK) but also complex interactions between MAZR, Gata3 and Myb in the activation and silencing of genes such as Cd4 and Cd8 as well as the gene that encodes ThPOK itself. A wide range of well-defined transcription factors, including signal transducer and activator of transcriptions (STATs), T-bet, Gata3, nuclear factor of activated T cell (NFAT), adaptor-related protein complex 1 (AP-1) and nuclear factor ?B (NF-?B), are known to shape T(h)1/T(h)2 differentiation. Runx and Gata3 also operate in this process, as do c-Maf and recombining binding protein for immunoglobulin J? region (RBP-J) and the chromatin-reorganizing protein special AT-rich sequence-binding protein 1 (SATB1). In this review, we briefly discuss how T-cell characteristics are acquired and become divergent from the point of view of transcriptional regulation. PMID:21948191

Naito, Taku; Tanaka, Hirokazu; Naoe, Yoshinori; Taniuchi, Ichiro

2011-11-01

10

Human Peripheral CD4+ V?1+ ??T Cells Can Develop into ??T Cells  

PubMed Central

The lifelong generation of ??T cells enables us to continuously build immunity against pathogens and malignancies despite the loss of thymic function with age. Homeostatic proliferation of post-thymic naïve and memory T cells and their transition into effector and long-lived memory cells balance the decreasing output of naïve T cells, and recent research suggests that also ??T-cell development independent from the thymus may occur. However, the sites and mechanisms of extrathymic T-cell development are not yet understood in detail. ??T cells represent a small fraction of the overall T-cell pool, and are endowed with tremendous phenotypic and functional plasticity. ??T cells that express the V?1 gene segment are a minor population in human peripheral blood but predominate in epithelial (and inflamed) tissues. Here, we characterize a CD4+ peripheral V?1+ ??T-cell subpopulation that expresses stem-cell and progenitor markers and is able to develop into functional ??T cells ex vivo in a simple culture system and in vivo. The route taken by this process resembles thymic T-cell development. However, it involves the re-organization of the V?1+ ??TCR into the ??TCR as a consequence of TCR-? chain downregulation and the expression of surface V?1+V?+ TCR components, which we believe function as surrogate pre-TCR. This transdifferentiation process is readily detectable in vivo in inflamed tissue. Our study provides a conceptual framework for extrathymic T-cell development and opens up a new vista in immunology that requires adaptive immune responses in infection, autoimmunity, and cancer to be reconsidered. PMID:25709606

Ziegler, Hendrik; Welker, Christian; Sterk, Marco; Haarer, Jan; Rammensee, Hans-Georg; Handgretinger, Rupert; Schilbach, Karin

2014-01-01

11

Partial defects of T cell development associated with poor T cell function  

PubMed Central

For many years, Severe Combined Immune Deficiency (SCID) diseases, characterized by virtual lack of circulating T cells and severe predisposition to infections since early in life, have been considered the prototypic forms of genetic defects of T cell development. More recently, advances in genome sequencing have allowed identification of a growing number of gene defects that cause severe, but incomplete, defects in T cell development and/or function. Along with recurrent and severe infections, and especially cutaneous viral infections, the clinical phenotype of these conditions is characterized by prominent immune dysregulation. PMID:23465662

Notarangelo, Luigi D.

2013-01-01

12

Normal Immune Development and Glucocorticoid-Induced Thymocyte Apoptosis in Mice Deficient for the T-Cell Death-Associated Gene 8 Receptor  

Microsoft Academic Search

T-cell death-associated gene 8 (TDAG8) is a G-protein-coupled receptor transcriptionally upregulated by glucocorticoids (GCs) and implicated by overexpression studies in psychosine-mediated inhibition of cytoki- nesis and in GC-induced apoptosis. To examine the physiological function of TDAG8, we generated knockout (KO) mice by homologous recombination. An enhanced green fluorescent protein reporter was knocked into the disrupted tdag8 locus to allow the

Caius G. Radu; Donghui Cheng; Amar Nijagal; Mireille Riedinger; Jami McLaughlin; Li V. Yang; James Johnson; Owen N. Witte

2006-01-01

13

T cell development in B cell-deficient mice. V. Stopping anti-mu treatment results in Igh-restricted expansion of the T suppressor cell repertoire concomitant with the development of normal immunoglobulin levels  

PubMed Central

B cell-deficient (anti-mu-treated) mice have proven to be a valuable tool with which to examine the influence of Ig idiotypic determinants upon the development of the Ts repertoire. We have previously reported that ABA-specific Ts repertoires matured in normal and Ig-deficient environments differ from one another in their composition, and consequently, their functionally expressed Igh restrictions. The present report characterizes the impact of natural development of mature B cell activity upon the composition of the Ts repertoire. After stopping anti-mu treatment of C.AL-20 mice, ABA-specific Ts repertoires undergo a defined expansion shown by their acquisition of an additional Ts network that displays Igh restrictions characteristic of normal C.AL- 20 mice. This Igh-1d-restricted repertoire can be readily shown within 2 wk of major increases in surface Ig spleen cells and total serum Ig levels in these mice. At the same time, the original Ts restriction specificity (Igh-1a-restricted) generated in the Ig-deficient environment of anti-mu. C.AL-20 mice, is not lost for at least 20 wk. The resulting dual Ts repertoire, characterized by expression of parallel, idiotypically restricted Ts networks, is demonstrable for at least 13 wk. These findings favor an important role for Ig determinants in determining the makeup of the T cell repertoire, and ultimately, the composition of immunologic networks as a whole. PMID:2941514

1986-01-01

14

ShcA Regulates Late Stages of T Cell Development and Peripheral CD4+ T Cell Numbers.  

PubMed

T cell development in the thymus is a highly regulated process that critically depends upon productive signaling via the preTCR at the ?-selection stage, as well as via the TCR for selection from the CD4(+)CD8(+) double-positive stage to the CD4 or CD8 single-positive stage. ShcA is an adapter protein expressed in thymocytes, and it is required for productive signaling through the preTCR, with impaired signaling via ShcA leading to a developmental block at the ?-selection checkpoint. However, the role of ShcA in subsequent stages of T cell development has not been addressed. In this study, we generated transgenic mice (CD4-Cre/ShcFFF mice) that specifically express a phosphorylation-defective dominant-negative ShcA mutant (ShcFFF) in late T cell development. Thymocytes in CD4-Cre/ShcFFF mice progressed normally through the ?-selection checkpoint, but displayed a significant reduction in the numbers of single-positive CD4(+) and CD8(+) thymocytes. Furthermore, CD4-Cre/ShcFFF mice, when bred with transgenic TCR mouse strains, had impaired signaling through the transgenic TCRs. Consistent with defective progression to the single-positive stage, CD4-Cre/ShcFFF mice also had significant peripheral lymphopenia. Moreover, these CD4-Cre/ShcFFF mice develop attenuated disease in CD4(+) T cell-dependent experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Collectively, these data identify an important role for the adapter protein ShcA in later stages of thymic T cell development and in peripheral T cell-dependent events. PMID:25595778

Buckley, Monica W; Trampont, Paul C; Arandjelovic, Sanja; Fond, Aaron M; Juncadella, Ignacio J; Ravichandran, Kodi S

2015-02-15

15

Runx3 regulates dendritic epidermal T cell development  

Microsoft Academic Search

The Runx3 transcription factor regulates development of T cells during thymopoiesis and TrkC sensory neurons during dorsal root ganglia neurogenesis. It also mediates transforming growth factor-? signaling in dendritic cells and is essential for development of skin Langerhans cells. Here, we report that Runx3 is involved in the development of skin dendritic epidermal T cells (DETCs); an important component of

Eilon Woolf; Ori Brenner; Dalia Goldenberg; Ditsa Levanon; Yoram Groner

2007-01-01

16

The role of ICOS in the development of CD4 T cell help and the reactivation of memory T cells  

E-print Network

The role of ICOS in the development of CD4 T cell help and the reactivation of memory T cells Simmi, Spain 3 Institute of Stem Cell Research, University of Edinburgh, King's Buildings, Edinburgh, UK We have addressed the role of the inducible costimulator (ICOS) in the development of T cell help for B

Maizels, Rick

17

Distinct p21 requirements for regulating normal and self-reactive T cells through IFN-? production  

PubMed Central

Self/non-self discrimination characterizes immunity and allows responses against pathogens but not self-antigens. Understanding the principles that govern this process is essential for designing autoimmunity treatments. p21 is thought to attenuate autoreactivity by limiting T cell expansion. Here, we provide direct evidence for a p21 role in controlling autoimmune T cell autoreactivity without affecting normal T cell responses. We studied C57BL/6, C57BL/6/lpr and MRL/lpr mice overexpressing p21 in T cells, and showed reduced autoreactivity and lymphadenopathy in C57BL/6/lpr, and reduced mortality in MRL/lpr mice. p21 inhibited effector/memory CD4+ CD8+ and CD4?CD8? lpr T cell accumulation without altering defective lpr apoptosis. This was mediated by a previously non-described p21 function in limiting T cell overactivation and overproduction of IFN-?, a key lupus cytokine. p21 did not affect normal T cell responses, revealing differential p21 requirements for autoreactive and normal T cell activity regulation. The underlying concept of these findings suggests potential treatments for lupus and autoimmune lymphoproliferative syndrome, without compromising normal immunity. PMID:25573673

Daszkiewicz, Lidia; Vázquez-Mateo, Cristina; Rackov, Gorjana; Ballesteros-Tato, André; Weber, Kathrin; Madrigal-Avilés, Adrián; Di Pilato, Mauro; Fotedar, Arun; Fotedar, Rati; Flores, Juana M.; Esteban, Mariano; Martínez-A, Carlos; Balomenos, Dimitrios

2015-01-01

18

Fine-tuning T cell receptor signaling to control T cell development.  

PubMed

T cell development from immature CD4(+)CD8(+) double-positive (DP) thymocytes to the mature CD4 or CD8 single-positive (SP) stage requires proper T cell receptor (TCR) signaling. The current working model of thymocyte development is that the strength of the TCR-mediated signal - from little-or-none, through intermediate, to strong - received by the immature cells determines whether they will undergo death by neglect, positive selection, or negative selection, respectively. In recent years, several developmentally regulated, stage-specifically expressed proteins and miRNAs have been found that act like fine-tuners for signal transduction and propagation downstream of the TCR. This allows them to govern thymocyte positive selection. Here, we summarize recent findings on these molecules and suggest new concepts of TCR positive-selection signaling. PMID:24951034

Fu, Guo; Rybakin, Vasily; Brzostek, Joanna; Paster, Wolfgang; Acuto, Oreste; Gascoigne, Nicholas R J

2014-07-01

19

CD8 T cell memory development: CD4 T cell help is appreciated  

Microsoft Academic Search

An important goal of vaccination strategies is to elicit long term, effective immunity. Therefore it is imperative to define\\u000a the parameters that regulate the development and preservation of the numbers and functional quality of cells that confer this\\u000a property to the host. CD8 T cells are a key component of the host adaptive immune response that helps eradicate invading viruses

Aaruni Khanolkar; Vladimir P. Badovinac; John T. Harty

2007-01-01

20

Sin1 regulates Treg development but is not required for T cell growth and proliferation  

PubMed Central

Summary Mammalian Sin1 plays key roles in the regulation of mitogen activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling. Sin1 is an essential component of mTOR complex (mTORC) 2. The function of Sin1 and mTORC2 remains largely unknown in T cells. Here we investigate Sin1 function in T cells using mice which lack Sin1 in the hematopoietic system. Sin1 deficiency blocks the mTORC2 dependent Akt phosphorylation in T cells during development and activation. Sin1 deficient T cells exhibit normal thymic cellularity and percentages of double negative, double positive and single positive CD4 and CD8 thymocytes. Sin1 deficiency does not impair T cell receptor (TCR) induced growth and proliferation, and normal CD4+ helper cell differentiation. However Sin1 deficiency results in an increased proportion of Foxp3+ natural T regulatory (nTreg) cells in the thymus. We show that the TGF-? dependent differentiation of CD4+ T cells in vitro is enhanced by the inhibition of mTOR but not loss of Sin1 function. Our results reveal that Sin1 and mTORC2 are dispensable for the development and activation of T cells but play a role in natural Treg cell differentiation. PMID:22678916

Chang, Xing; Lazorchak, Adam S.; Liu, Dou; Su, Bing

2013-01-01

21

Vitamin D receptor expression controls proliferation of naïve CD8+ T cells and development of CD8 mediated gastrointestinal inflammation  

PubMed Central

Background Vitamin D receptor (VDR) deficiency contributes to the development of experimental inflammatory bowel disease (IBD) in several different models. T cells have been shown to express the VDR, and T cells are targets of vitamin D. In this article we determined the effects of VDR expression on CD8+ T cells. Results VDR KO CD8+ T cells, but not WT CD8+ T cells, induced colitis in Rag KO recipients. In addition, co-transfer of VDR KO CD8+ T cells with naïve CD4+ T cells accelerated colitis development. The more severe colitis was associated with rapidly proliferating naïve VDR KO CD8+ T cells and increased IFN-? and IL-17 in the gut. VDR KO CD8+ T cells proliferated in vitro without antigen stimulation and did not downregulate CD62L and upregulate CD44 markers following proliferation that normally occurred in WT CD8+ T cells. The increased proliferation of VDR KO CD8+ cells was due in part to the higher production and response of the VDR KO cells to IL-2. Conclusions Our data indicate that expression of the VDR is required to prevent replication of quiescent CD8+ T cells. The inability to signal through the VDR resulted in the generation of pathogenic CD8+ T cells from rapidly proliferating cells that contributed to the development of IBD. PMID:24502291

2014-01-01

22

Attenuation of cytokine responsiveness during T cell development and differentiation.  

PubMed

Cytokines play critical roles during T cell development; however, it is unclear to what extent development is altered by the high levels of cytokines produced during immune responses. A potential mechanism to shield developing cells from cytokine influence is attenuation of cytokine signaling. Using intracellular staining and flow cytometry to detect cytokine-induced Stat phosphorylation, we analyzed the cytokine responsiveness of developmentally defined mouse T cells. We assessed CD4(-)CD8(-) (DN), CD4(+)CD8(+) (DP), CD4(+)CD8(-) (SP4), and CD4(-)CD8(+) (SP8) in the thymus, and CD4(+)CD44(lo) (naive), CD4(+)CD44(hi) (memory), CD8(+)CD44(lo) (naive), and CD8(+)CD44(hi) (memory) in the periphery for responsiveness to interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL- 10, IL-15, interferon-alpha (IFN-alpha), and IFN-gamma. SP thymocytes responded to a wider range of cytokines than did the less mature DN and DP subpopulations. DP thymocytes were nonresponsive to all cytokines tested except for modest responses to IL-4 and IFN-alpha. Peripheral naive and memory T cells also displayed differential cytokine sensitivity. Memory T cells were less responsive to the proinflammatory cytokines IL-6 and IFN-gamma when compared with naive T cells, and the memory CD4(+) subset was less responsive to IL-4. In summary, developing thymocytes and memory T cells appear to be resistant to the influences of numerous cytokines produced during immune responses. PMID:17032169

Marino, Julie H; Van De Wiele, C Justin; Everhart, Joshua M; Masengale, Rhonda; Naukam, Rebecca J; Schniederjan, Matthew J; Vo, Stephen; Teague, T Kent

2006-10-01

23

Function of the Nucleotide Exchange Activity of Vav1 in T cell Development and Activation*  

PubMed Central

The guanine nucleotide exchange factor (GEF) Vav1 is essential for transducing T cell antigen receptor (TCR) signals and therefore plays a critical role in the development and activation of T cells. It has been presumed that the GEF activity of Vav1 is important for its function; however, there has been no direct demonstration of this. Here, we generated mice expressing enzymatically inactive, but normally folded, Vav1 protein. Analysis of these mice showed that the GEF activity of Vav1 was necessary for the selection of thymocytes and for the optimal activation of T cells, including signal transduction to Rac1, Akt, and integrins. In contrast, the GEF activity of Vav1 was not required for TCR-induced calcium flux, activation of extracellular signal–regulated kinase (ERK) and protein kinase D1 (PKD1), and cell polarization. Thus, in T cells, the GEF activity of Vav1 is essential for some, but not all, of its functions. PMID:20009105

Saveliev, Alexander; Vanes, Lesley; Ksionda, Olga; Rapley, Jonathan; Smerdon, Stephen J.; Rittinger, Katrin; Tybulewicz, Victor L. J.

2012-01-01

24

Priming of CD4+ T cells and development of CD4+ T cell memory; lessons for malaria.  

PubMed

CD4 T cells play a central role in the immune response to malaria. They are required to help B cells produce the antibody that is essential for parasite clearance. They also produce cytokines that amplify the phagocytic and parasitocidal response of the innate immune system, as well as dampening this response later on to limit immunopathology. Therefore, understanding the mechanisms by which T helper cells are activated and the requirements for development of specific, and effective, T cell memory and immunity is essential in the quest for a malaria vaccine. In this paper on the CD4 session of the Immunology of Malaria Infections meeting, we summarize discussions of CD4 cell priming and memory in malaria and in vaccination and outline critical future lines of investigation. B. Stockinger and M.K. Jenkins proposed cutting edge experimental systems to study basic T cell biology in malaria. Critical parameters in T cell activation include the cell types involved, the route of infection and the timing and location and cell types involved in antigen presentation. A new generation of vaccines that induce CD4 T cell activation and memory are being developed with new adjuvants. Studies of T cell memory focus on differentiation and factors involved in maintenance of antigen specific T cells and control of the size of that population. To improve detection of T cell memory in the field, efforts will have to be made to distinguish antigen-specific responses from cytokine driven responses. PMID:16438673

Stephens, R; Langhorne, J

2006-01-01

25

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients.  

PubMed

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft-associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor ? (LXR?), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE. PMID:24463447

McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J; Isenberg, David A; Magee, Anthony I; Butters, Terry; Jury, Elizabeth C

2014-02-01

26

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients  

PubMed Central

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft–associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor ? (LXR?), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE. PMID:24463447

McDonald, Georgia; Deepak, Shantal; Miguel, Laura; Hall, Cleo J.; Isenberg, David A.; Magee, Anthony I.; Butters, Terry; Jury, Elizabeth C.

2014-01-01

27

Fli-1 Overexpression in Hematopoietic Progenitors Deregulates T Cell Development and Induces Pre-T Cell Lymphoblastic Leukaemia/Lymphoma  

PubMed Central

The Ets transcription factor Fli-1 is preferentially expressed in hematopoietic tissues and cells, including immature T cells, but the role of Fli-1 in T cell development has not been closely examined. To address this we retrovirally overexpressed Fli-1 in various in vitro and in vivo settings and analysed its effect on T cell development. We found that Fli-1 overexpression perturbed the DN to DP transition and inhibited CD4 development whilst enhancing CD8 development both in vitro and in vivo. Surprisingly, Fli-1 overexpression in vivo eventuated in development of pre-T cell lymphoblastic leukaemia/lymphoma (pre-T LBL). Known Fli-1 target genes such as the pro-survival Bcl-2 family members were not found to be upregulated. In contrast, we found increased NOTCH1 expression in all Fli-1 T cells and detected Notch1 mutations in all tumours. These data show a novel function for Fli-1 in T cell development and leukaemogenesis and provide a new mouse model of pre-T LBL to identify treatment options that target the Fli-1 and Notch1 signalling pathways. PMID:23667468

Smeets, Monique F. M. A.; Chan, Angela C.; Dagger, Samantha; Bradley, Cara K.; Wei, Andrew; Izon, David J.

2013-01-01

28

Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation.  

PubMed

The fidelity of T cell immunity depends greatly on coupling T cell receptor signaling with specific T cell effector functions. Here, we describe a chromatin-based mechanism that enables integration of TCR specificity into definite T cell lineage commitment. Using natural killer T cells (iNKT cell) as a model of a T cell subset that differentiates in response to specific TCR signaling, we identified a key role of histone H3 lysine 27 trimethylation (H3K27me3) in coupling iNKT cell TCR specificity with the generation of iNKT cells. We found that the Zbtb16/PLZF gene promoter that drives iNKT cell differentiation possesses a bivalent chromatin state characterized by the simultaneous presence of negative and positive H3K27me3 and H3K4me3 modifications. Depletion of H3K27me3 at the Zbtb16/PLZF promoter leads to uncoupling of iNKT cell development from TCR specificity and is associated with accumulation of iNKT-like CD4(+) cells that express a non-iNKT cell specific T cell repertoire. In turn, stabilization of H3K27me3 leads to a drastic reduction of the iNKT cell population. Our data suggest that H3K27me3 levels at the bivalent Zbtb16/PLZF gene define a threshold enabling precise coupling of TCR specificity to lineage commitment. PMID:25687282

Dobenecker, Marc-Werner; Kim, Jong Kyong; Marcello, Jonas; Fang, Terry C; Prinjha, Rab; Bosselut, Remy; Tarakhovsky, Alexander

2015-03-01

29

Bax alpha perturbs T cell development and affects cell cycle entry of T cells.  

PubMed Central

Bax alpha can heterodimerize with Bcl-2 and Bcl-X(L), countering their effects, as well as promoting apoptosis on overexpression. We show that bax alpha transgenic mice have greatly reduced numbers of mature T cells, which results from an impaired positive selection in the thymus. This perturbation in positive selection is accompanied by an increase in the number of cycling thymocytes. Further to this, mature T cells overexpressing Bax alpha have lower levels of p27Kip1 and enter S phase more rapidly in response to interleukin-2 stimulation than do control T cells, while the converse is true of bcl-2 transgenic T cells. These data indicate that apoptotic regulatory proteins can modulate the level of cell cycle-controlling proteins and thereby directly impact on the cell cycle. Images PMID:9003775

Brady, H J; Gil-Gómez, G; Kirberg, J; Berns, A J

1996-01-01

30

Tonic ubiquitylation controls T-cell receptor:CD3 complex expression during T-cell development  

PubMed Central

Expression of the T-cell receptor (TCR):CD3 complex is tightly regulated during T-cell development. The mechanism and physiological role of this regulation are unclear. Here, we show that the TCR:CD3 complex is constitutively ubiquitylated in immature double positive (DP) thymocytes, but not mature single positive (SP) thymocytes or splenic T cells. This steady state, tonic CD3 monoubiquitylation is mediated by the CD3? proline-rich sequence, Lck, c-Cbl, and SLAP, which collectively trigger the dynamin-dependent downmodulation, lysosomal sequestration and degradation of surface TCR:CD3 complexes. Blocking this tonic ubiquitylation by mutating all the lysines in the CD3 cytoplasmic tails significantly upregulates TCR levels on DP thymocytes. Mimicking monoubiquitylation by expression of a CD3?-monoubiquitin (monoUb) fusion molecule significantly reduces TCR levels on immature thymocytes. Moreover, modulating CD3 ubiquitylation alters immunological synapse (IS) formation and Erk phosphorylation, thereby shifting the signalling threshold for positive and negative selection, and regulatory T-cell development. Thus, tonic TCR:CD3 ubiquitylation results in precise regulation of TCR expression on immature T cells, which is required to maintain the fidelity of T-cell development. PMID:20150895

Wang, Haopeng; Holst, Jeff; Woo, Seng-Ryong; Guy, Cliff; Bettini, Matt; Wang, Yao; Shafer, Aaron; Naramura, Mayumi; Mingueneau, Michaël; Dragone, Leonard L; Hayes, Sandra M; Malissen, Bernard; Band, Hamid; Vignali, Dario A A

2010-01-01

31

Chromatin Remodeling by the T Cell Receptor (Tcr)-? Gene Enhancer during Early T Cell Development  

PubMed Central

Gene targeting studies have shown that T cell receptor (TCR)-? gene expression and recombination are inhibited after deletion of an enhancer (E?) located at the 3? end of the ?500-kb TCR-? locus. Using knockout mouse models, we have measured, at different regions throughout the TCR-? locus, the effects of E? deletion on molecular parameters believed to reflect epigenetic changes associated with the control of gene activation, including restriction endonuclease access to chromosomal DNA, germline transcription, DNA methylation, and histone H3 acetylation. Our results demonstrate that, in early developing thymocytes, E? contributes to major chromatin remodeling directed to an ?25-kb upstream domain comprised of the D?-J? locus regions. Accordingly, treatment of E?-deleted thymocytes with the histone deacetylase inhibitor trichostatin A relieved the block in TCR-? gene expression and promoted recombination within the D?-J? loci. Unexpectedly, however, epigenetic processes at distal V? genes on the 5? side of the locus and at the 3? proximal V?14 gene appear to be less dependent on E?, suggesting that E? activity is confined to a discrete region of the TCR-? locus. These findings have implications with respect to the developmental control of TCR-? gene recombination, and the process of allelic exclusion at this locus. PMID:10974029

Mathieu, Noëlle; Hempel, William M.; Spicuglia, Salvatore; Verthuy, Christophe; Ferrier, Pierre

2000-01-01

32

The Effects of TLR Activation on T-Cell Development and Differentiation  

PubMed Central

Invading pathogens have unique molecular signatures that are recognized by Toll-like receptors (TLRs) resulting in either activation of antigen-presenting cells (APCs) and/or costimulation of T cells inducing both innate and adaptive immunity. TLRs are also involved in T-cell development and can reprogram Treg cells to become helper cells. T cells consist of various subsets, that is, Th1, Th2, Th17, T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), regulatory T cells (Treg) and these originate from thymic progenitor thymocytes. T-cell receptor (TCR) activation in distinct T-cell subsets with different TLRs results in differing outcomes, for example, activation of TLR4 expressed in T cells promotes suppressive function of regulatory T cells (Treg), while activation of TLR6 expressed in T cells abrogates Treg function. The current state of knowledge of regarding TLR-mediated T-cell development and differentiation is reviewed. PMID:22737174

Jin, Bo; Sun, Tao; Yu, Xiao-Hong; Yang, Ying-Xiang; Yeo, Anthony E. T.

2012-01-01

33

T-cell accumulation and regulated on activation, normal T cell expressed and secreted upregulation in adipose tissue in obesity  

Technology Transfer Automated Retrieval System (TEKTRAN)

Obesity is associated with chronic inflammation, which includes increased macrophage accumulation in adipose tissue (AT) and upregulation of chemokines and cytokines. T cells also play important roles in chronic inflammatory diseases such as atherosclerosis but have not been well studied in obesity....

34

IL5Deficient Mice Have a Developmental Defect in CD5 + B1 Cells and Lack Eosinophilia but Have Normal Antibody and Cytotoxic T Cell Responses  

Microsoft Academic Search

Mice deficient in interleukin-5 (IL-5?\\/? mice) were generated by gene targeting in embryonal stem cells. Contrary to previous studies, no obligatory role for IL-5 was demonstrated in the regulation of conventional B (B-2) cells, in normal T cell–dependent antibody responses or in cytotoxic T cell development. However, CD5+ B cells (B-1 cells) in the peritoneal cavity were reduced by 50%–80%

Manfred Kopf; Frank Brombacher; Philip D Hodgkin; Alistair J Ramsay; Elizabeth A Milbourne; Wen J Dai; Karen S Ovington; Carolyn A Behm; Georges Köhler; Ian G Young; Klaus I Matthaei

1996-01-01

35

Chlamydia trachomatis Infection Alters the Development of Memory CD8 T Cells1  

E-print Network

Chlamydia trachomatis Infection Alters the Development of Memory CD8 T Cells1 Wendy P. Loomis the development of CD8 memory T cell responses specific for the Chlamydia Ag CrpA. The percentage of CrpA63 expressing the CrpA protein. These alterations in memory T cell development were correlated

Starnbach, Michael

36

Stimulated plasmacytoid dendritic cells impair human T-cell development  

PubMed Central

Thymic plasmacytoid dendritic cells (pDCs) are located predominantly in the medulla and at the corticomedullary junction, the entry site of bone marrow–derived multipotential precursor cells into the thymus, allowing for interactions between thymic pDCs and precursor cells. We demonstrate that in vitro–generated pDCs stimulated with CpG or virus impaired the development of human autologous CD34+CD1a– thymic progenitor cells into the T-cell lineage. Rescue by addition of neutralizing type I interferon (IFN) antibodies strongly implies that endogenously produced IFN-?/? is responsible for this inhibitory effect. Consistent with this notion, we show that exogenously added IFN-? had a similar impact on IL-7– and Notch ligand–induced development of thymic CD34+CD1a– progenitor cells into T cells, because induction of CD1a, CD4, CD8, and TCR/CD3 surface expression and rearrangements of TCR? V-DJ gene segments were severely impaired. In addition, IL-7–induced proliferation but not survival of the developing thymic progenitor cells was strongly inhibited by IFN-?. It is evident from our data that IFN-? inhibits the IL-7R signal transduction pathway, although this could not be attributed to interference with either IL-7R proximal (STAT5, Akt/PKB, Erk1/2) or distal (p27kip1, pRb) events. PMID:16917011

Schmidlin, Heike; Dontje, Wendy; Groot, Fedde; Ligthart, Suzanne J.; Colantonio, Arnaud D.; Oud, Monique E.; Schilder-Tol, Esther J.; Spaargaren, Marcel; Spits, Hergen; Uittenbogaart, Christel H.; Blom, Bianca

2006-01-01

37

Statistical Physics of T-Cell Development and Pathogen Specificity  

NASA Astrophysics Data System (ADS)

In addition to an innate immune system that battles pathogens in a nonspecific fashion, higher organisms, such as humans, possess an adaptive immune system to combat diverse (and evolving) microbial pathogens. Remarkably, the adaptive immune system mounts pathogen-specific responses, which can be recalled upon reinfection with the same pathogen. It is difficult to see how the adaptive immune system can be preprogrammed to respond specifically to a vast and unknown set of pathogens. Although major advances have been made in understanding pertinent molecular and cellular phenomena, the precise principles that govern many aspects of an immune response are largely unknown. We discuss complementary approaches from statistical mechanics and cell biology that can shed light on how key components of the adaptive immune system, T cells, develop to enable pathogen-specific responses against many diverse pathogens. The mechanistic understanding that emerges has implications for how host genetics may influence the development of T cells with differing responses to the human immunodeficiency virus (HIV) infection.

Košmrlj, Andrej; Kardar, Mehran; Chakraborty, Arup K.

2013-04-01

38

Foxo transcription factors control regulatory T cell development and function  

PubMed Central

SUMMARY Foxo transcription factors integrate extrinsic signals to regulate cell division, differentiation and survival, and specific functions of lymphoid and myeloid cells. Here we showed the absence of Foxo1 severely curtailed the development of Foxp3+ regulatory T (Treg) cells, and those that developed were nonfunctional in vivo. The loss of function included diminished CTLA-4 receptor expression as the Ctla4 gene was a direct target of Foxo1. T cell specific loss of Foxo1 resulted in exocrine pancreatitis, hind limb paralysis, multi-organ lymphocyte infiltration, anti-nuclear antibodies and expanded germinal centers. Foxo-mediated control over Treg cell specification was further revealed by the inability of TGF-? cytokine to suppress T-bet transcription factor in the absence of Foxo1, resulting in IFN-?-secretion. In addition the absence of Foxo3 exacerbated the effects of the loss of Foxo1. Thus, Foxo transcription factors guide the contingencies of T cell differentiation and specific functions of effector cell populations. PMID:21167754

Kerdiles, Yann M.; Stone, Erica L.; Beisner, Daniel L.; McGargill, Maureen A.; Ch'en, Irene L.; Stockmann, Christian; Katayama, Carol D.; Hedrick, Stephen M.

2010-01-01

39

The ThPOK transcription factor differentially affects the development and function of self-specific CD8+ T cells and regulatory CD4+ T cells  

PubMed Central

The zinc finger transcription factor ThPOK plays a crucial role in CD4 T-cell development and CD4/CD8 lineage decision. In ThPOK-deficient mice, developing T cells expressing MHC class II-restricted T-cell receptors are redirected into the CD8 T-cell lineage. In this study, we investigated whether the ThPOK transgene affected the development and function of two additional types of T cells, namely self-specific CD8 T cells and CD4+ FoxP3+ T regulatory cells. Self-specific CD8 T cells are characterized by high expression of CD44, CD122, Ly6C, 1B11 and proliferation in response to either IL-2 or IL-15. The ThPOK transgene converted these self-specific CD8 T cells into CD4 T cells. The converted CD4+ T cells are no longer self-reactive, lose the characteristics of self-specific CD8 T cells, acquire the properties of conventional CD4 T cells and survive poorly in peripheral lymphoid organs. By contrast, the ThPOK transgene promoted the development of CD4+ FoxP3+ regulatory T cells resulting in an increased recovery of CD4+ FoxP3+ regulatory T cells that expressed higher transforming growth factor-?-dependent suppressor activity. These studies indicate that the ThPOK transcription factor differentially affects the development and function of self-specific CD8 T cells and CD4+ FoxP3+ regulatory T cells. PMID:24708418

Twu, Yuh-Ching; Teh, Hung-Sia

2014-01-01

40

Developing T cell cancer immunotherapy in the dog with lymphoma.  

PubMed

Immunotherapy is not a new concept for veterinary medicine; however, adoptive T cell therapy is a new area of research in humans and canines alike. In humans, T cell therapy has been used against many different tumor histologies, including lymphoma, melanoma, and colon cancer. Although in dogs this approach has currently only been applied to lymphoma, other tumor types are under investigation. There are many different strategies used to take advantage of cell-mediated antitumor properties of T cells. This review will discuss many of the current strategies used in both humans and canines in regards to adoptive T cell therapy. PMID:24936037

O'Connor, Colleen M; Wilson-Robles, Heather

2014-01-01

41

Metabolic Regulation of Regulatory T Cell Development and Function  

PubMed Central

It is now well established that the effector T cell (Teff) response is regulated by a series of metabolic switches. Quiescent T cells predominantly require adenosine triphosphate-generating processes, whereas proliferating Teff require high metabolic flux through growth-promoting pathways, such as glycolysis. Pathways that control metabolism and immune cell function are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell effector functions. Furthermore, functionally distinct T cell subsets require distinct energetic and biosynthetic pathways to support their specific functional needs. In particular, naturally occurring regulatory T cells (Treg) are characterized by a unique metabolic signature distinct to that of conventional Teff cells. We here briefly review the signaling pathways that control Treg metabolism and how this metabolic phenotype integrates their differentiation and function. Ultimately, these metabolic features may provide new opportunities for the therapeutic modulation of unwanted immune responses. PMID:25477880

Coe, David John; Kishore, Madhav; Marelli-Berg, Federica

2014-01-01

42

Regulation of early T cell development by the PHD finger of histone lysine methyltransferase ASH1  

SciTech Connect

We have previously isolated a mammalian homologue of Drosophila discsabsent, small, orhomeotic-1 (ash1) from the murine thymus, and recently shown that its SET domain methylates histone H3 lysine 36 (K36). Expression of ASH1 has been reported to be increased in NOD thymocytes in a BDC2.5 clonotype background, but its function in T cell development has remained elusive. Here we report that the ash1 gene is expressed at high levels in thymocytes of mice deficient for rag1 or tcra genes. ASH1 proteins are present at peri-nuclei and as nuclear speckles in thymocytes. Some of the nuclear ASH1 co-localize with RAG2. Expression of the evolutionarily conserved PHD finger of ASH1 impairs T cell development at the DP stage, and causes increased transcription from the HoxA9 promoter in vitro. Moreover, the C-terminal part of ASH1 interacts with HDAC1 repression complexes, suggesting that the PHD finger of ASH1 may be involved in down-regulation of genes for normal development of {alpha}{beta} T cells.

Tanaka, Yujiro [Genome Structure and Expression, School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo 113-8610 (Japan)], E-mail: ytanaka.bgen@mri.tmd.ac.jp; Nakayama, Yasuhiro [Department of Genetics, Yale University School of Medicine, 300 Cedar St., New Haven, CT 06510 (United States); Taniguchi, Masaru [Department of Developmental Immunology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670 (Japan); Kioussis, Dimitris [Department of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA (United Kingdom)

2008-01-18

43

Gene therapy: is IL2RG oncogenic in T-cell development?  

PubMed

The gene IL2RG encodes the gamma-chain of the interleukin-2 receptor and is mutated in patients with X-linked severe combined immune deficiency (X-SCID). Woods et al. report the development of thymus tumours in a mouse model of X-SCID after correction by lentiviral overexpression of IL2RG and claim that these were caused by IL2RG itself. Here we find that retroviral overexpression of IL2RG in human CD34+ cells has no effect on T-cell development, whereas overexpression of the T-cell acute lymphoblastic leukaemia (T-ALL) oncogene LMO2 leads to severe abnormalities. Retroviral expression of IL2RG may therefore not be directly oncogenic--rather, the restoration of normal signalling by the interleukin-7 receptor to X-SCID precursor cells allows progression of T-cell development to stages that are permissive for the pro-leukaemic effects of ectopic LMO2. PMID:16988660

Pike-Overzet, Karin; de Ridder, Dick; Weerkamp, Floor; Baert, Miranda R M; Verstegen, Monique M; Brugman, Martijn H; Howe, Steven J; Reinders, Marcel J T; Thrasher, Adrian J; Wagemaker, Gerard; van Dongen, Jacques J M; Staal, Frank J T

2006-09-21

44

CCR10 is important for the development of skin-specific ??T cells by regulating their migration and location  

PubMed Central

Unlike conventional ?? T cells, which preferentially reside in secondary lymphoid organs for adaptive immune responses, various subsets of un-conventional T cells, such as the ?? T cells with innate properties, preferentially reside in epithelial tissues as the first line of defence. However, mechanisms underlying their tissue-specific development are not well understood. We herein report that among different thymic T cell subsets fetal thymic precursors of the prototypic skin intraepithelial V?3+ T lymphocytes (sIEL) were selected to display a unique pattern of homing molecules, including a high level of CCR10 expression that was important for their development into sIELs. In fetal CCR10 knockout mice, the V?3+ sIEL precursors developed normally in the thymus, but were defective in migrating into the skin. While the earlier defect in the skin-seeding by sIEL precursors was partially compensated for by their normal expansion in the skin of adult CCR10 knockout mice, the V?3+ sIELs displayed the abnormal morphology and increasingly accumulated in the dermal region of skin. These findings provide the definite evidence that CCR10 is important in the sIEL development by regulating the migration of sIEL precursors and their maintenance in proper regions of the skin and support the notion that unique homing properties of different thymic T cell subsets plays an important role in their peripheral location. PMID:20937851

Jin, Yan; Xia, Mingcan; Sun, Allen; Saylor, Christina M.; Xiong, Na

2011-01-01

45

Baylor researchers develop method of controlling T-cells:  

Cancer.gov

Cancer treatment with stem cell transplantation and specially modified immune system components called T-cells can enhance the chance of recovery from diseases such as leukemia or lymphoma, because each T-cell can act as a serial killer of many cancer cells. Despite their benefits, however, the T-cells are uncontrolled and can produce severe and even lethal side effects. Now these treatments can be made safer by using a new termination system that almost immediately controls the therapy if things go wrong, said researchers from the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital and The Methodist Hospital in a report in the current issue of the New England Journal of Medicine.

46

Differential Requirement for CCR4 and CCR7 during the Development of Innate and Adaptive ??T Cells in the Adult Thymus  

PubMed Central

??T cell development depends upon serial migration of thymocyte precursors through cortical and medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional ??T cells are subject to clonal deletion in the medulla, entry into the thymus medulla also fosters ??T cell differentiation. For example, during postnatal periods, the medulla is involved in the intrathymic generation of multiple ??T cell lineages, notably the induction of Foxp3+ regulatory T cell development and the completion of invariant NKT cell development. Although migration of conventional ??T cells to the medulla is mediated by the chemokine receptor CCR7, how other T cell subsets gain access to medullary areas during their normal development is not clear. In this study, we show that combining a panel of thymocyte maturation markers with cell surface analysis of CCR7 and CCR4 identifies distinct stages in the development of multiple ??T cell lineages in the thymus. Although Aire regulates expression of the CCR4 ligands CCL17 and CCL22, we show that CCR4 is dispensable for thymocyte migration and development in the adult thymus, demonstrating defective T cell development in Aire?/? mice is not because of a loss of CCR4-mediated migration. Moreover, we reveal that CCR7 controls the development of invariant NKT cells by enabling their access to IL-15 trans-presentation in the thymic medulla and influences the balance of early and late intrathymic stages of Foxp3+ regulatory T cell development. Collectively, our data identify novel roles for CCR7 during intrathymic T cell development, highlighting its importance in enabling multiple ??T cell lineages to access the thymic medulla. PMID:24990081

Cowan, Jennifer E.; McCarthy, Nicholas I.; Parnell, Sonia M.; White, Andrea J.; Bacon, Andrea; Serge, Arnauld; Irla, Magali; Lane, Peter J. L.; Jenkinson, Eric J.; Jenkinson, William E.

2014-01-01

47

Foxp3 programs the development and function of CD4+CD25+ regulatory T cells  

Microsoft Academic Search

CD4+CD25+ regulatory T cells are essential for the active suppression of autoimmunity. Here we report that the forkhead transcription factor Foxp3 is specifically expressed in CD4+CD25+ regulatory T cells and is required for their development. The lethal autoimmune syndrome observed in Foxp3-mutant scurfy mice and Foxp3-null mice results from a CD4+CD25+ regulatory T cell deficiency and not from a cell-intrinsic

Jason D. Fontenot; Marc A. Gavin; Alexander Y. Rudensky

2003-01-01

48

Role of Prolactin in the Recovered T-Cell Development of Early Partially Decapitated Chicken Embryo  

PubMed Central

Although different experimental approaches have suggested certain regulation of the mammalian immune system by the neuroendocrine system, the precise factors involved in the process are largely unknown. In previous reports, we demonstrated important changes in the thymic development of chickens deprived of the major neuroendocrine centers by the removal of embryonic prosencephalon at 33-38 hr of incubation (DCx embryos) (Herradón et al., 1991; Moreno et al., 1995). In these embryos, there was a stopping of T-cell maturation that resulted in an accumulation of the most immature T-cell subsets (CD4-CD8- cells and CD4-CD81o cells) and, accordingly, in decreased numbers of DP (CD4+CD8+) thymocytes and mature CD3+TcR?? + cells, but not CD3+TcR?? lymphocytes. In the present work, we restore the thymic histology as well as the percentage of distinct T-cell subsets of DCx embryos by supplying recombinant chicken prolactin, grafting of embryonic pituitary gland, or making cephalic chick-quail chimeras. The recovery was not, however, whole and the percentage of CD3+TcR?? thymocytes did not reach the normal values observed in 17-day-old control Sham-DCx embryos. The results are discussed on the basis of a key role for prolactin in chicken T-cell maturation. This hormone could regulate the transition of DN (CD4-CD8-) thymocytes to the DP (CD4+CD8+) cell compartment through its capacity for inducing IL-2 receptor expression on the former. PMID:9851358

Moreno, J.; Varas, A.; Vicente, A.

1998-01-01

49

CHARACTERIZATION OF NORMAL HUMAN LUNG LYMPHOCYTES AND INTERLEUKIN-2-INDUCED LUNG T CELL LINES  

EPA Science Inventory

Lymphocytes from the lower respiratory tract were obtained by bronchoalveolar lavage of healthy, non-smoking individuals. arious monoclonal antibodies characterizing activated T cells, helper-inducer and suppressor-inducer T cell subsets, and naive versus memory cells were used t...

50

CD4 + T cells with specific reactivity against astrovirus isolated from normal human small intestine  

Microsoft Academic Search

Background & Aims: The gut is the largest immunologic organ in the human body, but little is known about the antigen specificity of mucosal T cells. This study sought to determine whether T cells resident in the duodenal mucosa could recognize astrovirus, a common and clinically important gastroenteritis virus. Serum antibodies against astrovirus are prevalent, indicating frequent viral exposure and

Øyvind Molberg; Ellen M. Nilsen; Ludvig M. Sollid; Helge Scott; Per Brandtzaeg; Erik Thorsby; Knut E. A. Lundin

1998-01-01

51

Interleukin-1 Receptors Are Differentially Expressed in Normal and Psoriatic T Cells  

PubMed Central

This study was carried out to examine the possible role of interleukin-1 (IL-1) in the functional insufficiency of regulatory T cells in psoriasis, by comparing the expression of IL-1 receptors on healthy control and psoriatic T cells. Patients with moderate-to-severe chronic plaque psoriasis and healthy volunteers, matched in age and sex, were selected for all experiments. CD4+CD25? effector and CD4+CD25+CD127low regulatory T cells were separated and used for the experiments. Expression of the mRNA of IL-1 receptors (IL-1R1, IL-1R2, and sIL-1R2) was determined by quantitative real-time RT-PCR. Cell surface IL-1 receptor expression was assessed by flow cytometry. Relative expression of the signal transmitting IL-1 receptor type 1 (IL-1R1) mRNA is higher in resting psoriatic effector and regulatory T cells, and activation induces higher IL-1R1 protein expression in psoriatic T cells than in healthy cells. Psoriatic regulatory and effector T cells express increased mRNA levels of the decoy IL-1 receptors (IL-1R2 and sIL-1R2) upon activation compared to healthy counterparts. Psoriatic T cells release slightly more sIL-1R2 into their surrounding than healthy T cells. In conclusion, changes in the expression of IL-1 receptors in psoriatic regulatory and effector T cells could contribute to the pathogenesis of psoriasis. PMID:24665164

Kovács-Sólyom, Ferenc; Prihoda, Judit; Kui, Róbert; Kemény, Lajos; Gyulai, Rolland

2014-01-01

52

Differentiation of malignant B-lymphoma cells from normal and activated T-cell populations by their intrinsic autofluorescence  

PubMed Central

Patients with active posterior and intermediate uveitis have inflammatory cells in their vitreous; those with primary intraocular lymphoma have malignant B-lymphoma cells concomitantly. These cell types cannot be distinguished clinically. The goal of this study was to investigate intrinsic autofluorescence as a non-invasive way of differentiating immune and lymphomatous cell populations. Human primary T-cells were stimulated with or without anti-CD3 plus anti-CD28 stimulation. B-lymphoma cells (CA46) were cultured separately. Five experimental groups were prepared: unstimulated T-cells, stimulated T-cells, CA46 cells, stimulated T-cells mixed with CA46 cells at a ratio of 1:3, or mixed at a ratio of 3:1. Samples were excited with three wavelengths and imaged with a confocal microscope. For each condition, the autofluorescent emissions from the sample were measured. In separate experiments, T-cells or CA46 cells were injected into the anterior chamber of a Balb/C mouse eye and autofluorescence was measured. Pure T-cell and lymphoma populations were clearly distinguishable based on autofluorescence intensity spectra. CA46 cells were the least fluorescent when excited with 351nm light, but most fluorescent when excited with longer wavelengths like 488nm. Mixed populations of T-cells and CA46 cells had emission intensities that fell predictably in-between those of the pure populations. An ex vivo study demonstrated that CA46 cells could be detected based on their intrinsic autofluorescence. Our studies demonstrated that normal activated and malignant lymphocyte populations can be distinguished based on their intrinsic autofluorescent properties. Future work with in vivo models may prove useful in facilitating the diagnosis of uveitis and other ocular diseases. PMID:19458079

Pantanelli, Seth M.; Li, Zhuqing; Fariss, Robert; Mahesh, Sankaranarayana P.; Liu, Baoying; Nussenblatt, Robert B.

2009-01-01

53

Development of Promyelocytic Zinc Finger and ThPOK-Expressing Innate ?? T Cells Is Controlled by Strength of TCR Signaling and Id3  

PubMed Central

The broad-complex tramtrack and bric a brac-zinc finger transcriptional regulator(BTB-ZF), promyelocytic leukemia zinc finger (PLZF), was recently shown to control the development of the characteristic innate T cell phenotype and effector functions of NK T cells. Interestingly, the ectopic expression of PLZF was shown to push conventional T cells into an activated state that seems to be proinflammatory. The factors that control the normal expression of PLZF in lymphocytes are unknown. In this study, we show that PLZF expression is not restricted to NK T cells but is also expressed by a subset of ?? T cells, functionally defining distinct subsets of this innate T cell population. A second BTB-ZF gene, ThPOK, is important for the phenotype of the PLZF-expressing ?? T cells. Most importantly, TCR signal strength and expression of inhibitor of differentiation gene 3 control the frequency of PLZF-expressing ?? T cells. This study defines the factors that control the propensity of the immune system to produce potentially disease-causing T cell subsets. PMID:20038637

Alonzo, Eric S.; Gottschalk, Rachel A.; Das, Joy; Egawa, Takeshi; Hobbs, Robin M.; Pandolfi, Pier Paolo; Pereira, Pablo; Nichols, Kim E.; Koretzky, Gary A.; Jordan, Martha S.; Sant’Angelo, Derek B.

2014-01-01

54

T cell--specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation  

Microsoft Academic Search

Interleukin (IL)-10 is a regulator of inflammatory responses and is secreted by a variety of different cell types including T cells. T regulatory cells have been shown to suppress immune responses by IL-10-dependent, but also IL-10-independent, mechanisms. Herein, we address the role of T cell-derived IL-10 in mice with an inactivation of the IL-10 gene restricted to T cells generated

Axel Roers; Lisa Siewe; Elke Strittmatter; M. Deckert; D. Schluter; W. Stenzel; A. D. Gruber; T. Krieg; K. Rajewsky

2004-01-01

55

T Cell–specific Inactivation of the Interleukin 10 Gene in Mice Results in Enhanced T Cell Responses but Normal Innate Responses to Lipopolysaccharide or Skin Irritation  

PubMed Central

Interleukin (IL)-10 is a regulator of inflammatory responses and is secreted by a variety of different cell types including T cells. T regulatory cells have been shown to suppress immune responses by IL-10–dependent, but also IL-10–independent, mechanisms. Herein, we address the role of T cell–derived IL-10 in mice with an inactivation of the IL-10 gene restricted to T cells generated by Cre/loxP-mediated targeting of the IL-10 gene. Splenocytes from this T cell–specific mutant secrete increased amounts of proinflammatory cytokines after activation in vitro compared with show enhanced contact hypersensitivity reactions, and succumb to severe immunopathology upon infection with Toxoplasma gondii. Despite intact IL-10 genes in other cell types, the dysregulation of T cell responses observed in the T cell–specific IL-10 mutant closely resembles the phenotype in complete IL-10 deficiency. However, in contrast to complete IL-10 deficiency, sensitivity to endotoxic shock and irritant responses of the skin are not enhanced in the T cell–specific IL-10 mutant. Our data highlight the importance of T cell–derived IL-10 in the regulation of T cell responses and demonstrate that endotoxic shock and the irritant response of the skin are controlled by IL-10 from other cell types. PMID:15534372

Roers, Axel; Siewe, Lisa; Strittmatter, Elke; Deckert, Martina; Schlüter, Dirk; Stenzel, Werner; Gruber, Achim D.; Krieg, Thomas; Rajewsky, Klaus; Müller, Werner

2004-01-01

56

Human natural regulatory T cell development, suppressive function and post-thymic maturation in a humanized mouse model  

PubMed Central

CD4+ regulatory T (Treg) cells control adaptive immune responses and promote self-tolerance. Various humanized mouse models have been developed in efforts to reproduce and study a human immune system. However, in models that require T cell differentiation in the recipient murine thymus, only low numbers of T cells populate the peripheral immune systems. T cells are positively selected by mouse MHC and therefore do not function well in an HLA-restricted manner. In contrast, cotransplantation of human fetal thymus/liver and i.v. injection of CD34+ cells from the same donor achieves multilineage human lymphohematopoietic reconstitution, including dendritic cells (DCs) and formation of secondary lymphoid organs, in NOD/SCID mice. Strong antigen-specific immune responses and homeostatic expansion of human T cells that is dependent on peripheral human APCs occurs. We now demonstrate that FoxP3+ Helios+ “natural” Tregs develop normally in human fetal thymic grafts and are present in peripheral blood, spleen and lymph nodes of these humanized mice. Humanized mice exhibit normal reversal of CD45 isoform expression in association with thymic egress, post-thymic “naïve” to “activated” phenotypic conversion, and suppressive function. These studies demonstrate the utility of this humanized mouse model for the study of human Treg ontogeny, immunobiology and therapy. PMID:21876039

Onoe, Takashi; Kalscheuer, Hannes; Danzl, Nichole; Chittenden, Meredith; Zhao, Guiling; Yang, Yong-Guang; Sykes, Megan

2011-01-01

57

Interleukin-7 receptor alpha is essential for the development of gamma delta + T cells, but not natural killer cells  

PubMed Central

Mice that lack a functional gamma c subunit of the receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15 display profound defects in lymphoid development. The IL-7/IL-7R system represents a critical interaction for conventional T and B cell development. In this report, the role of IL-7R alpha in the development of lymphoid lineages other than conventional T and B cells was examined. We demonstrate that gamma delta + T cells were absent in IL-7R alpha-deficient mice, whereas the development and function of natural killer cells were normal. Thus, IL-7R alpha function is required for the development of gamma delta + T cells but not natural killer cells. PMID:8691145

1996-01-01

58

Oligoclonal CD8+ T cells play a critical role in the development of hypertension.  

PubMed

Recent studies have emphasized a role of adaptive immunity, and particularly T cells, in the genesis of hypertension. We sought to determine the T-cell subtypes that contribute to hypertension and renal inflammation in angiotensin II-induced hypertension. Using T-cell receptor spectratyping to examine T-cell receptor usage, we demonstrated that CD8(+) cells, but not CD4(+) cells, in the kidney exhibited altered T-cell receptor transcript lengths in V?3, 8.1, and 17 families in response to angiotensin II-induced hypertension. Clonality was not observed in other organs. The hypertension caused by angiotensin II in CD4(-/-) and MHCII(-/-) mice was similar to that observed in wild-type mice, whereas CD8(-/-) mice and OT1xRAG-1(-/-) mice, which have only 1 T-cell receptor, exhibited a blunted hypertensive response to angiotensin II. Adoptive transfer of pan T cells and CD8(+) T cells but not CD4(+)/CD25(-) cells conferred hypertension to RAG-1(-/-) mice. In contrast, transfer of CD4(+)/CD25(+) cells to wild-type mice receiving angiotensin II decreased blood pressure. Mice treated with angiotensin II exhibited increased numbers of kidney CD4(+) and CD8(+) T cells. In response to a sodium/volume challenge, wild-type and CD4(-/-) mice infused with angiotensin II retained water and sodium, whereas CD8(-/-) mice did not. CD8(-/-) mice were also protected against angiotensin-induced endothelial dysfunction and vascular remodeling in the kidney. These data suggest that in the development of hypertension, an oligoclonal population of CD8(+) cells accumulates in the kidney and likely contributes to hypertension by contributing to sodium and volume retention and vascular rarefaction. PMID:25259750

Trott, Daniel W; Thabet, Salim R; Kirabo, Annet; Saleh, Mohamed A; Itani, Hana; Norlander, Allison E; Wu, Jing; Goldstein, Anna; Arendshorst, William J; Madhur, Meena S; Chen, Wei; Li, Chung-I; Shyr, Yu; Harrison, David G

2014-11-01

59

Induction of T Cell Development from Hematopoietic Progenitor Cells by Delta-like-1 In Vitro  

Microsoft Academic Search

The molecular interactions provided by the thymic microenvironment that predicate T cell development remain obscure. Here, we show that a bone marrow stromal cell line ectopically expressing the Notch ligand Delta-like-1 loses its ability to support B cell lymphopoiesis, but acquires the capacity to induce the differentiation of hematopoietic progenitors into CD4 CD8 double- and single-positive T cells. Both ??-TCR+

Thomas M. Schmitt; Juan Carlos Zúñiga-Pflücker

2002-01-01

60

Control of Regulatory T Cell Development by the Transcription Factor Foxp3  

Microsoft Academic Search

Regulatory T cells engage in the maintenance of immunological self-tolerance by actively suppressing self-reactive lymphocytes. Little is known, however, about the molecular mechanism of their development. Here we show that Foxp3, which encodes a transcription factor that is genetically defective in an autoimmune and inflammatory syndrome in humans and mice, is specifically expressed in naturally arising CD4+ regulatory T cells.

Shohei Hori; Takashi Nomura; Shimon Sakaguchi

2003-01-01

61

Is trisomy cause or consequence of murine T cell leukemia development? Studies on Robertsonian translocation mice.  

PubMed Central

Trypsin-Giemsa banding studies on T cell leukemias induced in Robertsonian translocation mice by dimethylbenz[a]anthracene and Moloney leukemia virus show a trisomy of chromosome 15 even in cases in which chromosome 15 has undergone centromeric fusion with chromosomes 1, 5, or 6. These results suggest that the duplication of gene(s) located on chromosome 15 is of critical importance for murine T cell leukemia development. Images PMID:316545

Spira, J; Wiener, F; Ohno, S; Klein, G

1979-01-01

62

Monoclonal antibody (UCHL1) that recognises normal and neoplastic T cells in routinely fixed tissues  

Microsoft Academic Search

UCHL1 is a murine monoclonal antibody that recognises a 180-185 kD determinant on CD4 (72%) and CD8 (36%) positive T cells. This antibody is effective in formalin fixed and paraffin embedded tissues, using the immunoperoxidase method. One hundred and forty three cases of malignant lymphoma were examined. Neoplastic cells in 100% of cases of Mycosis fungoides (n = 10), 83%

A J Norton; A D Ramsay; S H Smith; P C Beverley; P G Isaacson

1986-01-01

63

Rho GTPase Cdc42 is essential for human T-cell development  

PubMed Central

Background Rho GTPases are involved in the regulation of many cell functions, including some related to the actin cytoskeleton. Different Rho GTPases have been shown to be important for T-cell development in mice. However, their role in human T-cell development has not yet been explored. Design and Methods We examined the expression and activation of Rho GTPases along different stages of T-cell development in the human thymus. Early stage human thymocytes were transduced with constitutively active and dominant negative mutants of different Rho GTPases to explore their role in human T-cell development, as analyzed in fetal thymus organ cultures. The use of these mutants as well as Rho GTPase-specific inhibitors allowed us to explore the role of GTPases in thymocyte migration. Results We found that the expression of several Rho GTPases is differently regulated during successive stages of T-cell development in man, suggesting a specific role in human thymopoiesis. In chimeric fetal thymus organ culture, T-cell development was not or only mildly affected by expression of dominant negative Rac1 and Rac2, but was severely impaired in the presence of dominant negative Cdc42, associated with enhanced apoptosis and reduced proliferation. Kinetic analysis revealed that Cdc42 is necessary in human T-cell development both before and after expression of the pre-T-cell receptor. Using inhibitors and retrovirally transferred mutants of the aforementioned Rho GTPases, we showed that only Rac1 is necessary for migration of different thymocyte subsets, including the early CD34+ fraction, towards stromal cell-derived factor-1?. Constitutively active mutants of Rac1, Rac2 and Cdc42 all impaired migration towards stromal cell-derived factor-1? and T-cell development to different degrees. Conclusions This is the first report on Rho GTPases in human T-cell development, showing the essential role of Cdc42. Our data suggest that enhanced apoptotic death and reduced proliferation rather than disturbed migration explains the decreased thymopoiesis induced by dominant negative Cdc42. PMID:20207844

Smits, Kaatje; Iannucci, Veronica; Stove, Veronique; Van Hauwe, Peter; Naessens, Evelien; Meuwissen, Pieter J.; Ariën, Kevin K.; Bentahir, Mostafa; Plum, Jean; Verhasselt, Bruno

2010-01-01

64

Characterization of In Vivo Dlg1 Deletion on T Cell Development and Function  

PubMed Central

Background The polarized reorganization of the T cell membrane and intracellular signaling molecules in response to T cell receptor (TCR) engagement has been implicated in the modulation of T cell development and effector responses. In siRNA-based studies Dlg1, a MAGUK scaffold protein and member of the Scribble polarity complex, has been shown to play a role in T cell polarity and TCR signal specificity, however the role of Dlg1 in T cell development and function in vivo remains unclear. Methodology/Principal Findings Here we present the combined data from three independently-derived dlg1-knockout mouse models; two germline deficient knockouts and one conditional knockout. While defects were not observed in T cell development, TCR-induced early phospho-signaling, actin-mediated events, or proliferation in any of the models, the acute knockdown of Dlg1 in Jurkat T cells diminished accumulation of actin at the IS. Further, while Th1-type cytokine production appeared unaffected in T cells derived from mice with a dlg1germline-deficiency, altered production of TCR-dependent Th1 and Th2-type cytokines was observed in T cells derived from mice with a conditional loss of dlg1 expression and T cells with acute Dlg1 suppression, suggesting a differential requirement for Dlg1 activity in signaling events leading to Th1 versus Th2 cytokine induction. The observed inconsistencies between these and other knockout models and siRNA strategies suggest that 1) compensatory upregulation of alternate gene(s) may be masking a role for dlg1 in controlling TCR-mediated events in dlg1 deficient mice and 2) the developmental stage during which dlg1 ablation begins may control the degree to which compensatory events occur. Conclusions/Significance These findings provide a potential explanation for the discrepancies observed in various studies using different dlg1-deficient T cell models and underscore the importance of acute dlg1 ablation to avoid the upregulation of compensatory mechanisms for future functional studies of the Dlg1 protein. PMID:23028902

Tomassian, Tamar; McMahon, Kerrie-Ann; Humbert, Patrick O.; Silva, Oscar; Round, June L.; Takamiya, Kogo; Huganir, Richard L.

2012-01-01

65

Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells  

Microsoft Academic Search

A recent nationwide survey of the lymphocyte subpopulations of leukaemia and lymphoma in Japan has disclosed a high incidence of adult T-cell leukaemia (ATL)1. One of the striking features of this disease is the clustering of patients in the southwestern part of Japan1,2. We have established a continuous culture line of leukaemic T cells from a patient with ATL3,4. This

Isao Miyoshi; Ichiro Kubonishi; Shizuo Yoshimoto; Tadaatsu Akagi; Yuji Ohtsuki; Yukimasa Shiraishi; Kinya Nagata; Yorio Hinuma

1981-01-01

66

Separation of Notch1 Promoted Lineage Commitment and Expansion/Transformation in Developing T Cells  

PubMed Central

Notch1 signaling is required for T cell development. We have previously demonstrated that expression of a dominant active Notch1 (ICN1) transgene in hematopoietic stem cells (HSCs) leads to thymic-independent development of CD4+CD8+ double-positive (DP) T cells in the bone marrow (BM). To understand the function of Notch1 in early stages of T cell development, we assessed the ability of ICN1 to induce extrathymic T lineage commitment in BM progenitors from mice that varied in their capacity to form a functional pre-T cell receptor (TCR). Whereas mice repopulated with ICN1 transduced HSCs from either recombinase deficient (Rag-2?/?) or Src homology 2 domain–containing leukocyte protein of 76 kD (SLP-76)?/? mice failed to develop DP BM cells, recipients of ICN1-transduced Rag-2?/? progenitors contained two novel BM cell populations indicative of pre-DP T cell development. These novel BM populations are characterized by their expression of CD3? and pre-T? mRNA and the surface proteins CD44 and CD25. In contrast, complementation of Rag-2?/? mice with a TCR? transgene restored ICN1-induced DP development in the BM within 3 wk after BM transfer (BMT). At later time points, this population selectively and consistently gave rise to T cell leukemia. These findings demonstrate that Notch signaling directs T lineage commitment from multipotent progenitor cells; however, both expansion and leukemic transformation of this population are dependent on T cell–specific signals associated with development of DP thymocytes. PMID:11435476

Allman, David; Karnell, Fredrick G.; Punt, Jennifer A.; Bakkour, Sonia; Xu, Lanwei; Myung, Peggy; Koretzky, Gary A.; Pui, John C.; Aster, Jon C.; Pear, Warren S.

2001-01-01

67

Notch Signaling in T-Cell Development and T-ALL  

PubMed Central

The Notch signaling pathway is an evolutionarily conserved cell signaling system present in most multicellular organisms, as it controls cell fate specification by regulating cell proliferation, differentiation, apoptosis, and survival. Regulation of the Notch signaling pathway can be achieved at multiple levels. Notch proteins are involved in lineage fate decisions in a variety of tissues in various species. Notch is essential for T lineage cell differentiation including T versus B and ?? versus ?? lineage specification. In this paper, we discuss Notch signaling in normal T-cell maturation and differentiation as well as in T-cell acute lymphoblastic lymphoma/leukemia. PMID:22111016

Li, Xiaoyu; von Boehmer, Harald

2011-01-01

68

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

PubMed Central

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

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

2013-01-01

69

From the cradle to the grave: activities of GATA-3 throughout T cell development and differentiation  

PubMed Central

Summary GATA family transcription factors play multiple vital roles in hematopoiesis in many cell lineages, and in particular, T cells require GATA-3 for execution of several developmental steps. Transcriptional activation of the Gata3 gene is observed throughout T-cell development and differentiation in stage-specific fashion. GATA-3 has been described as a master regulator of T-helper 2 (Th2) cell differentiation in mature CD4+ T cells. During T-cell development in the thymus, its roles in the CD4 vs. CD8 lineage choice and at the ?-selection checkpoint are the best characterized. In contrast, its importance prior to ?-selection has been obscured both by the developmental heterogeneity of double negative (DN) 1 thymocytes and the paucity of early T-lineage progenitors (ETPs), a subpopulation of DN1 cells that contains the most immature thymic progenitors that retain potent T-lineage developmental potential. By examining multiple lines of in vivo evidence procured through the analysis of Gata3 mutant mice, we have recently demonstrated that GATA-3 is additionally required at the earliest stage of thymopoiesis for the development of the ETP population. Here, we review the characterized functions of GATA-3 at each stage of T-cell development and discuss hypothetical molecular pathways that mediate these functions. PMID:20969588

Hosoya, Tomonori; Maillard, Ivan; Engel, James Douglas

2010-01-01

70

Kinetics of T-cell receptor-dependent antigen recognition determined in vivo by multi-spectral normalized epifluorescence laser scanning  

NASA Astrophysics Data System (ADS)

Detection of multiple fluorophores in conditions of low signal represents a limiting factor for the application of in vivo optical imaging techniques in immunology where fluorescent labels report for different functional characteristics. A noninvasive in vivo Multi-Spectral Normalized Epifluorescence Laser scanning (M-SNELS) method was developed for the simultaneous and quantitative detection of multiple fluorophores in low signal to noise ratios and used to follow T-cell activation and clonal expansion. Colocalized DsRed- and GFP-labeled T cells were followed in tandem during the mounting of an immune response. Spectral unmixing was used to distinguish the overlapping fluorescent emissions representative of the two distinct cell populations and longitudinal data reported the discrete pattern of antigen-driven proliferation. Retrieved values were validated both in vitro and in vivo with flow cytometry and significant correlation between all methodologies was achieved. Noninvasive M-SNELS successfully quantified two colocalized fluorescent populations and provides a valid alternative imaging approach to traditional invasive methods for detecting T cell dynamics.

Favicchio, Rosy; Zacharakis, Giannis; Oikonomaki, Katerina; Zacharopoulos, Athanasios; Mamalaki, Clio; Ripoll, Jorge

2012-07-01

71

Clinical Outcome of HIV Viraemic Controllers and Noncontrollers with Normal CD4 Counts Is Exclusively Determined by Antigen-Specific CD8+ T-Cell-Mediated HIV Suppression  

PubMed Central

In this cross-sectional study we evaluated T-cell responses using several assays to determine immune correlates of HIV control that distinguish untreated viraemic controllers (VC) from noncontrollers (NC) with similar CD4 counts. Samples were taken from 65 ART-naïve chronically HIV-infected VC and NC from Thailand with matching CD4 counts in the normal range (>450 cells/?l). We determined HIVp24-specific T-cell responses using standard Interferon-gamma (IFN?) ELISpot assays, and compared the functional quality of HIVp24-specific CD8+ T-cell responses using polychromatic flow cytometry. Finally, in vitro HIV suppression assays were performed to evaluate directly the activity of CD8+ T cells in HIV control. Autologous CD4+ T cells were infected with primary patient-derived HIV isolates and the HIV suppressive activity of CD8+ T cells was determined after co-culture, measuring production of HIVp24 Ag by ELISA. The HIVp24-specific T-cell responses of VC and NC could not completely be differentiated through measurement of IFN?-producing cells using ELISpot assays, nor by the absolute cell numbers of polyfunctional HIVp24-specific CD8+ T cells. However, in vitro HIV suppression assays showed clear differences between VC and NC. HIV suppressive activity, mediated by either ex vivo unstimulated CD8+ T cells or HIVp24-specific T-cell lines, was significantly greater using cells from VC than NC cells. Additionally, we were able to demonstrate a significant correlation between the level of HIV suppressive activity mediated by ex vivo unstimulated CD8+ T cells and plasma viral load (pVL) (Spearman r = -0.7345, p = 0.0003). This study provides evidence that in vitro HIV suppression assays are the most informative in the functional evaluation of CD8+ T-cell responses and can distinguish between VC and NC. PMID:25764310

Tansiri, Yada; Rowland-Jones, Sarah L.; Ananworanich, Jintanat; Hansasuta, Pokrath

2015-01-01

72

Stat5 synergizes with T cell receptor/antigen stimulation in the development of lymphoblastic lymphoma.  

PubMed

Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lymphoma induction was markedly enhanced by immunization or by the introduction of TCR transgenes. Remarkably, the Stat5 transgene potently induced development of CD8+ T cells, even in mice expressing a class II-restricted TCR transgene, with resulting CD8+ T cell lymphomas. These data demonstrate the oncogenic potential of dysregulated expression of a STAT protein that is not constitutively activated, and that TCR stimulation can contribute to this process. PMID:12835478

Kelly, John A; Spolski, Rosanne; Kovanen, Panu E; Suzuki, Takeshi; Bollenbacher, Julie; Pise-Masison, Cynthia A; Radonovich, Michael F; Lee, Stephen; Jenkins, Nancy A; Copeland, Neal G; Morse, Herbert C; Leonard, Warren J

2003-07-01

73

Development of Suppressor T-Cells in Mycobacterium habana-Infected Mice  

PubMed Central

Mice were infected intravenously with increasing numbers of Mycobacterium habana (simiae serotype II), and the levels of delayed-type hypersensitivity to purified protein derivative and M. habana cytoplasmic protein antigen were determined after 14, 30, and 90 days. A footpad delayed-type hypersensitivity response was seen in 14-day-infected mice and was followed by a persisting anergy. T-cell-enriched suspensions collected 30 and 90 days into the infection (anergic donors) showed depressed transformation indexes after phytohemagglutinin and M. habana cytoplasmic protein antigen treatment in vitro. The corresponding B-cell mitogen (lipopolysaccharide) responses were not affected. Mixing experiments with T-cell-enriched suspensions from day-90 M. habana-infected donors adoptively suppressed lymphocyte transformation by normal and day-14 spleen cells. This effect could be ablated by anti-theta serum and complement treatment of the day-90 cells, indicating that the lack of in vitro responsiveness to cytoplasmic protein antigen was mediated by a population of suppressor T-cells present in the heavily infected spleens. There was no evidence that similar cells were present in the spleens of the 14-day-infected animals. Suppressor T-cells could be induced in vitro by exposure of day-14 spleen cells to concanavalin A or M. habana cytoplasmic protein antigen before they were mixed with normal or day-14 indicator splenic lymphocytes. The timing of the appearance of suppressor T-cells in the infected spleens corresponded to a loss of footpad hypersensitivity by the M. habana-infected animals. PMID:158568

Watson, Susan R.; Collins, Frank M.

1979-01-01

74

Bioinformatic Description of Immunotherapy Targets for Pediatric T-Cell Leukemia and the Impact of Normal Gene Sets Used for Comparison  

PubMed Central

Pediatric lymphoid leukemia has the highest cure rate of all pediatric malignancies, yet due to its prevalence, still accounts for the majority of childhood cancer deaths and requires long-term highly toxic therapy. The ability to target B-cell ALL with immunoglobulin-like binders, whether anti-CD22 antibody or anti-CD19 CAR-Ts, has impacted treatment options for some patients. The development of new ways to target B-cell antigens continues at rapid pace. T-cell ALL accounts for up to 20% of childhood leukemia but has yet to see a set of high-value immunotherapeutic targets identified. To find new targets for T-ALL immunotherapy, we employed a bioinformatic comparison to broad normal tissue arrays, hematopoietic stem cells (HSC), and mature lymphocytes, then filtered the results for transcripts encoding plasma membrane proteins. T-ALL bears a core T-cell signature and transcripts encoding TCR/CD3 components and canonical markers of T-cell development predominate, especially when comparison was made to normal tissue or HSC. However, when comparison to mature lymphocytes was also undertaken, we identified two antigens that may drive, or be associated with leukemogenesis; TALLA-1 and hedgehog interacting protein. In addition, TCR subfamilies, CD1, activation and adhesion markers, membrane-organizing molecules, and receptors linked to metabolism and inflammation were also identified. Of these, only CD52, CD37, and CD98 are currently being targeted clinically. This work provides a set of targets to be considered for future development of immunotherapies for T-ALL. PMID:24959420

Orentas, Rimas J.; Nordlund, Jessica; He, Jianbin; Sindiri, Sivasish; Mackall, Crystal; Fry, Terry J.; Khan, Javed

2014-01-01

75

Nuclear factor of activated T cells in cancer development and treatment.  

PubMed

Since nuclear factor of activated T cells (NFAT) was first identified as a transcription factor in T cells, various NFAT isoforms have been discovered and investigated. Accumulating studies have suggested that NFATs are involved in many aspects of cancer, including carcinogenesis, cancer cell proliferation, metastasis, drug resistance and tumor microenvironment. Different NFAT isoforms have distinct functions in different cancers. The exact function of NFAT in cancer or the tumor microenvironment is context dependent. In this review, we summarize our current knowledge of NFAT regulation and function in cancer development and treatment. NFATs have emerged as a potential target for cancer prevention and therapy. PMID:25766658

Shou, Jiawei; Jing, Jing; Xie, Jiansheng; You, Liangkun; Jing, Zhao; Yao, Junlin; Han, Weidong; Pan, Hongming

2015-06-01

76

Impaired chemokine-induced migration during T-cell development in the absence of Jak 3.  

PubMed

The arrival of bone marrow T-cell progenitors to the thymus, and the directed migration of thymocytes, are thought to be regulated by the expression of chemokines and their receptors. Recent data has shown that the Jak/Stat signalling pathway is involved in chemokine receptor signalling. We have investigated the role of Jak 3 in chemokine-mediated signalling in the thymus using Jak 3(-/-) mice. These mice show defects in T-cell development, as well as in peripheral T-cell function, resulting in a hypoplastic thymus and an altered T-cell homeostasis. Here we demonstrate, for the first time, that bone marrow progenitors and thymocytes from Jak 3(-/-) mice have decreased chemotactic responses to CXCL12 and CCL25. We also show that Jak 3 is involved in signalling through CCR9 and CXCR4, and that specific inhibition of Jak 3 in wild-type progenitors and thymocytes decreases their chemotactic responses towards CCL25 and CXCL12. Finally, quantitative reverse transcription-polymerase chain reaction analysis showed that thymocytes from Jak 3(-/-) mice express similar levels of CXCR4 and CCR9 compared to wild-type mice. Altogether, deficient CCL25- and CXCL12-induced migration could result in a homing defect of T-cell progenitors to the thymus, as well as in a deficient thymocyte migration through the thymic stroma. Our results strongly suggest that the absence of Jak 3 affects T-cell development, not only through an impaired interleukin-7 receptor (IL-7R)-mediated signalling, but also through impaired chemokine-mediated responses, which are crucial for thymocyte migration and differentiation. PMID:15147562

Soldevila, Gloria; Licona, Ileana; Salgado, Alfonso; Ramírez, Marcela; Chávez, Ramsés; García-Zepeda, Eduardo

2004-06-01

77

Stat5 Synergizes with T Cell Receptor\\/Antigen Stimulation in the Development of Lymphoblastic Lymphoma  

Microsoft Academic Search

Signal transducer and activator of transcription (STAT) proteins are latent transcription factors that mediate a wide range of actions induced by cytokines, interferons, and growth factors. We now report the development of thymic T cell lymphoblastic lymphomas in transgenic mice in which Stat5a or Stat5b is overexpressed within the lymphoid compartment. The rate of lym- phoma induction was markedly enhanced

John A. Kelly; Rosanne Spolski; Panu E. Kovanen; Takeshi Suzuki; Julie Bollenbacher; Cynthia A. Pise-Masison; Michael F. Radonovich; Stephen Lee; Nancy A. Jenkins; Neal G. Copeland; Herbert C. Morse III; Warren J. Leonard

78

Orchestration of invariant natural killer T cell development by e and id proteins.  

PubMed

Natural killer T (NKT) cells are ?? T cells that express a semi-invariant T-cell receptor (TCR) along with natural killer (NK) cell markers and have an innate cell-like ability to produce a myriad of cytokines very quickly upon antigen exposure and subsequent activation. These cells are diverted from conventional single positive (SP) T-cell fate at the double positive (DP) stage, where TCR-mediated recognition of a lipid antigen presented on a CD1d molecule promotes their selection into the NKT lineage. Although many key regulatory molecules have been shown to play important roles in the development of NKT cells, the mechanism of lineage specification and acquisition of effector functions in these cells still remain to be fully addressed. In this review, we specifically discuss the role of a family of class-I helix-loop-helix proteins known as E proteins, and their antagonists Id proteins in NKT celldevelopment. Recent work has shown that these proteins play key roles in invariant NKT (iNKT) development, from the invariant TCR rearrangement to terminal differentiation and maturation. Elucidating these roles provides an opportunity to uncover the transcriptional network that separates NKT cells from concurrently developed conventional ?? T cells. PMID:25746046

Roy, Sumedha; Zhuang, Yuan

2015-01-01

79

Notch and T cell malignancy.  

PubMed

Notch signaling is required for normal T cell development. However, Notch expression must be precisely regulated as constitutive Notch signaling leads to T cell lymphomas. Recent evidence has provided insights into potential mechanisms of Notch-mediated lymphomagenesis and its relationship to T cell development. The evidence suggests that Notch likely interacts with several important cellular pathways and can cooperate with other oncogenes during lymphomagenesis. In particular, Notch appears to modulate pre-TCR signaling, inhibit the E2A pathway, and in murine leukemia models, frequently cooperates with Myc, E2A-PBX and dominant negative Ikaros dysregulation. This review will present current knowledge in these areas and explore theories on Notch-mediated T cell lymphomagenesis. PMID:15288258

Zweidler-McKay, Patrick A; Pear, Warren S

2004-10-01

80

268. CD19-Targeted Normal and CLL Patient T Cells Expanded with Beads Can Eradicate Systemic Tumors In Vivo  

Microsoft Academic Search

In order to conduct a clinical trial of adoptive therapy with genetically modified T cells in patients with CLL, we are investigating the feasibility of ex vivo T cell transduction and expansion using Xcyte™ Dynabeads® to generate sufficient numbers of biologically active tumor-reactive T cells. T cells are genetically modified to express 19-28z chimeric antigen receptor (CAR). The 19-28z CAR

J. Stefanski; R. Brentjens; D. Hollyman; M. Bonyhadi; M. Sadelain; I. Rivière

2006-01-01

81

The influence of T cell development on pathogen specificity and autoreactivity  

E-print Network

T cells orchestrate adaptive immune responses upon activation. T cell activation requires sufficiently strong binding of T cell receptors on their surface to short peptides derived from foreign proteins bound to protein ...

Kosmrlj, Andrej

82

Interleukin-4 Regulates Eomesodermin in CD8+ T Cell Development and Differentiation  

PubMed Central

Interleukin (IL)-4 is a cytokine classically associated with CD4+ T helper type 2 differentiation, but has been recently shown to also be required for the development of CD8+ innate-like lymphocytes. CD8+ innate-like lymphocytes are non-conventional lymphocytes that exhibit characteristics typically associated with memory CD8+ T cells, including expression of the T-box transcription factor Eomesodermin (Eomes). Here we investigate the signaling pathways required for IL-4 induction of Eomes and CD8+ innate-like lymphocyte markers in murine CD8SP thymocytes and peripheral CD8+ T cells. We demonstrate that IL-4 is sufficient to drive Eomes expression and the CD8+ innate-like lymphocyte phenotype through cooperation between STAT6- and Akt-dependent pathways. Furthermore, we show that while IL-4 has little effect on the induction of Eomes in the setting of robust T cell receptor (TCR) activation, this cytokine promotes Eomes in the setting of attenuated TCR stimulation in mature CD8+ T cells suggesting that cytokine signaling pathways may direct cell fate when TCR signals are limiting. PMID:25207963

Carty, Shannon A.; Koretzky, Gary A.; Jordan, Martha S.

2014-01-01

83

Regulation of the transcriptional program by DNA methylation during human ?? T-cell development  

PubMed Central

Thymocyte differentiation is a complex process involving well-defined sequential developmental stages that ultimately result in the generation of mature T-cells. In this study, we analyzed DNA methylation and gene expression profiles at successive human thymus developmental stages. Gain and loss of methylation occurred during thymocyte differentiation, but DNA demethylation was much more frequent than de novo methylation and more strongly correlated with gene expression. These changes took place in CpG-poor regions and were closely associated with T-cell differentiation and TCR function. Up to 88 genes that encode transcriptional regulators, some of whose functions in T-cell development are as yet unknown, were differentially methylated during differentiation. Interestingly, no reversion of accumulated DNA methylation changes was observed as differentiation progressed, except in a very small subset of key genes (RAG1, RAG2, CD8A, PTCRA, etc.), indicating that methylation changes are mostly unique and irreversible events. Our study explores the contribution of DNA methylation to T-cell lymphopoiesis and provides a fine-scale map of differentially methylated regions associated with gene expression changes. These can lay the molecular foundations for a better interpretation of the regulatory networks driving human thymopoiesis. PMID:25539926

Rodriguez, Ramon M.; Suarez-Alvarez, Beatriz; Mosén-Ansorena, David; García-Peydró, Marina; Fuentes, Patricia; García-León, María J.; Gonzalez-Lahera, Aintzane; Macias-Camara, Nuria; Toribio, María L.; Aransay, Ana M.; Lopez-Larrea, Carlos

2015-01-01

84

Design and development of therapies using chimeric antigen receptor-expressing T cells.  

PubMed

Investigators developed chimeric antigen receptors (CARs) for expression on T cells more than 25 years ago. When the CAR is derived from an antibody, the resultant cell should combine the desirable targeting features of an antibody (e.g. lack of requirement for major histocompatibility complex recognition, ability to recognize non-protein antigens) with the persistence, trafficking, and effector functions of a T cell. This article describes how the past two decades have seen a crescendo of research which has now begun to translate these potential benefits into effective treatments for patients with cancer. We describe the basic design of CARs, describe how antigenic targets are selected, and the initial clinical experience with CAR-T cells. Our review then describes our own and other investigators' work aimed at improving the function of CARs and reviews the clinical studies in hematological and solid malignancies that are beginning to exploit these approaches. Finally, we show the value of adding additional engineering features to CAR-T cells, irrespective of their target, to render them better suited to function in the tumor environment, and discuss how the safety of these heavily modified cells may be maintained. PMID:24329793

Dotti, Gianpietro; Gottschalk, Stephen; Savoldo, Barbara; Brenner, Malcolm K

2014-01-01

85

T Cell Memory  

Microsoft Academic Search

T cell memory induced by prior infection or vaccination provides enhanced protection against subsequent microbial infections.\\u000a The processes involved in generating and maintaining T cell memory are becoming better understood due to recent technological\\u000a advances in identifying memory T cells and monitoring their behavior and function in vivo. Memory T cells develop in response\\u000a to a progressive set of cues—starting

J. Tan; C. Surh

86

Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development.  

PubMed

Generation of CD8(+) memory T cells requires metabolic reprogramming that is characterized by enhanced mitochondrial fatty-acid oxidation (FAO). However, where the fatty acids (FA) that fuel this process come from remains unclear. While CD8(+) memory T cells engage FAO to a greater extent, we found that they acquired substantially fewer long-chain FA from their external environment than CD8(+) effector T (Teff) cells. Rather than using extracellular FA directly, memory T cells used extracellular glucose to support FAO and oxidative phosphorylation (OXPHOS), suggesting that lipids must be synthesized to generate the substrates needed for FAO. We have demonstrated that memory T cells rely on cell intrinsic expression of the lysosomal hydrolase LAL (lysosomal acid lipase) to mobilize FA for FAO and memory T cell development. Our observations link LAL to metabolic reprogramming in lymphocytes and show that cell intrinsic lipolysis is deterministic for memory T cell fate. PMID:25001241

O'Sullivan, David; van der Windt, Gerritje J W; Huang, Stanley Ching-Cheng; Curtis, Jonathan D; Chang, Chih-Hao; Buck, Michael D; Qiu, Jing; Smith, Amber M; Lam, Wing Y; DiPlato, Lisa M; Hsu, Fong-Fu; Birnbaum, Morris J; Pearce, Edward J; Pearce, Erika L

2014-07-17

87

Abnormal T cell development in CD3-zeta-/- mutant mice and identification of a novel T cell population in the intestine.  

PubMed Central

The T cell antigen receptor (TCR)-associated invariable membrane proteins (CD3-gamma, -delta, -epsilon and -zeta) are critical to the assembly and cell surface expression of the TCR/CD3 complex and to signal transduction upon engagement of TCR with antigen. Disruption of the CD3-zeta gene by homologous recombination resulted in a structurally abnormal thymus which primarily contained CD4- CD8- and TCR/CD3very lowCD4+CD8+ cells. Spleen and lymph nodes of CD3-zeta-/- mutant mice contained a normal number and ratio of CD4+ and CD8+ single positive cells that were TCR/CD3very low. These splenocytes did not respond to antibody cross-linking or mitogenic triggering. The V beta genes of CD4-CD8- and CD4+CD8+ thymocytes and splenic T cells were productively rearranged. These data demonstrated that (i) in the absence of the CD3-zeta chain, the CD4- CD8- thymocytes could differentiate to CD4+CD8+ TCR/CD3very low thymocytes, (ii) that thymic selection might have occurred, (iii) but that the transition to CD4+CD8- and CD4-CD8+ cells took place at a very low rate. Most strikingly, intraepithelial lymphocytes (IELs) isolated from the small intestine or the colon expressed normal levels of TCR/CD3 complexes on their surface which contained Fc epsilon RI gamma homodimers. In contrast to CD3-zeta containing IELs, these cells failed to proliferate after triggering with antibody cross-linking or mitogen. In comparison to thymus-derived peripheral T cells in the spleen and lymph nodes, the preferential expression of normal levels of TCR/CD3 in intestinal IELs suggested they mature via an independent extrathymic pathway. Images PMID:8223495

Liu, C P; Ueda, R; She, J; Sancho, J; Wang, B; Weddell, G; Loring, J; Kurahara, C; Dudley, E C; Hayday, A

1993-01-01

88

T-cell receptor gamma delta-expressing intraepithelial lymphocytes are present in normal and chronically inflamed human gingiva.  

PubMed Central

The phenotypic profile of leucocytes in diseased and normal gingival tissue was studied in situ and in isolated gingival mononuclear cell (GMC) preparations. T-cell receptor (TcR)gamma delta + cells showed preferential localization to epithelium, both in normal and inflamed gingiva, and were present in crevicular as well as oral epithelium. In normal gingiva > or = 30% of the isolated leucocytes expressed TcR gamma delta, of which the majority were CD4- CD8-, and expressed CD45RA. The proportion of TcR gamma delta + cells in GMC from periodontitis tissue varied between 2 and 32%. In contrast to normal gingiva the majority of TcR gamma delta + cells in diseased tissue were CD8+ and expressed CD45RO. Thus expression of the CD8 antigen on gingival TcR gamma delta + cells is probably a consequence of immune activation. Numerous Langerhans' cells and keratinocytes expressing the major histocompatibility complex (MHC) class I-like antigen, CD1, were present within normal and inflamed gingival epithelium in close proximity to the TcR gamma delta + cells. Most CD1a+ cells were scattered within oral epithelium. CD1c+ cells were localized close to the basal layer of crevicular epithelium. No CD1b+ cells were found. TcR alpha beta + cells, CD4+ and B cells were restricted to lamina propria of periodontitis lesions. The presence of intraepithelial TcR gamma delta + cells in normal gingiva suggests that they constitute the 'first line of defence' against the potentially harmful microflora in the oral cavity. Induction of CD8 and CD45RO antigens on TcR gamma delta + cells in periodontitis tissue indicate that they play a significant role in the disease. CD1 molecules on Langerhans' cells and keratinocytes may be the restriction elements for the CD8+ TcR gamma delta + cells. Images Figure 1 Figure 2 Figure 3 PMID:7685315

Lundqvist, C; Hammarström, M L

1993-01-01

89

Ectopic retroviral expression of LMO2, but not IL2Rgamma, blocks human T-cell development from CD34+ cells: implications for leukemogenesis in gene therapy.  

PubMed

The occurrence of leukemia in a gene therapy trial for SCID-X1 has highlighted insertional mutagenesis as an adverse effect. Although retroviral integration near the T-cell acute lymphoblastic leukemia (T-ALL) oncogene LIM-only protein 2 (LMO2) appears to be a common event, it is unclear why LMO2 was preferentially targeted. We show that of classical T-ALL oncogenes, LMO2 is most highly transcribed in CD34+ progenitor cells. Upon stimulation with growth factors typically used in gene therapy protocols transcription of LMO2, LYL1, TAL1 and TAN1 is most prominent. Therefore, these oncogenes may be susceptible to viral integration. The interleukin-2 receptor gamma chain (IL2Rgamma), which is mutated in SCID-X1, has been proposed as a cooperating oncogene to LMO2. However, we found that overexpressing IL2Rgamma had no effect on T-cell development. In contrast, retroviral overexpression of LMO2 in CD34+ cells caused severe abnormalities in T-cell development, but B-cell and myeloid development remained unaffected. Our data help explain why LMO2 was preferentially targeted over many of the other known T-ALL oncogenes. Furthermore, during T-cell development retrovirus-mediated expression of IL2Rgamma may not be directly oncogenic. Instead, restoration of normal IL7-receptor signaling may allow progression of T-cell development to stages where ectopic LMO2 expression causes aberrant thymocyte growth. PMID:17268520

Pike-Overzet, K; de Ridder, D; Weerkamp, F; Baert, M R M; Verstegen, M M A; Brugman, M H; Howe, S J; Reinders, M J T; Thrasher, A J; Wagemaker, G; van Dongen, J J M; Staal, F J T

2007-04-01

90

Requirement of monocytes and T-helper cells during development of tumor cell cytotoxicity in targeted T cells.  

PubMed

In cocultures of human placental alkaline phosphatase(PLAP)-positive MO4 tumor cells and human peripheral blood mononuclear cells (PBMC), also containing a heteroconjugate (7E8-OKT3) synthesized between the anti-PLAP monoclonal antibody 7E8 and the anti-CD3 antibody OKT3, and supplemented with low levels of recombinant interleukin-2 (rIL-2), T cells are progressively activated, resulting in tumor cell lysis. To unravel the contribution of PBMC subsets to the generation of this targetable cytotoxicity, PBMC subsets were studied after their isolation by cell sorting, either from fresh PBMC or from PBMC pre-activated with OKT3 and rIL-2. Whereas no targetable cytotoxicity was found in Fc-receptor-bearing CD3- cells, tumor cells were lysed by CD3+ T cells (mostly CD8+) isolated from pre-activated PBMC. When isolated from fresh PBMC, neither the CD8+ T cell subset, nor the total CD3+ T cell population developed significant targetable cytotoxicity, even in the presence of rIL-2. Thus, additional cell types are essential for the CD8+ T cell activation. Indeed, CD4+ T cells isolated from pre-activated but not from fresh PBMC were capable of eliciting cytotoxicity in fresh CD8+ T cells. The non-targeted monocytes were found to be the activators of the CD4+ T cells. In summary, targeting T cells to the surface of a tumor cell is not sufficient per se to achieve activation and lysis. The progressive tumor cell lysis by targeted T cells seems to be initiated by non-targeted monocytes activating CD4+ T cells, these cells in turn promoting CD8+ T cell activation, necessary for the development of cytotoxicity. PMID:8299118

Smans, K A; Hoylaerts, M F; De Broe, M E

1994-01-01

91

Models of Self-Peptide Sampling by Developing T Cells Identify Candidate Mechanisms of Thymic Selection  

PubMed Central

Conventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for cells within a range of responsiveness that allows the detection of foreign antigen without excessive responses to self. Regulatory T cells are thought to lie at the higher end of the spectrum of acceptable self-reactivity and play a crucial role in the control of autoimmunity and tolerance to innocuous antigens. While many studies have elucidated key elements influencing lineage commitment, we still lack a full understanding of how thymocytes integrate signals obtained by sampling self-peptides to make fate decisions. To address this problem, we apply stochastic models of signal integration by T cells to data from a study quantifying the development of the two lineages using controllable levels of agonist peptide in the thymus. We find two models are able to explain the observations; one in which T cells continually re-assess fate decisions on the basis of multiple summed proximal signals from TCR-pMHC interactions; and another in which TCR sensitivity is modulated over time, such that contact with the same pMHC ligand may lead to divergent outcomes at different stages of development. Neither model requires that T and T are differentially susceptible to deletion or that the two lineages need qualitatively different signals for development, as have been proposed. We find additional support for the variable-sensitivity model, which is able to explain apparently paradoxical observations regarding the effect of partial and strong agonists on T and T development. PMID:23935465

Bains, Iren; van Santen, Hisse M.; Seddon, Benedict; Yates, Andrew J.

2013-01-01

92

TCR Affinity for Self-Ligands Influences the Development and Function of Encephalitogenic T Cells  

PubMed Central

The specificity and affinity of self-reactive T cells is likely to impact the development of autoimmune-disease causing T cells in the thymus as well as their function in the periphery. We identified a naturally occurring, low affinity variant of an MBP Ac1-11/I-Au specific TCR that is known to induce EAE. Thymocytes in mice carrying the transgenes for this low affinity TCR were poorly positively selected, as compared to their high affinity TCR expressing counterparts. Nonetheless, CD4 T cells bearing the low affinity TCR accumulated in the periphery of the mice. Unlike mice expressing the high affinity TCR, these mice very rarely developed disease. However, if endogenous TCR expression was eliminated by breeding to RAG1 deficient mice, 100% of the mice carrying either the high or the low affinity versions of the TCR developed EAE. Intriguingly, while the incidence of EAE increased, the age of onset of disease in both mice was identical. These data suggest disease onset occurs during a short window of mouse development. PMID:21437282

Sant'Angelo, Derek B.

2011-01-01

93

Intrathymic IL-7: The where, when, and why of IL-7 signaling during T cell development  

PubMed Central

The thymus is the birthplace of all T lineage cells. But the thymus is also a cradle as it provides the environment for further maturation and differentiation of immature thymocytes. While many factors contribute to make the thymus a unique place for T cell development, here we review the essential role of intrathymic interleukin-7 (IL-7). In the absence of IL-7 signaling, survival, proliferation and differentiation of immature thymocytes are all severely impaired. Consequently, IL-7 is critical to nurture and guide T precursor cells through the diverse steps of thymic maturation. Interestingly, even as IL-7 signaling is such a critical factor, IL-7 signaling must be also actively suppressed during specific stages of T cell differentiation. These contradictory observations are puzzling but can be satisfactorily explained when understanding the developmental context of IL-7 signaling. In this regard, here we will discuss the spatiotemporal expression of intrathymic IL-7 and address the stage-specific effects of IL-7 signaling in developing thymocytes. Specifically, we will review other facets of intrathymic IL-7 beyond its role as a pro-survival factor and so clarify and reaffirm the unique role of IL-7 as a prime factor in T cell development and differentiation. PMID:22421571

Hong, Changwan; Luckey, Megan; Park, Jung-Hyun

2012-01-01

94

Heme Exporter FLVCR Is Required for T Cell Development and Peripheral Survival.  

PubMed

All aerobic cells and organisms must synthesize heme from the amino acid glycine and the tricarboxylic acid cycle intermediate succinyl CoA for incorporation into hemoproteins, such as the cytochromes needed for oxidative phosphorylation. Most studies on heme regulation have been done in erythroid cells or hepatocytes; however, much less is known about heme metabolism in other cell types. The feline leukemia virus subgroup C receptor (FLVCR) is a 12-transmembrane domain surface protein that exports heme from cells, and it was shown to be required for erythroid development. In this article, we show that deletion of Flvcr in murine hematopoietic precursors caused a complete block in ?? T cell development at the CD4(+)CD8(+) double-positive stage, although other lymphoid lineages were not affected. Moreover, FLVCR was required for the proliferation and survival of peripheral CD4(+) and CD8(+) T cells. These studies identify a novel and unexpected role for FLVCR, a major facilitator superfamily metabolite transporter, in T cell development and suggest that heme metabolism is particularly important in the T lineage. PMID:25582857

Philip, Mary; Funkhouser, Scott A; Chiu, Edison Y; Phelps, Susan R; Delrow, Jeffrey J; Cox, James; Fink, Pamela J; Abkowitz, Janis L

2015-02-15

95

Characterization of human interleukin 2 receptor (Tac antigen) in normal and leukemic T cells: co-expression of normal and aberrant receptors on Hut-102 cells.  

PubMed

Human interleukin 2 receptors ( IL2R ) from various cell sources such as mitogen-activated normal human T cells, adult T cell leukemia (ATL)-derived cell line cells (MT-1, ATL-6, Hut-102), and a natural killer-like cell line YT cells, were studied both by one- and two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), with a monoclonal anti- IL2R antibody (anti-Tac). In synthetic labeling with [35S]methionine, anti-Tac specifically precipitated two glycoproteins, one with m.w. of 60,000 to 65,000 and pI 4.2 to 4.7, and the other with m.w. about 40,000 and pI 6.2 to 6.5. A study of surface iodination revealed that the former component was membrane-associated mature IL2R , and a pulse-chase study showed that the latter component was a precursor for IL2R that already possessed tunicamycin-sensitive N-linked sugar side chain(s). This precursor was found to be posttranslationally processed into mature IL2R by further glycosylation within 240 min. Among the cells studied, a human T cell leukemia virus-positive leukemic cell line, Hut-102, was distinctive in that it possessed an additional membrane glycoprotein (m.w. 55,000 to 60,000, pI 4.2 to 5.0) also defined by anti-Tac. This unique glycoprotein of Hut-102 cells appeared to be an aberrant IL2R . PMID:6327813

Wano, Y; Uchiyama, T; Fukui, K; Maeda, M; Uchino, H; Yodoi, J

1984-06-01

96

78 FR 69429 - Prospective Grant of Exclusive License: The Development of Modified T-cells for the Treatment of...  

Federal Register 2010, 2011, 2012, 2013, 2014

...License: The Development of Modified T-cells for the Treatment of Multiple Myeloma AGENCY...Chimeric Antigen Receptors Targeting B-cell Maturation Antigen'' [HHS Ref. E-040-2012...receptor (CAR)-expressing human T-cells directed against B-cell Maturation...

2013-11-19

97

New Insights into the Roles of Stat5a/b and Stat3 in T Cell Development and Differentiation  

PubMed Central

T cell development and differentiation is carefully orchestrated by a series of cytokines. The importance of STAT family proteins in mediating signals by these cytokines is well-known, but new information on the role of STATs in novel aspects of T cell function and new T cell subsets continues to accumulate. Recent studies have placed Stat5a/b and Stat3 center stage in T cell development and differentiation. Stat5a/b are indispensable in T regulatory (Treg) cell development and maintenance, and negatively regulate T helper 17 (Th17) cell differentiation. Conversely, Stat3 is essential for Th17 differentiation and inhibits Treg cells. The balance of Treg and Th17 cells is thought to be critical in maintaining immune tolerance, while preserving effective host defense. Therefore, Stat5a/b and Stat3 are emerging to be key players in T cell differentiation and homeostasis. PMID:18708155

Wei, Lai; Laurence, Arian; O'Shea, John J.

2009-01-01

98

The Nuclear Receptor Nr4a1 Controls CD8 T Cell Development Through Transcriptional Suppression of Runx3  

PubMed Central

The NR4A nuclear receptor family member Nr4a1 is strongly induced in thymocytes undergoing selection, and has been shown to control the development of Treg cells; however the role of Nr4a1 in CD8+ T cells remains undefined. Here we report a novel role for Nr4a1 in regulating the development and frequency of CD8+ T cells through direct transcriptional control of Runx3. We discovered that Nr4a1 recruits the corepressor, CoREST to suppress Runx3 expression in CD8+ T cells. Loss of Nr4a1 results in increased Runx3 expression in thymocytes which consequently causes a 2-fold increase in the frequency and total number of intrathymic and peripheral CD8+ T cells. Our findings establish Nr4a1 as a novel and critical player in the regulation of CD8 T cell development through the direct suppression of Runx3. PMID:25762306

Nowyhed, Heba N.; Huynh, Tridu R.; Blatchley, Amy; Wu, Runpei; Thomas, Graham D.; Hedrick, Catherine C.

2015-01-01

99

Day/night changes of thymus-deriving natural regulatory T cell development and function.  

PubMed

Activity of the immune system shows day/night rhythmicity. Changes in the migration and biological activities of immune cells are strongly regulated by the HPA axis. Another mechanism governing the level of the immune response is based on the suppressive activity of natural regulatory T cells CD4+CD25+Foxp3+ (nTregs) which play a crucial role in the maintenance of self-tolerance and immune homeostasis. The aim of our study was to answer the question: are nTregs changing their development and suppressive activity according to day/night cycle? We demonstrated the effect of day time on nTreg distribution in the thymus and their suppressive potential to inhibit the proliferation of activated responder T cells. PMID:25052584

Kiernozek, Ewelina; Kowalik, Anna; Markowska, Magdalena; Kozlowska, Ewa; Drela, Nadzieja

2014-09-15

100

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development  

PubMed Central

The quest for a prophylactic AIDS vaccine is ongoing, but it is now clear that the successful vaccine must elicit protective antibody responses. Accordingly, intense efforts are underway to identify immunogens that elicit these responses. Regardless of the mechanism of antibody-mediated protection, be it neutralization, Fc-mediated effector function, or both, antibody persistence and appropriate T-cell help are significant problems confronting the development of a successful AIDS vaccine. Here, we discuss the evidence illustrating the poor persistence of antibody responses to Env, the envelope glycoprotein of HIV-1, and the related problem of CD4+ T-cell responses that compromise vaccine efficacy by creating excess cellular targets of HIV-1 infection. Finally, we propose solutions to both problems that are applicable to all Env-based AIDS vaccines regardless of the mechanism of antibody-mediated protection. PMID:25349379

Lewis, George K.; DeVico, Anthony L.; Gallo, Robert C.

2014-01-01

101

High numbers of IL2-producing CD8M T cells during viral infection: correlation with stable memory development  

Microsoft Academic Search

Using infections with lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus in mice as model systems, we have investigated the ability of antigen-primed CD8M T cells generated in the context of viral infections to produce IL-2. Our results indicate that acute immunizing infection normally leads to generation of high numbers of IL-2-producing antigen-specific CD8M T cells. By costaining for IL-2

Nanna Ny Kristensen; Jan Pravsgaard Christensen; Allan Randrup Thomsen

102

Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation  

PubMed Central

The discovery of Ten Eleven Translocation proteins, enzymes that oxidize 5-methylcytosine (5mC) in DNA, has revealed novel mechanisms for the regulation of DNA methylation. We have mapped 5-hydroxymethylcytosine (5hmC) at different stages of T-cell development in the thymus and T-cell differentiation in the periphery. We show that 5hmC is enriched in the gene body of highly expressed genes at all developmental stages and that its presence correlates positively with gene expression. Further emphasizing the connection with gene expression, we find that 5hmC is enriched in active thymus-specific enhancers and that genes encoding key transcriptional regulators display high intragenic 5hmC levels in precursor cells at those developmental stages where they exert a positive effect. Our data constitute a valuable resource that will facilitate detailed analysis of the role of 5hmC in T-cell development and differentiation. PMID:25071199

Tsagaratou, Ageliki; Äijö, Tarmo; Lio, Chan-Wang J.; Yue, Xiaojing; Huang, Yun; Jacobsen, Steven E.; Lähdesmäki, Harri; Rao, Anjana

2014-01-01

103

Generation of Functional Thymic Epithelium from Human Embryonic Stem Cells that Supports Host T Cell Development  

PubMed Central

SUMMARY Inducing immune tolerance to prevent rejection is a key step toward successful engraftment of stem-cell-derived tissue in a clinical setting. Using human pluripotent stem cells to generate thymic epithelial cells (TECs) capable of supporting T cell development represents a promising approach to reach this goal; however, progress toward generating functional TECs has been limited. Here, we describe a robust in vitro method to direct differentiation of human embryonic stem cells (hESCs) into thymic epithelial progenitors (TEPs) by precise regulation of TGF?, BMP4, RA, Wnt, Shh, and FGF signaling. The hESC-derived TEPs further mature into functional TECs that support T cell development upon transplantation into thymus-deficient mice. Importantly, the engrafted TEPs produce T cells capable of in vitro proliferation as well as in vivo immune responses. Thus, hESC-derived TEP grafts may have broad applications for enhancing engraftment in cell-based therapies as well as restoring age-and stress-related thymic decline. PMID:23684540

Parent, Audrey V.; Russ, Holger A.; Khan, Imran S.; LaFlam, Taylor N.; Metzger, Todd C.; Anderson, Mark S.; Hebrok, Matthias

2013-01-01

104

Cyclic adenosine 5’-monophosphate response element modulator ? suppresses spleen tyrosine kinase expression in normal but not in SLE T cells  

PubMed Central

Objective T cells from patients with systemic lupus erythematosus (SLE) display increased amounts of spleen tyrosine kinase (SYK) which is involved in the aberrant CD3/T cell receptor-mediated signaling process and increased amounts of cAMP response element modulator (CREM) ? which suppresses the production of interleukin-2. Because SYK expression can be suppressed by CREM ? we asked why CREM ? fails to suppress SYK expression in SLE T cells. Methods Healthy T cells were overexpressed with CREM ? expression vector and SYK expression and phosphorylation was measured. A newly identified CRE site on SYK promoter was characterized by ChIP and EMSA. The CREM ?-mediated repression of SYK expression was further evaluated by analyzing SYK promoter activity. T cells from SLE patients and healthy individuals were subjected to ChIP to evaluate the CREM ? binding and histone-H3 acetylation. Results We demonstrate that increased CREM ? level can suppress SYK expression by direct binding on a CRE site of the SYK promoter in T cells from healthy individuals but failed to do so in SLE T cells. We demonstrate that failure of CREM ? to suppress SYK expression in SLE T cells is due to weaker binding to the CRE site of the SYK promoter compared to healthy T cells because the promoter site is hypoacetylatylated and therefore of limited access to transcription factors. Conclusions Epigenetic alteration of the SYK promoter in SLE T cells results in inability of the transcriptional repressor CREM ? to bind and suppress the expression of SYK resulting in aberrant T cell signaling. PMID:21953500

Ghosh, Debjani; Kis-Toth, Katalin; Juang, Yuang-Taung; Tsokos, George C.

2011-01-01

105

Design and Development of Therapies using Chimeric Antigen Receptor-Expressing T cells  

PubMed Central

Summary Investigators developed chimeric antigen receptors (CARs) for expression on T cells more than 25 years ago. When the CAR is derived from an antibody, the resultant cell should combine the desirable targeting features of an antibody (e.g. lack of requirement for major histocompatibility complex recognition, ability to recognize non-protein antigens) with the persistence, trafficking and effector functions of a T-cell. This article describes how the past two decades have seen a crescendo of research which has now begun to translate these potential benefits into effective treatments for patients with cancer. We describe the basic design of CARs, describe how antigenic targets are selected, and the initial clinical experience with CART cells. Our review then describes our own and other investigators’ work aimed at improving the function of CARs and reviews the clinical studies in hematological and solid malignancies that are beginning to exploit these approaches. Finally, we show the value of adding additional engineering features to CAR-T cells, irrespective of their target, to render them better suited to function in the tumor environment, and discuss how the safety of these heavily modified cells may be maintained. PMID:24329793

Dotti, Gianpietro; Gottschalk, Stephen; Savoldo, Barbara; Brenner, Malcolm K

2013-01-01

106

Notch dimerization is required for leukemogenesis and T-cell development.  

PubMed

Notch signaling regulates myriad cellular functions by activating transcription, yet how Notch selectively activates different transcriptional targets is poorly understood. The core Notch transcriptional activation complex can bind DNA as a monomer, but it can also dimerize on DNA-binding sites that are properly oriented and spaced. However, the significance of Notch dimerization is unknown. Here, we show that dimeric Notch transcriptional complexes are required for T-cell maturation and leukemic transformation but are dispensable for T-cell fate specification from a multipotential precursor. The varying requirements for Notch dimerization result from the differential sensitivity of specific Notch target genes. In particular, c-Myc and pre-T-cell antigen receptor ? (Ptcra) are dimerization-dependent targets, whereas Hey1 and CD25 are not. These findings identify functionally important differences in the responsiveness among Notch target genes attributable to the formation of higher-order complexes. Consequently, it may be possible to develop a new class of Notch inhibitors that selectively block outcomes that depend on Notch dimerization (e.g., leukemogenesis). PMID:20935071

Liu, Hudan; Chi, Anthony W S; Arnett, Kelly L; Chiang, Mark Y; Xu, Lanwei; Shestova, Olga; Wang, Hongfang; Li, Yue-Ming; Bhandoola, Avinash; Aster, Jon C; Blacklow, Stephen C; Pear, Warren S

2010-11-01

107

Notch dimerization is required for leukemogenesis and T-cell development  

PubMed Central

Notch signaling regulates myriad cellular functions by activating transcription, yet how Notch selectively activates different transcriptional targets is poorly understood. The core Notch transcriptional activation complex can bind DNA as a monomer, but it can also dimerize on DNA-binding sites that are properly oriented and spaced. However, the significance of Notch dimerization is unknown. Here, we show that dimeric Notch transcriptional complexes are required for T-cell maturation and leukemic transformation but are dispensable for T-cell fate specification from a multipotential precursor. The varying requirements for Notch dimerization result from the differential sensitivity of specific Notch target genes. In particular, c-Myc and pre-T-cell antigen receptor ? (Ptcra) are dimerization-dependent targets, whereas Hey1 and CD25 are not. These findings identify functionally important differences in the responsiveness among Notch target genes attributable to the formation of higher-order complexes. Consequently, it may be possible to develop a new class of Notch inhibitors that selectively block outcomes that depend on Notch dimerization (e.g., leukemogenesis). PMID:20935071

Liu, Hudan; Chi, Anthony W.S.; Arnett, Kelly L.; Chiang, Mark Y.; Xu, Lanwei; Shestova, Olga; Wang, Hongfang; Li, Yue-Ming; Bhandoola, Avinash; Aster, Jon C.; Blacklow, Stephen C.; Pear, Warren S.

2010-01-01

108

Helios-positive functional regulatory T cells are decreased in decidua of miscarriage cases with normal fetal chromosomal content.  

PubMed

Regulatory (Treg) T cells play essential roles in the maintenance of allogeneic pregnancy in mice and humans. Recent data show that Foxp3 expression occurs in both immuno-suppressive Treg and -nonsuppressive effector T (Teff) cells upon activation in humans. Samstein et al. (2012) reported that inducible Treg (iTreg) cells enforce maternal-fetal tolerance in placental mammals. Therefore, we should reanalyze which types of Treg cell play an important role in the maintenance of allogeneic pregnancy. In this study, we studied the frequencies of naïve Treg cells, effector Treg cells, Foxp3(+) Teff cells, Helios(+) naturally occurring Treg (nTreg) cells, and Helios(-) iTreg cells using flow cytometry. The frequencies of effector Treg cells and Foxp3(+) Teff cells among CD4(+)Foxp3(+) cells in the decidua of miscarriage cases with a normal embryo karyotype (n=8) were significantly lower (P=0.0105) and significantly higher (P=0.0258) than those in normally progressing pregnancies (n=11), respectively. However, these frequencies in miscarriages with an abnormal embryo karyotype (n=15) were similar to those in normally progressing pregnancies. The frequencies of these cell populations in the three groups were unchanged in peripheral blood; on the other hand, most of the effector Treg cells in the decidua were Helios(+) nTreg cells and these frequencies were significantly higher than those in peripheral blood, while those among effector Treg and naïve Treg cells in the decidua and peripheral blood were similar among the three groups. These data suggest that decreased Helios(+) effector nTreg might play an important role in the maintenance of pregnancy in humans. PMID:25453751

Inada, Kumiko; Shima, Tomoko; Ito, Mika; Ushijima, Akemi; Saito, Shigeru

2015-02-01

109

Ionizing radiation and autoimmunity: Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells  

SciTech Connect

Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and the peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4[sup +] T cells mediated the autoimmune prevention but CD8[sup +] T cells did not. CD4[sup +] T cells also appeared to mediate the TLI-induced autoimmune disease because CD4[sup +] T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells. 62 refs., 9 figs., 2 tabs.

Sakaguchi, N.; Sakaguchi, S. (Stanford Univ. School of Medicine, CA (United States) Scripps Research Institute, La Jolla, CA (United States) PRESTO, JRDC, Institute of Phical and Chemical Research, Tsukuba, Ibaraki (Japan)); Miyai, K. (Univ. of California, San Diego, LA Jolla, CA (United States))

1992-11-01

110

Development of leukemia in mice transgenic for the tax gene of human T-cell leukemia virus type I.  

PubMed Central

The human T-cell leukemia virus type I Tax protein trans-activates several cellular genes implicated in T-cell replication and activation. To investigate its leukemogenic potential, Tax was targeted to the mature T-lymphocyte compartment in transgenic mice by using the human granzyme B promoter. These mice developed large granular lymphocytic leukemia, demonstrating that expression of Tax in the lymphocyte compartment is sufficient for the development of leukemia. Furthermore, these observations suggest that human T-cell leukemia virus infection may be involved in the development of large granular lymphocytic leukemia. Images Fig. 1 Fig. 2 Fig. 4 PMID:7862633

Grossman, W J; Kimata, J T; Wong, F H; Zutter, M; Ley, T J; Ratner, L

1995-01-01

111

Clonal deletion of self-reactive T cells at the early stage of T cell development in thymus of radiation bone marrow chimeras  

SciTech Connect

Sequential appearance of T cell subpopulations occurs in the thymocytes of irradiated C3H/He mice (H-2k, Mls-1b2a, Thy-1.2) after transplantation with bone marrow cells of AKR/J mice (H-2k, Mls-1a2b, Thy-1.1) (AKR----C3H chimeras). The donor-derived thymocytes of AKR----C3H chimeras on day 14 after bone marrow transplantation (BMT) contained a large number of blastlike CD4+CD8+ cells which represent relatively immature thymocytes, whereas those on day 21 after BMT consisted of small sized CD4+,CD8+ cells which represent a great part in normal thymocytes. To define the developmental stage at which clonal deletion of self-reactive T cells occurs in adult thymus, we followed the fate of V beta 6- or V beta 11-bearing T cells in the donor-derived thymocytes at the early stage of AKR----C3H chimeras. Mature thymocytes expressing high intensity of V beta 6 or V beta 11, which are involved in recognition of Mls-1a or MHC I-E gene products, respectively, were deleted from the donor-derived thymocytes on day 21. Immature thymocytes expressing low intensity of V beta 6 in CD3low thymocyte fraction decreased in proportion, whereas those expressing low intensity of V beta 11 rather increased in proportion in the donor-derived thymocytes of AKR----C3H chimeras from day 14 to day 21 after BMT. These results suggest that the clonal deletion of V beta 6-positive cells occurs just at the stage of immature CD3lowCD4+CD8+ cells, whereas the clonal deletion of V beta 11-positive cells may begin at the transitional stage from CD3lowCD4+CD8+ cells to CD3high single positive cells. Timing of negative selection of thymocytes may vary in distinct T cells capable of recognizing different self-Ag.

Matsuzaki, G.; Yoshikai, Y.; Ogimoto, M.; Kishihara, K.; Nomoto, K. (Kyushu Univ., Fukuoka (Japan))

1990-07-01

112

Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5.  

PubMed

The loss of Gimap5 (GTPase of the immune-associated protein 5) gene function is the underlying cause of lymphopenia and autoimmune diabetes in the BioBreeding (BB) rat. The in vivo function of murine gimap5 is largely unknown. We show that selective gene ablation of the mouse gimap5 gene impairs the final intrathymic maturation of CD8 and CD4 T cells and compromises the survival of postthymic CD4 and CD8 cells, replicating findings in the BB rat model. In addition, gimap5 deficiency imposes a block of natural killer (NK)- and NKT-cell differentiation. Development of NK/NKT cells is restored on transfer of gimap5(-/-) bone marrow into a wild-type environment. Mice lacking gimap5 have a median survival of 15 weeks, exhibit chronic hepatic hematopoiesis, and in later stages show pronounced hepatocyte apoptosis, leading to liver failure. This pathology persists in a Rag2-deficient background in the absence of mature B, T, or NK cells and cannot be adoptively transferred by transplanting gimap5(-/-) bone marrow into wild-type recipients. We conclude that mouse gimap5 is necessary for the survival of peripheral T cells, NK/NKT-cell development, and the maintenance of normal liver function. These functions involve cell-intrinsic as well as cell-extrinsic mechanisms. PMID:18796632

Schulteis, Ryan D; Chu, Haiyan; Dai, Xuezhi; Chen, Yuhong; Edwards, Brandon; Haribhai, Dipica; Williams, Calvin B; Malarkannan, Subramaniam; Hessner, Martin J; Glisic-Milosavljevic, Sanja; Jana, Srikanta; Kerschen, Edward J; Ghosh, Soumitra; Wang, Demin; Kwitek, Anne E; Lernmark, Ake; Gorski, Jack; Weiler, Hartmut

2008-12-15

113

Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5  

PubMed Central

The loss of Gimap5 (GTPase of the immune-associated protein 5) gene function is the underlying cause of lymphopenia and autoimmune diabetes in the BioBreeding (BB) rat. The in vivo function of murine gimap5 is largely unknown. We show that selective gene ablation of the mouse gimap5 gene impairs the final intrathymic maturation of CD8 and CD4 T cells and compromises the survival of postthymic CD4 and CD8 cells, replicating findings in the BB rat model. In addition, gimap5 deficiency imposes a block of natural killer (NK)- and NKT-cell differentiation. Development of NK/NKT cells is restored on transfer of gimap5?/? bone marrow into a wild-type environment. Mice lacking gimap5 have a median survival of 15 weeks, exhibit chronic hepatic hematopoiesis, and in later stages show pronounced hepatocyte apoptosis, leading to liver failure. This pathology persists in a Rag2-deficient background in the absence of mature B, T, or NK cells and cannot be adoptively transferred by transplanting gimap5?/? bone marrow into wild-type recipients. We conclude that mouse gimap5 is necessary for the survival of peripheral T cells, NK/NKT-cell development, and the maintenance of normal liver function. These functions involve cell-intrinsic as well as cell-extrinsic mechanisms. PMID:18796632

Schulteis, Ryan D.; Chu, Haiyan; Dai, Xuezhi; Chen, Yuhong; Edwards, Brandon; Haribhai, Dipica; Williams, Calvin B.; Malarkannan, Subramaniam; Hessner, Martin J.; Glisic-Milosavljevic, Sanja; Jana, Srikanta; Kerschen, Edward J.; Ghosh, Soumitra; Wang, Demin; Kwitek, Anne E.; Lernmark, Ake; Gorski, Jack

2008-01-01

114

Association between regulated upon activation, normal T cells expressed and secreted (RANTES) -28C\\/G polymorphism and asthma risk - A Meta-Analysis  

Microsoft Academic Search

Regulated upon activation, normal T-cell expressed and secreted (RANTES) is one of the most extensively studied C-C chemokines in allergic inflammation. A growing body of evi- dence suggests that many cell types present in asthmatic airways have the capacity to gen- erate RANTES, which directly supported the potential role of RANTES in asthma. A number of studies have evaluated the

Qiaoqiao Fang; Furu Wang; Deyu Zhao

2010-01-01

115

Estradiol and Interleukin1 Exert a Synergistic Stimulatory Effect on the Expression of the Chemokine Regulated upon Activation, Normal T Cell Expressed, and Secreted in Endometriotic Cells  

Microsoft Academic Search

Endometriosis, commonly associated with intraperitoneal in- flammation, is estrogen dependent. Possible links between the immunoinflammatory and endocrine changes observed in endometriotic women have been poorly understood. In this study, we report that estradiol (E2) and IL-1 exert a syner- gistic stimulatory action on RANTES (regulated upon activa- tion, normal T cell expressed, and secreted) expression by endometriotic cells. Treatment of

ALI AKOUM; RODOLPHE MAHEUX

116

The Influence of T Cell Development on Pathogen Specificity and Autoreactivity  

NASA Astrophysics Data System (ADS)

T cells orchestrate adaptive immune responses upon activation. T cell activation requires sufficiently strong binding of T cell receptors on their surface to short peptides derived from foreign proteins bound to protein products of the major histocompatibility (MHC) gene products, which are displayed on the surface of antigen presenting cells. T cells can also interact with peptide-MHC complexes, where the peptide is derived from host (self) proteins. A diverse repertoire of relatively self-tolerant T cell receptors is selected in the thymus. We study a model, computationally and analytically, to describe how thymic selection shapes the repertoire of T cell receptors, such that T cell receptor recognition of pathogenic peptides is both specific and degenerate. We also discuss the escape probability of autoimmune T cells from the thymus.

Košmrlj, Andrej; Kardar, Mehran; Chakraborty, Arup K.

2012-10-01

117

Development of suppressor T cells in mice heavily infected with mycobacteria.  

PubMed Central

Specific pathogen-free B6D2 mice were infected intravenously with 10(8) viable BCG, M. habana or M. simiae and the level of tuberculin hypersensitivity to 2.5 micrograms PPD or cytoplasmic protein antigens (CPA) prepared from the other organisms was determined using the footpad swelling test with increasing time after infection. This was correlated with the growth or persistence of mycobacterial populations within the liver. Spleen cells were removed from these infected mice and the level of blast transformation following exposure to PHA, PPD or M. habana or M. simiae CPA was measured in vitro. Early in the mycobacterial infections (day 14) thymidine incorporation by the spleen cells was significantly enchanced followed by a profound depression in incorporation rates as the infection progressed. The mechanism of this depressed response involved the production of suppressor T cells in the spleen. In the case of the M. simiae or M. habana infection, cells capable of mediating suppression were still present even after 12 months of infection. In the BCG infection, suppressor T cells declined with time so that by 4 months incorporation rates were back to normal and suppressor cells were no longer detectable in the spleens of the infected animals. PMID:6449470

Watson, S R; Collins, F M

1980-01-01

118

Interferon ? Derived from CD4 ? T Cells Is Sufficient to Mediate T Helper Cell Type 1 Development  

E-print Network

Interferon ? (IFN-?) has been implicated in T helper type 1 (Th1) cell development through its ability to optimize interleukin 12 (IL-12) production from macrophages and IL-12 receptor expression on activated T cells. Various systems have suggested a role for IFN- ? derived from the innate immune system, particularly natural killer (NK) cells, in mediating Th1 differentiation in vivo. We tested this requirement by reconstituting T cell and IFN- ? doubly deficient mice with wild-type CD4 ? T cells and challenging the mice with pathogens that elicited either minimal or robust IL-12 in vivo (Leishmania major or Listeria monocytogenes, respectively). Th1 cells developed under both conditions, and this was unaffected by the presence or absence of IFN- ? in non-T cells. Reconstitution with IFN-?–deficient CD4 ? T cells could not reestablish control over L. major, even in the presence of IFN- ? from the NK compartment. These data demonstrate that activated T cells can maintain responsiveness to IL-12 through elaboration of endogenous IFN- ? without requirement for an exogenous source of this cytokine. Key words: T helper type 1 cells • interferon ? • natural killer cells • Leishmania • Listeria The development of CD4 ? T cell subsets remains an important topic in understanding mechanisms by which protective or detrimental T effector cell populations arise (1, 2). Critical cytokines that promote the appearance

119

A genome-wide regulatory network identifies key transcription factors for memory CD8[superscript +] T-cell development  

E-print Network

Memory CD8[superscript +] T-cell development is defined by the expression of a specific set of memory signature genes. Despite recent progress, many components of the transcriptional control of memory CD8[superscript +] ...

Hu, Guangan

120

Inhibitor of DNA Binding 3 Limits Development of Murine Slam-Associated Adaptor Protein-Dependent “Innate” ?? T cells  

PubMed Central

Background Id3 is a dominant antagonist of E protein transcription factor activity that is induced by signals emanating from the ?? and ?? T cell receptor (TCR). Mice lacking Id3 were previously shown to have subtle defects in positive and negative selection of TCR??+ T lymphocytes. More recently, Id3?/? mice on a C57BL/6 background were shown to have a dramatic expansion of ?? T cells. Methodology/Principal Findings Here we report that mice lacking Id3 have reduced thymocyte numbers but increased production of ?? T cells that express a V?1.1+V?6.3+ receptor with restricted junctional diversity. These V?1.1+V?6.3+ T cells have multiple characteristics associated with “innate” lymphocytes such as natural killer T (NKT) cells including an activated phenotype, expression of the transcription factor PLZF, and rapid production of IFNg and interleukin-4. Moreover, like other “innate” lymphocyte populations, development of Id3?/? V?1.1+V?6.3+ T cells requires the signaling adapter protein SAP. Conclusions Our data provide novel insight into the requirements for development of V?1.1+V?6.3+ T cells and indicate a role for Id3 in repressing the response of “innate” ?? T cells to SAP-mediated expansion or survival. PMID:20174563

Verykokakis, Mihalis; Boos, Markus D.; Bendelac, Albert; Adams, Erin J.; Pereira, Pablo; Kee, Barbara L.

2010-01-01

121

T Cell Factor-1 Controls the Lifetime of CD4+ CD8+ Thymocytes In Vivo and Distal T Cell Receptor ?-Chain Rearrangement Required for NKT Cell Development  

PubMed Central

Natural killer T (NKT) cells are a component of innate and adaptive immune systems implicated in immune, autoimmune responses and in the control of obesity and cancer. NKT cells develop from common CD4+ CD8+ double positive (DP) thymocyte precursors after the rearrangement and expression of T cell receptor (TCR) V?14-J?18 gene. Temporal regulation and late appearance of V?14-J?18 rearrangement in immature DP thymocytes has been demonstrated. However, the precise control of lifetime of DP thymocytes in vivo that enables distal rearrangements remains incompletely defined. Here we demonstrate that T cell factor (TCF)-1, encoded by the Tcf7 gene, is critical for the extended lifetime of DP thymocytes. TCF-1-deficient DP thymocytes fail to undergo TCR V?14-J?18 rearrangement and produce significantly fewer NKT cells. Ectopic expression of Bcl-xL permits V?14-J?18 rearrangement and rescues NKT cell development. We report that TCF-1 regulates expression of ROR?t, which regulates DP thymocyte survival by controlling expression of Bcl-xL. We posit that TCF-1 along with its cofactors controls the lifetime of DP thymocytes in vivo. PMID:25536344

Sen, Jyoti Misra

2014-01-01

122

HIV-1 transgenic rat CD4+ T cells develop decreased CD28 responsiveness and suboptimal Lck tyrosine dephosphorylation following activation  

SciTech Connect

Impaired CD4+ T cell responses, resulting in dysregulated T-helper 1 (Th1) effector and memory responses, are a common result of HIV-1 infection. These defects are often preceded by decreased expression and function of the {alpha}/{beta} T cell receptor (TCR)-CD3 complex and of co-stimulatory molecules including CD28, resulting in altered T cell proliferation, cytokine secretion and cell survival. We have previously shown that HIV Tg rats have defective development of T cell effector function and generation of specific effector/memory T cell subsets. Here we identify abnormalities in activated HIV-1 Tg rat CD4+ T cells that include decreased pY505 dephosphorylation of Lck (required for Lck activation), decreased CD28 function, reduced expression of the anti-apoptotic molecule Bcl-xL, decreased secretion of the mitogenic lympokine interleukin-2 (IL-2) and increased activation induced apoptosis. These events likely lead to defects in antigen-specific signaling and may help explain the disruption of Th1 responses and the generation of specific effector/memory subsets in transgenic CD4+ T cells.

Yadav, Anjana [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Pati, Shibani [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Nyugen, Anhthu [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Barabitskaja, Oxana [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Mondal, Prosanta [Department of Epidemiology and Prevention, Institute of Human Virology, University of Maryland, Baltimore, MD 21201 (United States); Anderson, Michael [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Gallo, Robert C. [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States); Huso, David L. [Division of Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205 (United States); Reid, William [Division of Basic Science, Institute of Human Virology, University of Maryland, Rm S616, 725, West Lombard Street, Baltimore, MD 21201 (United States)]. E-mail: reid@umbi.umd.edu

2006-09-30

123

Incomplete Normalization of Regulatory T-Cell Frequency in the Gut Mucosa of Colombian HIV-Infected Patients Receiving Long-Term Antiretroviral Treatment  

PubMed Central

Introduction To evaluate the effect of late initiation of HAART and poor immune reconstitution on the frequency of regulatory T-cells (Treg) in the peripheral blood and gut of HIV-infected patients, we studied Colombian HIV-infected patients who had been on suppressive HAART for at least one year. They had undetectable viremia but were either immunological responders (HIR); (CD4 counts >500 cells/µl) or non-immunological responders (NIR); (CD4 T-cell count <300 cells/µl). Untreated HIV-infected patients and uninfected controls from the same region were also evaluated. Methods Frequency and phenotype of regulatory T-cells (Treg) were analyzed in gut biopsies and blood samples. The functional effect of Treg depletion on CMV and HIV responses was determined. Markers of immune activation and circulating LPS levels were quantified. Results Untreated patients exhibited high Treg frequency in PBMC and gut, and their Treg express high levels of CTLA-4 and PD-1. Although HAART significantly decreased mucosal Treg frequency, it did not normalize it in any of the treated groups (HIR and NIR patients). Treg normalization was observed in the blood of HIR patients following HAART, but did not occur in NIR patients. Treg from HIV-infected patients (treated or not) suppressed HIV and hCMV-specific T-cells from gut and blood. Plasma LPS levels and percentage of HLA-DR+CD38+ T-cells were significantly elevated in all infected groups compared to controls. Conclusions These findings suggest that control of viral replication is not sufficient to normalize gut Treg frequency in patients, independent of their response to HAART. Furthermore, persistence of functional Treg in the gut appears to be associated with the failure of HAART to repair mucosal damage. PMID:23967152

Rueda, Cesar M.; Velilla, Paula A.

2013-01-01

124

Normal T lymphocytes can express two different T cell receptor beta chains: implications for the mechanism of allelic exclusion.  

PubMed

We have examined the extent of allelic exclusion at the T cell receptor (TCR) beta locus using monoclonal antibodies specific for V beta products. A small proportion (approximately 1%) of human peripheral blood T cells express two V beta as determined by flow cytometric analysis, isolation of representative clones, and sequencing of the corresponding V beta chains. Dual beta T cells are present in both the CD45R0+ and CD45R0- subset. These results indicate that dual beta expression is compatible with both central and peripheral selection. They also suggest that the substantial degree of TCR beta allelic exclusion is dependent only on asynchronous rearrangements at the beta locus, whereas the role of the pre-TCR is limited to signaling the presence of at least one functional beta protein. PMID:7699339

Padovan, E; Giachino, C; Cella, M; Valitutti, S; Acuto, O; Lanzavecchia, A

1995-04-01

125

Human T-cell growth factor: partial amino acid sequence, cDNA cloning, and organization and expression in normal and leukemic cells.  

PubMed Central

The partial amino acid sequences of human T-cell growth factors (TCGFs) isolated from normal peripheral blood lymphocytes and from a leukemia T-cell line (Jurkat) show that the amino-terminal sequences of the two proteins (15 residues) are identical. Oligonucleotides based on the published Jurkat TCGF DNA sequence were used to isolate six cDNA clones of TCGF mRNA from normal lymphocytes. The predicted amino acid sequence of normal lymphocyte TCGF was identical to the sequence of the Jurkat protein, showing that the differences in biochemical properties of the two proteins result from post-translational events. Amino acid and nucleotide sequence data suggest that TCGF is derived from a precursor polypeptide that is cleaved at the amino terminus but not at the carboxyl terminus. Hybridization of the cloned lymphocyte TCGF cDNA to cellular DNA and RNA strongly suggested that the TCGF gene is expressed as a single mRNA species from a single-copy gene. No differences in the organization of the TCGF gene in normal, leukemic, and human T-cell leukemia/lymphoma virus-infected cells was detected regardless of whether they produce TCGF or not. Images PMID:6201860

Clark, S C; Arya, S K; Wong-Staal, F; Matsumoto-Kobayashi, M; Kay, R M; Kaufman, R J; Brown, E L; Shoemaker, C; Copeland, T; Oroszlan, S

1984-01-01

126

Disordered T-cell development and T-cell malignancies in SCL LMO1 double-transgenic mice: parallels with E2A-deficient mice.  

PubMed

The gene most commonly activated by chromosomal rearrangements in patients with T-cell acute lymphoblastic leukemia (T-ALL) is SCL/tal. In collaboration with LMO1 or LMO2, the thymic expression of SCL/tal leads to T-ALL at a young age with a high degree of penetrance in transgenic mice. We now show that SCL LMO1 double-transgenic mice display thymocyte developmental abnormalities in terms of proliferation, apoptosis, clonality, and immunophenotype prior to the onset of a frank malignancy. At 4 weeks of age, thymocytes from SCL LMO1 mice show 70% fewer total thymocytes, with increased rates of both proliferation and apoptosis, than control thymocytes. At this age, a clonal population of thymocytes begins to populate the thymus, as evidenced by oligoclonal T-cell-receptor gene rearrangements. Also, there is a dramatic increase in immature CD44(+) CD25(-) cells, a decrease in the more mature CD4(+) CD8(+) cells, and development of an abnormal CD44(+) CD8(+) population. An identical pattern of premalignant changes is seen with either a full-length SCL protein or an amino-terminal truncated protein which lacks the SCL transactivation domain, demonstrating that the amino-terminal portion of SCL is not important for leukemogenesis. Lastly, we show that the T-ALL which develop in the SCL LMO1 mice are strikingly similar to those which develop in E2A null mice, supporting the hypothesis that SCL exerts its oncogenic action through a functional inactivation of E proteins. PMID:10373552

Chervinsky, D S; Zhao, X F; Lam, D H; Ellsworth, M; Gross, K W; Aplan, P D

1999-07-01

127

Development and characterization of Histoplasma capsulatum-reactive murine T-cell lines and clones  

NASA Technical Reports Server (NTRS)

Several Histoplasma capsulatum-reactive murine cloned T-cell lines (TCLs) were isolated from spleens of C57BL/6 mice immunized with viable H. capsulatum yeast cells, using the methodology of Kimoto and Fathman (1980). These T-cells were characterized phenotypically as Thy-1.2(+) Lyt-1(+) L3T4(+) Lyt-2(-), that is, as the helper/inducer phenotype. The cloned T cells proliferate in response to histoplasmin and, in some cases, to heterologous fungal anigens. Upon injection of mice with the antigen, the T-cells mediate local delayed-type hypersensitivity responses and, after stimulation, release regulatory lymphokines.

Deepe, George S., Jr.; Smith, James G.; Denman, David; Bullock, Ward E.; Sonnenfeld, Gerald

1986-01-01

128

Evidence against T-cell development in the adult human intestinal mucosa based upon lack of terminal deoxynucleotidyltransferase expression.  

PubMed Central

Several lines of evidence indicate that a subset of murine intestinal intraepithelial lymphocytes (iIEL), particularly those which express the CD8 alpha alpha homodimer, mature extrathymically. This study confirms that a small fraction of adult human iIEL also express the CD8 alpha alpha homodimer and demonstrates that most of these cells in the small intestine are T cells using the alpha beta T-cell receptor (TCR). Whether these cells or other subsets of adult human iIEL mature extrathymically in the intestine was assessed by measuring the expression of terminal deoxynucleotidyltransferase (TdT), an enzyme expressed exclusively by immature lymphocytes. Very low levels of TdT message could be detected by polymerase chain reaction (PCR) amplification in some iIEL samples. The level of TdT expression was assayed by competitive PCR amplification and compared with thymocytes and peripheral blood lymphocytes. These measurements indicated that the number of immature T cells expressing TdT in the intestinal epithelium was less than one cell per 10(7) lymphocytes. This demonstrates that there are few if any TdT expressing immature T cells in the adult human intestinal mucosa and indicates, therefore, that T-cell development in the intestinal mucosa does not contribute significantly to the T-cell repertoire of the adult human intestine. Images Figure 1 Figure 2 Figure 3 PMID:8778025

Taplin, M E; Frantz, M E; Canning, C; Ritz, J; Blumberg, R S; Balk, S P

1996-01-01

129

The major CD8 T cell effector memory subset in the normal and Chlamydia trachomatis-infected human endocervix is low in perforin  

PubMed Central

Background The local tissue microenvironment plays an important role in the induction, homing, maintenance and development of effector functions of T cells. Thus, site-specific differences in phenotypes of mucosal and systemic T cell populations have been observed. Chlamydia trachomatis most commonly infects the endocervix in women, yet little is known about Chlamydia-specific effector T cell immunity at this unique mucosal site. Our previous flow-cytometry-based study of cervical-cytobrush retrieved cells indicated that CD8 T cells are significantly increased in the C. trachomatis-infected human endocervix. The cytolytic function of CD8 T cells is important in the protective immunity against many intracellular pathogens, and requires the cytolytic granule perforin to facilitate the entry of other molecules that mediate the lysis of target cells. Determination of perforin expression of the CD8 T cell population in the endocervix would therefore provide insights on the granule-mediated cytolytic potential of these cells at this site. Results Our histological data revealed that C. trachomatis-infected tissues have significantly higher numbers of CD3 and CD8 T cells compared to non-infected tissues (p<0.01), and that the majority of CD8+ cells do not express perforin in situ. A subsequent flow cytometric analysis of paired blood and endocervix-derived cells (n=16) revealed that while all the CD8 T cell subsets: naïve, effector memory (TEM), central memory (TCM) and terminally differentiated effector memory (TEMRA) can be found in the blood, the endocervix is populated mainly by the TEM CD8 T cell subset. Our data also showed that perforin expression in the TEM population is significantly lower in the endocervix than in the blood of C. trachomatis positive women (n=15; p<0.0001), as well as in C. trachomatis-negative individuals (n=6; p<0.05). Interestingly, our in vitro co-culture study suggests that the exposure of HeLa 229 cervical epithelial cells to IFN gamma could potentially induce a decrease in perforin content in CD8 TEM cells in the same microenvironment. Conclusions The low perforin content of CD8 TEM cells in the endocervix, the local site of C. trachomatis infection in women, may reflect the unique immunological environment that balances immune protection against sexually transmitted infections and immune- tolerance to support conception. PMID:23216954

2012-01-01

130

Blocked negative selection of developing T cells in mice expressing the baculovirus p35 caspase inhibitor.  

PubMed Central

Clonal deletion in the thymus by apoptosis is involved in purging the immune system of self-reactive T lymphocytes (negative selection). Cysteine proteases (caspases) belonging to the CPP32 family are activated during this process. We have produced transgenic mice expressing baculovirus p35, a broad-range caspase inhibitor. Thymocytes from p35 transgenic mice were resistant in vitro to several apoptosis-inducing agents; this resistance correlated with the inhibition of CPP32-like activity. Negative selection in vivo of thymocytes triggered by two exogenous antigens, staphylococcal enterotoxin B superantigen and an antigenic peptide in the F5 T-cell receptor transgenic model, was specifically inhibited in p35 transgenic mice. Our results provide direct evidence for caspase involvement in negative selection during thymocyte development. PMID:9878059

Izquierdo, M; Grandien, A; Criado, L M; Robles, S; Leonardo, E; Albar, J P; de Buitrago, G G; Martínez-A, C

1999-01-01

131

Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development.  

PubMed

The catalytic activity of Zap70 is crucial for T cell antigen receptor (TCR) signaling, but the quantitative and temporal requirements for its function in thymocyte development are not known. Using a chemical-genetic system to selectively and reversibly inhibit Zap70 catalytic activity in a model of synchronized thymic selection, we showed that CD4(+)CD8(+) thymocytes integrate multiple, transient, Zap70-dependent signals over more than 36 h to reach a cumulative threshold for positive selection, whereas 1 h of signaling was sufficient for negative selection. Titration of Zap70 activity resulted in graded reductions in positive and negative selection but did not decrease the cumulative TCR signals integrated by positively selected OT-I cells, which revealed heterogeneity, even among CD4(+)CD8(+) thymocytes expressing identical TCRs undergoing positive selection. PMID:24908390

Au-Yeung, Byron B; Melichar, Heather J; Ross, Jenny O; Cheng, Debra A; Zikherman, Julie; Shokat, Kevan M; Robey, Ellen A; Weiss, Arthur

2014-07-01

132

Developing Patterns of T Cell Memory to Environmental Allergens in the First Two Years of Life  

Microsoft Academic Search

Several recent studies have demonstrated cord blood mononuclear cell (CBMC) proliferation in response to food and inhalant allergens, suggesting that initial T-cell-priming may occur in utero. The findings below from an ongoing prospective study on 60 subjects provide initial information on the nature of accompanying T cell cytokine responses. We demonstrate CBMC proliferation following culture with house dust mite and

Susan L. Prescott; Claudia Macaubas; Akihiro Yabuhara; Thierry J. Venaille; Barbara J. Holt; Walid Habre; Richard Loh; Peter D. Sly; P. G. Holt

1997-01-01

133

Differential requirement for IL-2 and IL-15 during bifurcated development of thymic regulatory T cells.  

PubMed

The developmental pathways of regulatory T cells (T(reg)) generation in the thymus are not fully understood. In this study, we reconstituted thymic development of Zap70-deficient thymocytes with a tetracycline-inducible Zap70 transgene to allow temporal dissection of T(reg) development. We find that T(reg) develop with distinctive kinetics, first appearing by day 4 among CD4 single-positive (SP) thymocytes. Accepted models of CD25(+)Foxp3(+) T(reg) selection suggest development via CD25(+)Foxp3(-) CD4 SP precursors. In contrast, our kinetic analysis revealed the presence of abundant CD25(-)Foxp3(+) cells that are highly efficient at maturing to CD25(+)Foxp3(+) cells in response to IL-2. CD25(-)Foxp3(+) cells more closely resembled mature T(reg) both with respect to kinetics of development and avidity for self-peptide MHC. These population also exhibited distinct requirements for cytokines during their development. CD25(-)Foxp3(+) cells were IL-15 dependent, whereas generation of CD25(+)Foxp3(+) specifically required IL-2. Finally, we found that IL-2 and IL-15 arose from distinct sources in vivo. IL-15 was of stromal origin, whereas IL-2 was of exclusively from hemopoetic cells that depended on intact CD4 lineage development but not either Ag-experienced or NKT cells. PMID:25348623

Marshall, Daniel; Sinclair, Charles; Tung, Sim; Seddon, Benedict

2014-12-01

134

Antigen-Bearing Dendritic Cells Regulate the Diverse Pattern of Memory CD8 T Cell Development in Different Tissues  

E-print Network

Memory T cells of the effector type (TEM) account for the characteristic rapidity of memory T-cell responses, whereas memory T cells of the central type (TCM) account for long-lasting, vigorously proliferating memory T-cell ...

Shen, Ching-Hung

135

Catecholamines as immunomodulators: a role for adrenoceptor-mediated mechanisms in fine tuning of T-cell development.  

PubMed

In its simplest form, effective T cell-mediated immunity emanates from the expansion of specific T cells activated in response to antigen. In establishing and maintaining the peripheral T-cell pool, the thymus plays a critical role. It does so by providing a microenvironment within which T-cell precursors proliferate, differentiate and undergo selection processes to create a fully functional population of major histocompatibility complex restricted, self-tolerant T cells. The control of the thymic function involves intrathymic, as well as sympathetic nervous and endocrine system signalling. In addition to postganglionic noradrenergic fibres, both thymic lymphoid and non-lymphoid cells, including epithelial cells and macrophages, have been demonstrated to express tyrosine hydroxylase (TH), and suggested to form a local non-neural catecholaminergic cell network. A higher level of noradrenaline has been found in male than in female rat thymi, and a role of gonadal hormones in providing this dimorphism has been demonstrated. In addition, thymic lymphoid and non-lymphoid cells, including those expressing TH, have been found to bear beta- and alpha1-adrenoceptors (ARs) and a role of gonadal hormones in regulation of, at least, beta-AR density and signalling has been suggested. These findings have also entailed conclusion that catecholamines (CAs) influence T-cell development, not only via neurocrine/endocrine, but also via autocrine/paracrine action. Generally, CAs have been shown to exert an inhibitory influence on thymopoiesis. Role of alpha1- and beta-AR-mediated mechanisms in maintaining thymic homeostasis and in fine tuning of both conventional and regulatory T-cell development is discussed in the manuscript. PMID:18976969

Leposavi?, Gordana; Pilipovi?, Ivan; Radojevi?, Katarina; Pesi?, Vesna; Perisi?, Milica; Kosec, Dusko

2008-12-15

136

Functional CD8+ but not CD4+ T cell responses develop independent of thymic epithelial MHC  

PubMed Central

The role of nonthymic epithelial (non-TE) MHC in T cell repertoire selection remains controversial. To analyze the relative roles of thymic epithelial (TE) and non-TE MHC in T cell repertoire selection, we have generated tetraparental aggregation chimeras (B6-nude?BALB/c and B6?BALB/c-nude) harboring T and B cells from both parents, whereas TE cells originated exclusively from the non-nude donor. These chimeras mounted protective virus-specific TE and non-TE MHC-restricted T cell responses. To further evaluate whether non-TE MHC alone was sufficient to generate a functional T cell repertoire, we generated tetraparental aggregation chimeras lacking MHC class II (B6-nude?MHCII?/?) or both MHC molecules (B6-nude?MHCI?/?II?/?) on TE cells, but not on cells of B6-nude origin. Chimeras with MHC-deficient TE cells mounted functional virus-specific CD8+ but not CD4+ T cell responses. Thus, maturation of functional CD4+ T cell responses required MHC class II on thymic epithelium, whereas CD8+ T cells matured in the absence of TE MHC. PMID:16983067

Martinic, Marianne M.; van den Broek, Maries F.; Rülicke, Thomas; Huber, Christoph; Odermatt, Bernhard; Reith, Walter; Horvath, Edit; Zellweger, Raphael; Fink, Katja; Recher, Mike; Eschli, Bruno; Hengartner, Hans; Zinkernagel, Rolf M.

2006-01-01

137

T cells fail to develop in the human skin-cell explants system; an inconvenient truth  

Microsoft Academic Search

Background  Haplo-identical hematopoietic stem cell (HSC) transplantation is very successful in eradicating haematological tumours, but\\u000a the long post-transplant T-lymphopenic phase is responsible for high morbidity and mortality rates. Clark et al. have described a skin-explant system capable of producing host-tolerant donor-HSC derived T-cells. Because this T-cell production\\u000a platform has the potential to replenish the T-cell levels following transplantation, we set out

Bob Meek; Catharina HMJ Van Elssen; Mirelle JAJ Huijskens; Sjoukje JC van der Stegen; Siebe Tonnaer; Stijn BJ Lumeij; Joris Vanderlocht; Mark A Kirkland; Reinout Hesselink; Wilfred TV Germeraad; Gerard MJ Bos

2011-01-01

138

CD4 T cells with effector memory phenotype and function develop in the sterile environment of the fetus.  

PubMed

The T cell compartment is considered to be naïve and dedicated to the development of tolerance during fetal development. We have identified and characterized a population of fetally developed CD4 T cells with an effector memory phenotype (TEM), which are present in cord blood. This population is polyclonal and has phenotypic features similar to those of conventional adult memory T cells, such as CD45RO expression. These cells express low levels of CD25 but are distinct from regulatory T cells because they lack Foxp3 expression. After T cell receptor activation, neonatal TEM cells readily produced tumor necrosis factor-? (TNF-?) and granulocyte-macrophage colony-stimulating factor (GM-CSF). We also detected interferon-? (IFN-?)-producing T helper 1 (TH1) cells and interleukin-4 (IL-4)/IL-13-producing TH2-like cells, but not IL-17-producing cells. We used chemokine receptor expression patterns to divide this TEM population into different subsets and identified distinct transcriptional programs using whole-genome microarray analysis. IFN-? was found in CXCR3(+) TEM cells, whereas IL-4 was found in both CXCR3(+) TEM cells and CCR4(+) TEM cells. CCR6(+) TEM cells displayed a genetic signature that corresponded to TH17 cells but failed to produce IL-17A. However, the TH17 function of TEM cells was observed in the presence of IL-1? and IL-23. In summary, in the absence of reported pathology or any major infectious history, T cells with a memory-like phenotype develop in an environment thought to be sterile during fetal development and display a large variety of inflammatory effector functions associated with CD4 TH cells at birth. PMID:24871133

Zhang, Xiaoming; Mozeleski, Brian; Lemoine, Sebastien; Dériaud, Edith; Lim, Annick; Zhivaki, Dania; Azria, Elie; Le Ray, Camille; Roguet, Gwenaelle; Launay, Odile; Vanet, Anne; Leclerc, Claude; Lo-Man, Richard

2014-05-28

139

Angiolymphoid hyperplasia with eosinophilia developing in a patient with history of peripheral T-cell lymphoma: evidence for multicentric T-cell lymphoproliferative process  

PubMed Central

Background Angiolymphoid hyperplasia with eosinophilia (ALHE) is a vasocentric process characterized by infiltrates of lymphocytes and eosinophils, usually affecting the muscular arteries of the head and neck. Currently it is unclear whether it is a reactive or neoplastic process. Report We present a 61-year-old African American male with a twenty year history of superficial skin patches involving the head and neck region. An excisional biopsy of a right submental lymph node revealed an atypical T-cell lymphocytic process, diagnosed as peripheral T-cell lymphoma after immunophenotyping and molecular studies. Three months later the patient underwent a biopsy of a left temporal nodule that was diagnosed as ALHE. Subsequently, at two year follow-up, the patient was diagnosed with Mycosis Fungoides. Polymerase chain reaction for T cell receptor gamma showed the same T-cell receptor gene rearrangement in both the temporal mass and the right submental lymph node. Conclusion ALHE with molecular evidence of monoclonality is extremely unusual, as is the association with nodal peripheral T-cell nodal lymphoma. The findings of this case support our hypothesis that ALHE might be an early form of T-cell lymphoma. PMID:18510751

Gonzalez-Cuyar, Luis F; Tavora, Fabio; Zhao, X Frank; Wang, Guanghua; Auerbach, Aaron; Aguilera, Nadine; Burke, Allen P

2008-01-01

140

Effect of Schlafen 2 on natural killer and T cell development from common T/natural killer progenitors.  

PubMed

Natural Killer (NK) cells are thought to develop from common lymphoid progenitors in the bone marrow. Even though thymus is not essential for NK cell development, T-cell/natural killer-cell (T/NK) precursors, DN1 (CD44+CD25-) and DN2 (CD44+CD25+) when cultured on an OP9 stroma, give rise to some NK1.1 cells. Genes of the Schlafen (Slfn) family are involved in hematopoietic and immune processes. The contribution of the Slfn genes in NK cell development from Double Negative (DN) cells is unknown. We transduced DN1 and DN2 progenitors prepared from C57BL/6 (B6) mouse thymus with Schlafen 1 (Slfnl) and Schlafen 2 (Slfn2) genes using Mig retroviral vector containing the Green Fluorescent Protein (GFP) gene and cultured those transduced progenitors on OP9 and OP9 stroma expressing the Notch ligand Delta-like 1 (OP9-DL 1) with appropriate cytokines to see if they affect generating NK and T-cells differently. Maturation of both NK and T cells from immature T/NK thymocytes hampered by Slfn1 and Slfn2 transduction but we got a small number of Slfn1 and Slfn2 expressing cells upon culture of transduced DN progenitors on stroma cells. There was no difference between Slfn1 expressing (GFP+) and none expressing T cells regarding CD3 expression but all mature NK cells were from Slfn1 negative population. Slfn2 completely blocked maturation of T cells but there was no difference between Slfn2 expressing and none expressing NK cells. Based on our findings both Slfn1 and Slfn2 interfere with maturation of DN2 progenitors but T cell development is more sensitive to Slfn2 expression than NK cell. PMID:22514877

Ahmadi, S; Veinotte, L L

2011-11-15

141

Iron Prevents the Development of Experimental Cerebral Malaria by Attenuating CXCR3-Mediated T Cell Chemotaxis  

PubMed Central

Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Previous studies have suggested that iron overload can suppress the generation of a cytotoxic immune response; however, the effect of iron on experimental cerebral malaria (ECM) is yet unknown. Here we determined that the incidence of ECM was markedly reduced in mice treated with iron dextran. Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain. CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFN?-responsiveness, as indicated by mitigated expression of IFN?R2 and T-bet. Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells. Altogether, these results suggest that iron is able to inhibit ECM pathology by attenuating the capacity of T cells to migrate to the brain. PMID:25768944

Van Den Ham, Kristin M.; Shio, Marina Tiemi; Rainone, Anthony; Fournier, Sylvie; Krawczyk, Connie M.; Olivier, Martin

2015-01-01

142

From Murine to Human Nude/SCID: The Thymus, T-Cell Development and the Missing Link  

PubMed Central

Primary immunodeficiencies (PIDs) are disorders of the immune system, which lead to increased susceptibility to infections. T-cell defects, which may affect T-cell development/function, are approximately 11% of reported PIDs. The pathogenic mechanisms are related to molecular alterations not only of genes selectively expressed in hematopoietic cells but also of the stromal component of the thymus that represents the primary lymphoid organ for T-cell differentiation. With this regard, the prototype of athymic disorders due to abnormal stroma is the Nude/SCID syndrome, first described in mice in 1966. In man, the DiGeorge Syndrome (DGS) has long been considered the human prototype of a severe T-cell differentiation defect. More recently, the human equivalent of the murine Nude/SCID has been described, contributing to unravel important issues of the T-cell ontogeny in humans. Both mice and human diseases are due to alterations of the FOXN1, a developmentally regulated transcription factor selectively expressed in skin and thymic epithelia. PMID:22474479

Romano, Rosa; Palamaro, Loredana; Fusco, Anna; Iannace, Leucio; Maio, Stefano; Vigliano, Ilaria; Giardino, Giuliana; Pignata, Claudio

2012-01-01

143

Technical advance: ascorbic acid induces development of double-positive T cells from human hematopoietic stem cells in the absence of stromal cells.  

PubMed

The efficacy of donor HSCT is partly reduced as a result of slow post-transplantation immune recovery. In particular, T cell regeneration is generally delayed, resulting in high infection-related mortality in the first years post-transplantation. Adoptive transfer of in vitro-generated human T cell progenitors seems a promising approach to accelerate T cell recovery in immunocompromised patients. AA may enhance T cell proliferation and differentiation in a controlled, feeder-free environment containing Notch ligands and defined growth factors. Our experiments show a pivotal role for AA during human in vitro T cell development. The blocking of NOS diminished this effect, indicating a role for the citrulline/NO cycle. AA promotes the transition of proT1 to proT2 cells and of preT to DP T cells. Furthermore, the addition of AA to feeder cocultures resulted in development of DP and SP T cells, whereas without AA, a preT cell-stage arrest occurred. We conclude that neither DLL4-expressing feeder cells nor feeder cell conditioned media are required for generating DP T cells from CB and G-CSF-mobilized HSCs and that generation and proliferation of proT and DP T cells are greatly improved by AA. This technology could potentially be used to generate T cell progenitors for adoptive therapy. PMID:25157026

Huijskens, Mirelle J A J; Walczak, Mateusz; Koller, Nicole; Briedé, Jacob J; Senden-Gijsbers, Birgit L M G; Schnijderberg, Melanie C; Bos, Gerard M J; Germeraad, Wilfred T V

2014-12-01

144

Normal growth and development  

MedlinePLUS

... nutrition can cause problems with a child's intellectual development. A child with a poor diet may be tired and ... care provider if you have concerns about your child's growth and development. Related topics include: Developmental milestones record - 4 months ...

145

Age-associated plasticity of ?1-adrenoceptor-mediated tuning of T-cell development.  

PubMed

Alpha(1)-adrenoceptors (?(1)-ARs) are involved in neuro-thymic and thymic intercellular communications, and consequently modulation of T-cell development. Ageing is associated with a number of changes in noradrenergic neuro-effector transmission, and possibly intercellular noradrenaline (NA)-mediated communication resulting in altered responses of target cells to NA. Thus, in old animals an altered NA modulation of thymopoiesis via ?(1)-ARs may be expected. To test this hypothesis, in old and young adult Wistar rats we examined: 1) thymic NA levels, density of noradrenergic innervation and NA synthesizing cells, as well as ?(1)-AR expression, and 2) then the effects of 14-day-long treatment with the ?(1)-AR blocker, urapidil, on thymocyte development. Overall, the first part of study suggested augmented NA signalling to thymic cells via ?(1)-ARs due to increased NA availability and ?(1)-AR thymocyte surface density in old rats. The second part of study supported this assumption. Namely, although in rats of both ages urapidil affected the same thymocyte developmental steps ultimately leading to changes in the relative number of the most mature single positive TCR??(high) thymocytes, its effects were generally more prominent in old animals. Following urapidil treatment, the percentages of CD4+CD8- cells, including those showing a regulatory CD4+CD25+RT6.1- phenotype, were increased, while CD4-CD8+ cells decreased. In old rats, an augmented thymic escape of immature CD4+CD8+ cells was also registered. In rats of both ages the thymic changes were accompanied by alterations in the proportions of major cell populations in the T-lymphocyte compartment of both peripheral blood and spleen, leading to an increase in the CD4+/CD8+ T-cell ratio. These alterations were also more pronounced in old rats. Moreover, in old rats following urapidil treatment the proportion of TCR??+cells in the periphery was slightly greater reflecting, most likely, partly enhanced thymic production of regulatory CD161+TCR??+cells. Thus, the study indirectly suggests an age-associated increase in the basal ?(1)-AR-mediated inhibitory influence of NA on thymopoiesis. PMID:20800673

Leposavi?, G; Peši?, V; Stoji?-Vukani?, Z; Radojevi?, K; Arsenovi?-Ranin, N; Kosec, D; Periši?, M; Pilipovi?, I

2010-12-01

146

A retinoic acid–dependent checkpoint in the development of CD4+ T cell–mediated immunity  

PubMed Central

It is known that vitamin A and its metabolite, retinoic acid (RA), are essential for host defense. However, the mechanisms for how RA controls inflammation are incompletely understood. The findings presented in this study show that RA signaling occurs concurrent with the development of inflammation. In models of vaccination and allogeneic graft rejection, whole body imaging reveals that RA signaling is temporally and spatially restricted to the site of inflammation. Conditional ablation of RA signaling in T cells significantly interferes with CD4+ T cell effector function, migration, and polarity. These findings provide a new perspective of the role of RA as a mediator directly controlling CD4+ T cell differentiation and immunity. PMID:21859847

Pino-Lagos, Karina; Guo, Yanxia; Brown, Chrysothemis; Alexander, Matthew P.; Elgueta, Raúl; Bennett, Kathryn A.; De Vries, Victor; Nowak, Elizabeth; Blomhoff, Rune; Sockanathan, Shanthini; Chandraratna, Roshantha A.; Dmitrovsky, Ethan

2011-01-01

147

THEMIS, a new T cell specific protein important for late thymocyte development  

PubMed Central

During positive selection, thymocytes transition through a stage during which T cell receptor (TCR) signaling controls CD4 versus CD8 lineage choice and subsequent maturation. Here, we describe a new T cell specific protein, THEMIS, that performs a distinct function during this stage. In Themis-/- mice, thymocyte selection was impaired and the number of transitional CD4+CD8int thymocytes as well as CD4 and CD8 single positive thymocytes was decreased. Remarkably, although no overt TCR-proximal signaling deficiencies were detected, Themis-/-CD4+CD8int thymocytes exhibited developmental defects consistent with attenuated signaling that were reversible by increased TCR stimulation. These results identify THEMIS as a critical component of the T cell developmental program and suggest that THEMIS functions to sustain and/or integrate signals required for proper lineage commitment and maturation. PMID:19597498

Lesourne, Renaud; Uehara, Shoji; Lee, Jan; Song, Ki-Duk; Li, LiQi; Pinkhasov, Julia; Zhang, Yongqing; Weng, Nan-Ping; Wildt, Kathryn F.; Wang, Lie; Bosselut, Remy; Love, Paul E.

2010-01-01

148

Alveolar macrophages and T cells from sarcoid, but not normal lung, are permissive to adenovirus infection and allow analysis of NF-kappa b-dependent signaling pathways.  

PubMed

Adenovirus (Adv)-mediated gene transfer requires efficient infection of target cells. The objective of this study was to establish whether alveolar macrophages (AM) and T cells (AT) from sarcoid patients were permissive to infection with Adv vectors and if this property could be used to investigate cytokine gene regulation. Sarcoid and normal bronchoalveolar lavage (BAL) specimens infected with Adv vectors expressing either beta-galactosidase or a green fluorescent protein were analyzed for transgene expression by fluorescence-activated cell sorter (FACS) and direct immunofluorescence, respectively. Expression of surface antigens previously associated with Adv infection, the coxsackie/adenovirus receptor (CAR), alpha v beta 3, and alpha v beta 5 integrins, was also assessed using FACS analysis. Sarcoid AM and AT were found to efficiently express Adv transgenes, unlike AM from normal volunteers, peripheral blood monocytes, and peripheral blood T cells. Cells permissive to Adv infection expressed the CAR and alpha v beta 5 integrin (also alpha v beta 3 integrin for AM). The data indicate that the upregulation of Adv receptors and the ability to infect sarcoid AM and AT are related to the inflammatory environment within the lung. Having demonstrated efficient Adv-mediated transgene delivery to sarcoid AM and AT, a construct encoding porcine I kappa B alpha was then used to investigate the requirement for nuclear factor (NF)-kappa B in the regulation of cytokine gene expression in pulmonary sarcoidosis. Overexpression of I kappa B alpha in sarcoid BAL specimens indicated that tumor necrosis factor-alpha and interleukin (IL)-6 production by AM and interferon (IFN)-gamma production by AT is NF-kappa B dependent, whereas IL-4 production by AT is NF-kappa B independent. This is the first occasion that the requirement for NF-kappa B in IFN-gamma gene expression within primary human T cells has been demonstrated. The results of this study have implications for the future investigation of molecular pathways in inflammatory lung disease. PMID:11509322

Conron, M; Bondeson, J; Pantelidis, P; Beynon, H L; Feldmann, M; duBois, R M; Foxwell, B M

2001-08-01

149

Effect of Cytomegalovirus Co-Infection on Normalization of Selected T-Cell Subsets in Children with Perinatally Acquired HIV Infection Treated with Combination Antiretroviral Therapy  

PubMed Central

Background We examined the effect of cytomegalovirus (CMV) co-infection and viremia on reconstitution of selected CD4+ and CD8+ T-cell subsets in perinatally HIV-infected (PHIV+) children ? 1-year old who participated in a partially randomized, open-label, 96-week combination antiretroviral therapy (cART)-algorithm study. Methods Participants were categorized as CMV-naïve, CMV-positive (CMV+) viremic, and CMV+ aviremic, based on blood, urine, or throat culture, CMV IgG and DNA polymerase chain reaction measured at baseline. At weeks 0, 12, 20 and 40, T-cell subsets including naïve (CD62L+CD45RA+; CD95-CD28+), activated (CD38+HLA-DR+) and terminally differentiated (CD62L-CD45RA+; CD95+CD28-) CD4+ and CD8+ T-cells were measured by flow cytometry. Results Of the 107 participants included in the analysis, 14% were CMV+ viremic; 49% CMV+ aviremic; 37% CMV-naïve. In longitudinal adjusted models, compared with CMV+ status, baseline CMV-naïve status was significantly associated with faster recovery of CD8+CD62L+CD45RA+% and CD8+CD95-CD28+% and faster decrease of CD8+CD95+CD28-%, independent of HIV VL response to treatment, cART regimen and baseline CD4%. Surprisingly, CMV status did not have a significant impact on longitudinal trends in CD8+CD38+HLA-DR+%. CMV status did not have a significant impact on any CD4+ T-cell subsets. Conclusions In this cohort of PHIV+ children, the normalization of naïve and terminally differentiated CD8+ T-cell subsets in response to cART was detrimentally affected by the presence of CMV co-infection. These findings may have implications for adjunctive treatment strategies targeting CMV co-infection in PHIV+ children, especially those that are now adults or reaching young adulthood and may have accelerated immunologic aging, increased opportunistic infections and aging diseases of the immune system. PMID:25794163

Kapetanovic, Suad; Aaron, Lisa; Montepiedra, Grace; Anthony, Patricia; Thuvamontolrat, Kasalyn; Pahwa, Savita; Burchett, Sandra; Weinberg, Adriana; Kovacs, Andrea

2015-01-01

150

Antigen Presenting Cells Expressing High Levels of PD-L2 Sustain the Development of CD4-T Cell Memory1  

PubMed Central

The role APCs play in the transition of T cells from effector to memory remains largely undefined. This is likely due to the low frequency at which long-lived T cells arise which hinders analysis of the events involved in memory development. Herein, we used TCR transgenic T cells to increase the frequency of long-lived T cells and developed a transfer model suitable for defining the contribution of APCs to the development of CD4-T cell memory. Accordingly, naive TCR transgenic T cells were stimulated in vitro with Ag presented by different types of APCs, transferred into MHC class II-deficient (MHC II?/?) mice for parking, and the hosts were later analyzed for long-lived T cell frequency or challenged with suboptimal dose of Ag and the long-lived cells-driven memory responses were measured. The findings indicate that B cells and CD8?+ DCs sustained elevated frequencies of long-lived T cells which yielded rapid and robust memory responses upon re-challenge with sub-optimal dose of Ag. Furthermore, both types of APCs had significant Programmed Death Ligand 2 (PD-L2) expression prior to Ag stimulation, which was maintained at a high level during presentation of Ag to T cells. Blockade of PD-L2 interaction with its receptor Programmed Death (PD-1) nullified the development of memory responses. These previously unrecognized findings suggest that targeting specific APCs for Ag presentation during vaccination could prove effective against microbial infections. PMID:20709947

Ellis, Jason S.; Guloglu, F. Betul; Tartar, Danielle M.; Hoeman, Christine M.; Haymaker, Cara L.; Cascio, Jason A.; Wan, Xiaoxiao; Dhakal, Mermagya; VanMorlan, Amie; Yahng, Seung-Hi; Zaghouani, Habib

2010-01-01

151

Epigenetic plasticity of Cd8a locus during CD8+ T-cell development and effector differentiation and reprogramming  

PubMed Central

Modulation of CD8 coreceptor levels can profoundly affect T-cell sensitivity to antigen. Here we show that the heritable downregulation of CD8 during type 2 polarization of murine CD8+ effector T cells in vitro and in vivo is associated with CpG methylation of several regions of the Cd8a locus. These epigenetic modifications are maintained long-term in vivo following adoptive transfer. Even after extended type 2 polarization, however, some CD8low effector cells respond to interferon-? by re-expressing CD8 and a type 1 cytokine profile in association with partial Cd8a demethylation. Cd8a methylation signatures in naive, polarized and repolarized cells are distinct from those observed during the initiation, maintenance and silencing of CD8 expression by developing T cells in the thymus. This persistent capacity for epigenetic reprogramming of coreceptor levels on effector CD8+ T cells enables the heritable tuning of antigen sensitivity in parallel with changes in type 1/type 2 cytokine balance. PMID:24675400

Harland, Kim L.; Day, E. Bridie; Apte, Simon H.; Russ, Brendan E.; Doherty, Peter C.; Turner, Stephen J.; Kelso, Anne

2014-01-01

152

Strategy Escalation: An emerging paradigm for safe clinical development of T cell gene therapies  

Microsoft Academic Search

Gene therapy techniques are being applied to modify T cells with chimeric antigen receptors (CARs) for therapeutic ends. The versatility of this platform has spawned multiple options for their application with new permutations in strategies continually being invented, a testimony to the creative energies of many investigators. The field is rapidly expanding with immense potential for impact against diverse cancers.

Richard Paul Junghans

2010-01-01

153

Restoration of T-cell homeostasis after T-cell depletion  

Microsoft Academic Search

T-cell homeostasis appears to be maintained throughout much of normal adult life independent ofde-novoproduction from hematopoietic stem cells via thymopoiesis. Instead, peripheral mechanisms are generally sufficient to maintain normal T-cell number, function and adequate TCR repertoire diversity in healthy hosts. Studies of T-cell regeneration in animals, however, have shown that full restoration of T-cell homeostasis after profound T-cell depletion is

Crystal L. Mackall; Frances T. Hakim; Ronald E. Gress

1997-01-01

154

T-Cell Factor/?-Catenin Activity is Suppressed Normally in Two Independent Models of Autosomal Dominant Polycystic Kidney Disease  

PubMed Central

During murine kidney development, canonical WNT signalling is highly active in the renal tubules until about embryonic day E16-E18 when ?-catenin transcriptional activity becomes progressively restricted to the nephrogenic zone. Several in vitro studies have found a link between cilial signalling and ?-catenin regulation. The cilial protein genes PKD1 and PKD2 are known to be mutated in autosomal dominant polycystic kidney disease and previous studies proposed that these mutations could lead to a failure to suppress canonical WNT signalling activity; aberrant activity might then contribute to the cystic phenotype. However, in this study, we show that suppression of canonical WNT activity, defined by a TCF/?-catenin-lacZ reporter, is normal in two independent models of polycystic kidney disease. We crossed a TCF/?-catenin-lacZ reporter mouse with mice Pkd1 or Pkd2 mutations and found that there was no ?-galactosidase staining in cells lining the renal cysts. This suggests that excessive ?-catenin transcriptional activity may not contribute to cystogenesis in these models of autosomal dominant polycystic kidney disease. PMID:21389971

Miller, Michelle M.; Iglesias, Diana M.; Zhang, Zhao; Corsini, Rachel; Chu, LeeLee; Murawski, Inga; Gupta, Indra; Somlo, Stefan; Germino, Gregory G.; Goodyer, Paul R.

2013-01-01

155

The Nuclear Effector of Wnt-Signaling, Tcf1, Functions as a T-Cell–Specific Tumor Suppressor for Development of Lymphomas  

PubMed Central

The HMG-box factor Tcf1 is required during T-cell development in the thymus and mediates the nuclear response to Wnt signals. Tcf1?/? mice have previously been characterized and show developmental blocks at the CD4?CD8? double negative (DN) to CD4+CD8+ double positive transition. Due to the blocks in T-cell development, Tcf1?/? mice normally have a very small thymus. Unexpectedly, a large proportion of Tcf1?/? mice spontaneously develop thymic lymphomas with 50% of mice developing a thymic lymphoma/leukemia at the age of 16 wk. These lymphomas are clonal, highly metastatic, and paradoxically show high Wnt signaling when crossed with Wnt reporter mice and have high expression of Wnt target genes Lef1 and Axin2. In wild-type thymocytes, Tcf1 is higher expressed than Lef1, with a predominance of Wnt inhibitory isoforms. Loss of Tcf1 as repressor of Lef1 leads to high Wnt activity and is the initiating event in lymphoma development, which is exacerbated by activating Notch1 mutations. Thus, Notch1 and loss of Tcf1 functionally act as collaborating oncogenic events. Tcf1 deficiency predisposes to the development of thymic lymphomas by ectopic up-regulation of Lef1 due to lack of Tcf1 repressive isoforms and frequently by cooperating activating mutations in Notch1. Tcf1 therefore functions as a T-cell–specific tumor suppressor gene, besides its established role as a Wnt responsive transcription factor. Thus, Tcf1 acts as a molecular switch between proliferative and repressive signals during T-lymphocyte development in the thymus. PMID:23185135

Tiemessen, Machteld M.; Baert, Miranda R. M.; Schonewille, Tom; Brugman, Martijn H.; Famili, Farbod; Salvatori, Daniela C. F.; Meijerink, Jules P. P.; Ozbek, Ugur; Clevers, Hans; van Dongen, Jacques J. M.; Staal, Frank J. T.

2012-01-01

156

Disordered T-Cell Development and T-Cell Malignancies in SCL LMO1 Double-Transgenic Mice: Parallels with E2A-Deficient Mice  

Microsoft Academic Search

The gene most commonly activated by chromosomal rearrangements in patients with T-cell acute lympho- blastic leukemia (T-ALL) is SCL\\/tal. In collaboration with LMO1 or LMO2, the thymic expression of SCL\\/tal leads to T-ALL at a young age with a high degree of penetrance in transgenic mice. We now show that SCL LMO1 double-transgenic mice display thymocyte developmental abnormalities in terms

DAVID S. CHERVINSKY; XIAN-FENG ZHAO; DU H. LAM; MARYKAY ELLSWORTH; KENNETH W. GROSS; PETER D. APLAN

1999-01-01

157

The MAR-binding protein SATB1 orchestrates temporal and spatial expression of multiple genes during T-cell development  

SciTech Connect

SATB1 is expressed primarily in thymocytes and can act as a transcriptional repressor. SATB1 binds in vivo to the matrix attachment regions (MARs) of DNA, which are implicated in the loop domain organization of chromatin. The role of MAR-binding proteins in specific cell lineages is unknown. We generated SATB1-null mice to determine how SATB1 functions in the T-cell lineage. SATB1-null mice are small in size, have disproportionately small thymi and spleens, and die at 3 weeks of age. At the cellular level, multiple defects in T-cell development were observed. Immature CD3-CD4-CD8 triple negative (TN) thymocytes were greatly reduced in number, and thymocyte development was blocked mainly at the DP stage. The few peripheral CD4{sup +} single positive (SP) cells underwent apoptosis and failed to proliferate in response to activating stimuli. At the molecular level, among 589 genes examined, at least 2% of genes including a proto-oncogene, cytokine receptor genes, and apoptosis-related genes were derepressed at inappropriate stages of T-cell development in SATB1-null mice. For example, IL-2R{alpha} and IL-7R{alpha} genes were ectopically transcribed in CD4{sup 4+}-CD{sup 8+} double positive (DP) thymocytes. SATB1 appears to orchestrate the temporal and spatial expression of genes during T-cell development, thereby ensuring the proper development of this lineage. Our data provide the first evidence that MAR-binding proteins can act as global regulators of cell function in specific cell lineages.

Alvarez, John D.; Yasui, Dag H.; Niida, Hiroyuki; Joh, Tadashi; Loh, Dennis Y.; Kowhi-Shigematsu, Terumi

2000-02-24

158

Foxn1 maintains thymic epithelial cells to support T-cell development via mcm2 in zebrafish  

PubMed Central

The thymus is mainly comprised of thymic epithelial cells (TECs), which form the unique thymic epithelial microenvironment essential for intrathymic T-cell development. Foxn1, a member of the forkhead transcription factor family, is required for establishing a functional thymic rudiment. However, the molecular mechanisms underlying the function of Foxn1 are still largely unclear. Here, we show that Foxn1 functions in thymus development through Mcm2 in the zebrafish. We demonstrate that, in foxn1 knockdown embryos, the thymic rudiment is reduced and T-cell development is impaired. Genome-wide expression profiling shows that a number of genes, including some known thymopoiesis genes, are dysregulated during the initiation of the thymus primordium and immigration of T-cell progenitors to the thymus. Functional and epistatic studies show that mcm2 and cdca7 are downstream of Foxn1, and mcm2 is a direct target gene of Foxn1 in TECs. Finally, we find that the thymus defects in foxn1 and mcm2 morphants might be attributed to reduced cell proliferation rather than apoptosis. Our results reveal that the foxn1-mcm2 axis plays a central role in the genetic regulatory network controlling thymus development in zebrafish. PMID:23213226

Wang, Lu; Wang, Sifeng; Gao, Ya; Wei, Yonglong; Liu, Feng

2012-01-01

159

The Role of Erk1 and Erk2 in Multiple Stages of T Cell Development  

Microsoft Academic Search

Summary Activation of extracellular-signal-regulated protein ki- nase (Erk) is central to growth-factor-receptor-medi- ated signaling including that originating from the T cell antigen receptor. It integrates cytoplasmic signals to effect changes in transcription associated with differ- entiation, proliferation, and survival. In this report, we present an analysis of mice with targeted deletions in Erk1 and Erk2 to assess the relationship between

April M. Fischer; Carol D. Katayama; Giles Pagès; Jacques Pouysségur; Stephen M. Hedrick

2005-01-01

160

ITK tunes IL-4-induced development of innate memory CD8+ T cells in a ?? T and invariant NKT cell-independent manner.  

PubMed

True memory CD8(+) T cells develop post antigenic exposure and can provide life-long immune protection. More recently, other types of memory CD8(+) T cells have been described, such as the memory-like CD8(+) T cells (IMP; CD44(hi)CD122(+)) that arise spontaneously in Itk(-/-) mice, which are suggested to develop as a result of IL-4 secreted by NKT-like ?? T or PLZF(+) NKT cells found in Itk(-/-) mice. However, we report here that whereas IMP CD8(+) T cell development in Itk(-/-) mice is dependent on IL-4/STAT6 signaling, it is not dependent on any ?? T or iNKT cells. Our experiments suggest that the IMP develops as a result of tuning of the CD8(+) T cell response to exogenous IL-4 and TCR triggering by ITK and challenge the current model of IMP CD8(+) T cell development as a result of NKT-like ?? T or iNKT cells. These findings suggest that some naive CD8(+) T cells may be preprogrammed by weak homeostatic TCR signals in the presence of IL-4 to become memory phenotype cells with the ability to elaborate effector function rapidly. The role of ITK in this process suggests a mechanism by which IMP CD8(+) T cells can be generated rapidly in response to infection. PMID:24620029

Huang, Weishan; Huang, Fei; Kannan, Arun Kumar; Hu, Jianfang; August, Avery

2014-07-01

161

NOVEL NONCLASSSICAL MHC CLASS IB GENES ASSOCIATED WITH CD8 T CELL DEVELOPMENT AND THYMIC TUMORS  

PubMed Central

In jawed vertebrates, the heterogeneous nonclassical MHC class Ib (class Ib) gene family encodes molecules structurally similar to classical MHC class Ia (class Ia) but with more limited tissue distribution and lower polymorphism. In mammals, class Ib gene products are involved in stress responses, malignancy and differentiation of intrathymic CD8 T cells. The frog Xenopus laevis possesses at least 20 class Ib genes (XNCs), and 9 subfamilies have been defined so far. We have characterized two novel subfamilies, XNC10 and XNC11. XNC10 is phylogenetically and structurally distinct from both class Ia and other XNC genes. Besides thymic lymphoid tumors, XNC10 is preferentially expressed by circulating T cells and thymocytes of the CD8 lineage both in adult and in larvae from the onset of thymus organogenesis. XNC11 is expressed only by thymocytes and upregulated by several thymic lymphoid tumors. These data provide the first evidence of the expression of any class Ib genes in Xenopus larvae, and suggests evolutionary relationships between certain class Ib genes, malignancy and CD8 T cell ontogeny. PMID:19237199

Goyos, Ana; Ohta, Yuko; Guselnikov, Sergey; Robert, Jacques

2009-01-01

162

The orphan nuclear receptor Ear-2 (Nr2f6) is a novel negative regulator of T cell development.  

PubMed

We describe a novel role for the orphan nuclear receptor Ear-2 in regulating T cell development. Retrovirus-mediated overexpression of Ear-2 (EAR-2++) in a bone marrow (BM) transplantation assay resulted in limited T cell development and a greater than tenfold decrease in thymus size and cellularity relative to controls. Ear-2-transduced murine BM hematopoietic stem cells (HSCs) in OP9-DL1 cultures showed a proliferation deficit during days 1-5 after induction of differentiation, which corresponded to increased expression of the cell cycle regulators p21 (cdkn1a) and p27 (cdkn1b), as well as increased expression of Hes1, Notch3, Egr1, and Scl (Tal1) and decreased expression of Gli1, Gfi-1, HoxA9, PU.1, Nrarp, and Tcf1. In addition, there was a block in differentiation at the DN4 to double-positive (DP) transition accompanied by an increase in apoptosis, similar to the deficit seen in the ROR?t null mouse. Gene expression profiling revealed that, like the ROR?t-deficient mouse, EAR-2++ DP cells had decreased expression of BclXL and increased expression of the proapoptosis gene Bad. In addition, EAR-2++ DP cells had decreased expression of Bcl11b, PU.1, and HoxA9, and increased expression of Id2. Based on these findings, we conclude that EAR-2++ cells were able to migrate to, but not fully repopulate, the thymus because of a cell-intrinsic defect in the proliferation of DN1 cells followed by a block in differentiation from the DN4 to DP stage of T cell development. We conclude that Ear-2 is a novel negative regulator of T-cell development and that downregulation of Ear-2 is indispensable for the proliferation of DN1 cells and the survival of DN4-DP cells. PMID:24096122

Ichim, Christine V; Dervovi?, Džana D; Zúñiga-Pflücker, Juan Carlos; Wells, Richard A

2014-01-01

163

Human T Cell Lymphotropic Virus Type 1 Infection and Early Neurologic Development: A Pilot Study of 48 Children  

PubMed Central

To determine whether human T cell lymphotropic virus type 1 (HTLV-1) infection is associated with delayed neurological development, we examined 48 Peruvian children with exposure to HTLV-1 who were identified at the Instituto Materno-Perinatal. Compared with 38 HTLV-1–seronegative children, the 10 seropositive children did not have higher rates of neurodevelopmental delay. Long-term follow-up is planned. PMID:15472866

Montano, S. M.; Zunt, J. R.; Rodriguez, L.; Quispe, I.; Rodriguez, C.; Altamirano, J.; Bautista, C. T.; Alarcón, J. O. V.; Longstreth, W. T.; Holmes, K. K.

2009-01-01

164

Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination  

Microsoft Academic Search

Cancer vaccine trials frequently report on immunological responses, without any clinical benefit. This paradox may reflect\\u000a the challenge of discriminating between effective and pointless immune responses and sparse knowledge on their long-term development.\\u000a Here, we have analyzed T cell responses in long-term survivors after peptide vaccination. There were three main study aims:\\u000a (1) to characterize the immune response in patients

Jon Amund Kyte; Sissel Trachsel; Bente Risberg; Per thor Straten; Kari Lislerud; Gustav Gaudernack

2009-01-01

165

Identification of stem cell transcriptional programs normally expressed in embryonic and neural stem cells in alloreactive CD8+ T cells mediating graft-versus-host disease  

PubMed Central

A hallmark of graft-versus-host-disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is the cytopathic injury of host tissues mediated by persistent alloreactive effector T cells (TE). However, the mechanisms that regulate the persistence of alloreactive TE during GVHD remain largely unknown. Using mouse GVHD models, we demonstrate that alloreactive CD8+ TE rapidly diminished in vivo when adoptively transferred into irradiated secondary congenic recipient mice. In contrast, although alloreactive CD8+ TE underwent massive apoptosis upon chronic exposure to alloantigens, they proliferated in vivo in secondary allogeneic recipients, persisted and caused severe GVHD. Thus, the continuous proliferation of alloreactive CD8+ TE, which is mediated by alloantigenic stimuli rather than homeostatic factors, is critical to maintaining their persistence. Gene expression profile analysis revealed that while alloreactive CD8+ TE increased the expression of genes associated with cell death, they activated a group of stem cell genes normally expressed in embryonic and neural stem cells. Most of these stem cell genes are associated with cell cycle regulation, DNA replication, chromatin modification and transcription. One of these genes, Ezh2, which encodes a chromatin modifying enzyme, was abundantly expressed in CD8+ TE. Silencing Ezh2 significantly reduced the proliferation of alloantigen-activated CD8+ T cells. Thus, these findings identify that a group of stem cell genes could play important roles in sustaining terminally differentiated alloreactive CD8+ TE and may be therapeutic targets for controlling GVHD. PMID:20116439

Kato, Koji; Cui, Shuaiying; Kuick, Rork; Mineishi, Shin; Hexner, Elizabeth; Ferrara, James LM; Emerson, Stephen G.; Zhang, Yi

2010-01-01

166

Ikaros Sets the Potential for Th17 Lineage Gene Expression through Effects on Chromatin State in Early T Cell Development*  

PubMed Central

Th17 cells are important effectors of immunity to extracellular pathogens, particularly at mucosal surfaces, but they can also contribute to pathologic tissue inflammation and autoimmunity. Defining the multitude of factors that influence their development is therefore of paramount importance. Our previous studies using Ikaros?/? CD4+ T cells implicated Ikaros in Th1 versus Th2 lineage decisions. Here we demonstrate that Ikaros also regulates Th17 differentiation through its ability to promote expression of multiple Th17 lineage-determining genes, including Ahr, Runx1, Rorc, Il17a, and Il22. Ikaros exerts its influence on the chromatin remodeling of these loci at two distinct stages in CD4+ T helper cell development. In naive cells, Ikaros is required to limit repressive chromatin modifications at these gene loci, thus maintaining the potential for expression of the Th17 gene program. Subsequently, Ikaros is essential for the acquisition of permissive histone marks in response to Th17 polarizing signals. Additionally, Ikaros represses the expression of genes that limit Th17 development, including Foxp3 and Tbx21. These data define new targets of the action of Ikaros and indicate that Ikaros plays a critical role in CD4+ T cell differentiation by integrating specific cytokine cues and directing epigenetic modifications that facilitate activation or repression of relevant genes that drive T cell lineage choice. PMID:24145030

Wong, Larry Y.; Hatfield, Julianne K.; Brown, Melissa A.

2013-01-01

167

Mnk1 and 2 are dispensable for T cell development and activation but important for the pathogenesis of experimental autoimmune encephalomyelitis.  

PubMed

T cell development and activation are usually accompanied by expansion and production of numerous proteins that require active translation. The eukaryotic translation initiation factor 4E (eIF4E) binds to the 5' cap structure of mRNA and is critical for cap-dependent translational initiation. It has been hypothesized that MAPK-interacting kinase 1 and 2 (Mnk1/2) promote cap-dependent translation by phosphorylating eIF4E at serine 209 (S209). Pharmacologic studies using inhibitors have suggested that Mnk1/2 have important roles in T cells. However, genetic evidence supporting such conclusions is lacking. Moreover, the signaling pathways that regulate Mnk1/2 in T cells remain unclear. We demonstrate that TCR engagement activates Mnk1/2 in primary T cells. Such activation is dependent on Ras-Erk1/2 signaling and is inhibited by diacylglycerol kinases ? and ?. Mnk1/2 double deficiency in mice abolishes TCR-induced eIF4E S209 phosphorylation, indicating their absolute requirement for eIF4E S209 phosphorylation. However, Mnk1/2 double deficiency does not affect the development of conventional ?? T cells, regulatory T cells, or NKT cells. Furthermore, T cell activation, in vivo primary and memory CD8 T cell responses to microbial infection, and NKT cell cytokine production were not obviously altered by Mnk1/2 deficiency. Although Mnk1/2 deficiency causes decreased IL-17 and IFN-? production by CD4 T cells following immunization of mice with myelin oligodendrocyte glycoprotein peptide in complete Freund's adjuvant, correlating with milder experimental autoimmune encephalomyelitis scores, it does not affect Th cell differentiation in vitro. Together, these data suggest that Mnk1/2 has a minimal role in T cell development and activation but may regulate non-T cell lineages to control Th1 and Th17 differentiation in vivo. PMID:23269249

Gorentla, Balachandra K; Krishna, Sruti; Shin, Jinwook; Inoue, Makoto; Shinohara, Mari L; Grayson, Jason M; Fukunaga, Rikiro; Zhong, Xiao-Ping

2013-02-01

168

Stochastic modelling of T cell repertoire maintenance  

E-print Network

progenitor BONE MARROW THYMUS Positive and negative selection Memory T cellSelf antigen (Survival signal + lymphoid vessels = peripheral lymphoid organs bone marrow T cell development 1 Precursor T cells are bornStochastic modelling of T cell repertoire maintenance Hugo van den Berg1 Emily Stirk2 C. M.-P.2 1

Wirosoetisno, Djoko

169

Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4+ T cells.  

PubMed

Evidence links chronic inflammation with cancer, but cellular mechanisms involved in this process remain unclear. We have demonstrated that in humans, inflammatory conditions that predispose to development of skin and colon tumors are associated with accumulation in tissues of CD33(+)S100A9(+) cells, the phenotype typical for myeloid-derived suppressor cells in cancer or immature myeloid cells (IMCs) in tumor-free hosts. To identify the direct role of these cells in tumor development, we used S100A9 transgenic mice to create the conditions for topical accumulation of these cells in the skin in the absence of infection or tissue damage. These mice demonstrated accumulation of granulocytic IMCs in the skin upon topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in a dramatic increase in the formation of papillomas during epidermal carcinogenesis. The effect of IMCs on tumorigenesis was not associated with immune suppression, but with CCL4 (chemokine [C-C motif] ligand 4)-mediated recruitment of IL-17-producing CD4(+) T cells. This chemokine was released by activated IMCs. Elimination of CD4(+) T cells or blockade of CCL4 or IL-17 abrogated the increase in tumor formation caused by myeloid cells. Thus, this study implicates accumulation of IMCs as an initial step in facilitation of tumor formation, followed by the recruitment of CD4(+) T cells. PMID:25667306

Ortiz, Myrna L; Kumar, Vinit; Martner, Anna; Mony, Sridevi; Donthireddy, Laxminarasimha; Condamine, Thomas; Seykora, John; Knight, Stella C; Malietzis, George; Lee, Gui Han; Moorghen, Morgan; Lenox, Brianna; Luetteke, Noreen; Celis, Esteban; Gabrilovich, Dmitry

2015-03-01

170

T cell development requires constraint of the myeloid regulator C/EBPa by the Notch target and transcriptional repressor Hes1  

PubMed Central

Notch signaling induces gene expression of the T cell lineage and discourages alternative fate outcomes. Hematopoietic deficiency in the Notch target Hes1 results in severe T cell lineage defects; however, the underlying mechanism is unknown. We found here that Hes1 constrained myeloid gene-expression programs in T cell progenitor cells, as deletion of the myeloid regulator C/EBPa restored the development of T cells from Hes1-deficient progenitor cells. Repression of Cebpa by Hes1 required its DNA-binding and Groucho-recruitment domains. Hes1-deficient multipotent progenitor cells showed a developmental bias toward myeloid and dendritic cells after Notch signaling, whereas Hes1-deficient lymphoid progenitor cells required additional cytokine signaling for diversion into the myeloid lineage. Our findings establish the importance of constraining developmental programs of the myeloid lineage early in T cell development. PMID:24185616

De Obaldia, Maria Elena; Bell, J Jeremiah; Wang, Xinxin; Harly, Christelle; Yashiro-Ohtani, Yumi; DeLong, Jonathan H; Zlotoff, Daniel A; Sultana, Dil Afroz; Pear, Warren S; Bhandoola, Avinash

2014-01-01

171

T cell development requires constraint of the myeloid regulator C/EBP-? by the Notch target and transcriptional repressor Hes1.  

PubMed

Notch signaling induces gene expression of the T cell lineage and discourages alternative fate outcomes. Hematopoietic deficiency in the Notch target Hes1 results in severe T cell lineage defects; however, the underlying mechanism is unknown. We found here that Hes1 constrained myeloid gene-expression programs in T cell progenitor cells, as deletion of the myeloid regulator C/EBP-? restored the development of T cells from Hes1-deficient progenitor cells. Repression of Cebpa by Hes1 required its DNA-binding and Groucho-recruitment domains. Hes1-deficient multipotent progenitor cells showed a developmental bias toward myeloid cells and dendritic cells after Notch signaling, whereas Hes1-deficient lymphoid progenitor cells required additional cytokine signaling for diversion into the myeloid lineage. Our findings establish the importance of constraining developmental programs of the myeloid lineage early in T cell development. PMID:24185616

De Obaldia, Maria Elena; Bell, J Jeremiah; Wang, Xinxin; Harly, Christelle; Yashiro-Ohtani, Yumi; DeLong, Jonathan H; Zlotoff, Daniel A; Sultana, Dil Afroz; Pear, Warren S; Bhandoola, Avinash

2013-12-01

172

Hierarchical self-tolerance to T cell determinants within the ubiquitous nuclear self-antigen La (SS-B) permits induction of systemic autoimmunity in normal mice  

PubMed Central

Systemic autoimmune diseases are frequently associated with clustering of high titer autoantibody responses towards nuclear self-antigens. Little is known, however, about the extent of immune tolerance to the target nuclear antigens or the events leading to the complex autoantibody responses that are characteristic of systemic autoimmunity. To address these issues, we have examined the mouse immune response to La autoantigen (mLa) and the homologous human La antigen (hLa), which are components of the La(SS-B)/Ro(SS-A) ribonucleoprotein (RNP) complex targeted in systemic lupus erythematosus and primary Sjogren's syndrome. The findings reveal the presence of hierarchical T cell tolerance involving multiple autodeterminants within the La autoantigen expressed by normal H-2k and H-2a mice. At one end of this spectrum, there was no detectable T or B cell autoimmunity observed in mice that were immunized with the immunodominant mLa287-301 determinant, which differed by a single residue in its core sequence from the homologous but highly immunogenic human La288-302 determinant. Interestingly, the mLa287-301 peptide acted as an altered peptide ligand that specifically antagonized the activation of an hLa288-302-specific T cell hybridoma. In contrast to the tolerogenic mLa287-301 determinant, a range of autoimmune potential was identified among poorly tolerizing, subdominant self-peptides present within mouse La autoantigen. Notably, immunization of normal mice with the autologous subdominant La25-44 and La106-129 determinants resulted in limited or no detectable autoantibody response. In contrast, immunization with the subdominant mouse La13-30 determinant induced a proliferative T cell response associated with the appearance of specific autoantibodies recognizing multiple intrastructural (La) and intermolecular components (Ro) of the murine La/Ro RNP. The findings suggest how diversified autoimmunity might follow initiation of immunity to simple peptide mimics of poorly tolerogenic determinants that are present within ubiquitous self-antigens. PMID:8920873

1996-01-01

173

The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development  

PubMed Central

CD4+ regulatory T cells (Treg cells) expressing the transcription factor Foxp3 play a pivotal role in maintaining peripheral tolerance by inhibiting the expansion and function of pathogenic conventional T cells (Tconv cells). In this study, we show that a locus on rat chromosome 9 controls the size of the natural Treg cell compartment. Fine mapping of this locus with interval-specific congenic lines and association experiments using single nucleotide polymorphisms (SNPs) identified a nonsynonymous SNP in the Vav1 gene that leads to the substitution of an arginine by a tryptophan (p.Arg63Trp). This p.Arg63Trp polymorphism is associated with increased proportion and absolute numbers of Treg cells in the thymus and peripheral lymphoid organs, without impacting the size of the Tconv cell compartment. This polymorphism is also responsible for Vav1 constitutive activation, revealed by its tyrosine 174 hyperphosphorylation and increased guanine nucleotide exchange factor activity. Moreover, it induces a marked reduction in Vav1 cellular contents and a reduction of Ca2+ flux after TCR engagement. Together, our data reveal a key role for Vav1-dependent T cell antigen receptor signaling in natural Treg cell development. PMID:21948080

Colacios, Céline; Casemayou, Audrey; Dejean, Anne S.; Gaits-Iacovoni, Frédérique; Pedros, Christophe; Bernard, Isabelle; Lagrange, Dominique; Deckert, Marcel; Lamouroux, Lucille; Jagodic, Maja; Olsson, Tomas; Liblau, Roland S.; Fournié, Gilbert J.

2011-01-01

174

Influence of HIV and HCV on T cell antigen presentation and challenges in the development of vaccines.  

PubMed

Some of the central challenges for developing effective vaccines against HIV and hepatitis C virus (HCV) are similar. Both infections are caused by small, highly mutable, rapidly replicating RNA viruses with the ability to establish long-term chronic pathogenic infection in human hosts. HIV has caused 60 million infections globally and HCV 180 million and both viruses may co-exist among certain populations by virtue of common blood-borne, sexual, or vertical transmission. Persistence of both pathogens is achieved by evasion of intrinsic, innate, and adaptive immune defenses but with some distinct mechanisms reflecting their differences in evolutionary history, replication characteristics, cell tropism, and visibility to mucosal versus systemic and hepatic immune responses. A potent and durable antibody and T cell response is a likely requirement of future HIV and HCV vaccines. Perhaps the single biggest difference between the two vaccine design challenges is that in HCV, a natural model of protective immunity can be found in those who resolve acute infection spontaneously. Such spontaneous resolvers exhibit durable and functional CD4(+) and CD8(+) T cell responses (Diepolder et al., 1995; Cooper et al., 1999; Thimme et al., 2001; Grakoui et al., 2003; Lauer et al., 2004; Schulze Zur Wiesch et al., 2012). However, frequent re-infection suggests partial or lack of protective immunity against heterologous HCV strains, possibly indicative of the degree of genetic diversity of circulating HCV genotypes and subtypes. There is no natural model of protective immunity in HIV, however, studies of "elite controllers," or individuals who have durably suppressed levels of plasma HIV RNA without antiretroviral therapy, has provided the strongest evidence for CD8(+) T cell responses in controlling viremia and limiting reservoir burden in established infection. Here we compare and contrast the specific mechanisms of immune evasion used by HIV and HCV, which subvert adaptive human leukocyte antigen (HLA)-restricted T cell immunity in natural infection, and the challenges these pose for designing effective preventative or therapeutic vaccines. PMID:25352836

John, Mina; Gaudieri, Silvana

2014-01-01

175

Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma.  

PubMed

No curative treatment exists for glioblastoma, with median survival times of less than 2 years from diagnosis. As an approach to develop immune-based therapies for glioblastoma, we sought to target antigens expressed in glioma stem cells (GSCs). GSCs have multiple properties that make them significantly more representative of glioma tumors than established glioma cell lines. Epidermal growth factor receptor variant III (EGFRvIII) is the result of a novel tumor-specific gene rearrangement that produces a unique protein expressed in approximately 30% of gliomas, and is an ideal target for immunotherapy. Using PCR primers spanning the EGFRvIII-specific deletion, we found that this tumor-specific gene is expressed in three of three GCS lines. Based on the sequence information of seven EGFRvIII-specific monoclonal antibodies (mAbs), we assembled chimeric antigen receptors (CARs) and evaluated the ability of CAR-engineered T cells to recognize EGFRvIII. Three of these anti-EGFRvIII CAR-engineered T cells produced the effector cytokine, interferon-?, and lysed antigen-expressing target cells. We concentrated development on a CAR produced from human mAb 139, which specifically recognized GSC lines and glioma cell lines expressing mutant EGFRvIII, but not wild-type EGFR and did not recognize any normal human cell tested. Using the 139-based CAR, T cells from glioblastoma patients could be genetically engineered to recognize EGFRvIII-expressing tumors and could be expanded ex vivo to large numbers, and maintained their antitumor activity. Based on these observations, a ?-retroviral vector expressing this EGFRvIII CAR was produced for clinical application. PMID:22780919

Morgan, Richard A; Johnson, Laura A; Davis, Jeremy L; Zheng, Zhili; Woolard, Kevin D; Reap, Elizabeth A; Feldman, Steven A; Chinnasamy, Nachimuthu; Kuan, Chien-Tsun; Song, Hua; Zhang, Wei; Fine, Howard A; Rosenberg, Steven A

2012-10-01

176

Ex Vivo ?-Retroviral Gene Therapy of Dogs with X-linked Severe Combined Immunodeficiency and the Development of a Thymic T Cell Lymphoma  

PubMed Central

We have previously shown that in vivo ?-retroviral gene therapy of dogs with X-linked severe combined immunodeficiency (XSCID) results in sustained T cell reconstitution and sustained marking in myeloid and B cells for up to 4 years with no evidence of any serious adverse effects. The purpose of this study was to determine whether ex vivo ?-retroviral gene therapy of XSCID dogs results in a similar outcome. Eight of 12 XSCID dogs treated with an average of dose of 5.8 × 106 transduced CD34+ cells/kg successfully engrafted producing normal numbers of gene-corrected CD45RA+ (naïve) T cells. However, this was followed by a steady decrease in CD45RA+ T cells, T cell diversity, and thymic output as measured by T cell receptor excision circles (TRECs) resulting in a T cell lymphopenia. None of the dogs survived past 11 months post treatment. At necropsy, few gene-corrected thymocytes were observed correlating with the TREC levels and one of the dogs was diagnosed with a thymic T cell lymphoma that was attributed to the gene therapy. This study highlights the outcome differences between the ex vivo and in vivo approach to ?-retroviral gene therapy and is the first to document a serious adverse event following gene therapy in a canine model of a human genetic disease. PMID:21536334

Kennedy, Douglas R.; Hartnett, Brian J.; Kennedy, Jeffrey S.; Vernau, William; Moore, Peter F.; O’Malley, Thomas; Burkly, Linda C.; Henthorn, Paula S.; Felsburg, Peter J.

2011-01-01

177

Impaired development of V gamma 3 dendritic epidermal T cells in p56lck protein tyrosine kinase-deficient and CD45 protein tyrosine phosphatase- deficient mice  

PubMed Central

To determine whether p56lck protein tyrosine kinase and CD45 protein tyrosine phosphatase are involved in the signal transduction during intrathymic differentiation of gamma/delta T cells, we have examined the development of T cells expressing V gamma 3 T cell receptor (TCR) in mice deficient for either protein. The skin from both mice contained significantly reduced numbers of dendritic epidermal T cells expressing decreased levels of V gamma 3 TCR at the cell surface. Analysis of the fetal thymus from these mice suggested that maturation of V gamma 3 thymocytes was blocked at the immature stage that was characterized by the low level of V gamma 3 TCR and the high level of heat stable antigen. These results imply that both p56lck and CD45 are involved in the signal transduction during maturation of V gamma 3 T cells in the fetal thymus. PMID:7807014

1995-01-01

178

Unexpected Role for the B cell-specific Src Family Kinase Blk in the Development of IL-17-Producing ?? T Cells  

PubMed Central

The Ag receptors on ?? and ?? T cells differ not only in the nature of the ligands that they recognize but also in their signaling potential. We hypothesized that the differences in ??- and ??TCR signal transduction were due to differences in the intracellular signaling pathways coupled to these two TCRs. To investigate this, we employed transcriptional profiling to identify genes encoding signaling molecules that are differentially expressed in mature ?? and ?? T cell populations. Unexpectedly, we found that B lymphoid kinase (Blk), a Src family kinase expressed primarily in B cells, is expressed in ?? T cells but not in ?? T cells. Analysis of Blk-deficient mice revealed that Blk is required for the development of IL-17-producing ?? T cells. Furthermore, Blk is expressed in lymphoid precursors and, in this capacity, plays a role in regulating thymus cellularity during ontogeny. PMID:20974990

Laird, Renee M.; Laky, Karen; Hayes, Sandra M.

2010-01-01

179

CD4+ T cells are required for development of a murine retrovirus- induced immunodeficiency syndrome (MAIDS)  

PubMed Central

Mice depleted in vivo of CD4+ Th cells by treatment with mAb GK1.5 were found to be resistant to the lymphoproliferative/immunodeficiency disease (MAIDS) induced in intact mice by infection with the mixture of LP-BM5 murine leukemia viruses. Depleted mice did not develop lymphadenopathy or splenomegaly, had normal serum IgM levels, normal CTL responses to alloantigens, and were able to generate PFC responses to Th-independent antigens even though frequencies of virus-producing spleen cells were comparable in depleted and intact mice. Depletion of CD4+ Th cells after infection resulted in a reversal of many abnormalities exhibited by infected controls; spleen weights, serum IgM levels, and allogeneic CTL responses of treated mice were comparable to those of uninfected controls. These results demonstrate that dysfunction of CD4+ Th cells is central to the induction and progression of both T and B cell abnormalities in MAIDS. PMID:2842430

1988-01-01

180

ERK1-Deficient Mice Show Normal T Cell Effector Function and Are Highly Susceptible to Experimental Autoimmune  

E-print Network

oligodendrocyte glycoprotein peptide 35­55 and to the prototypic foreign Ag OVA are not impaired as compared- myelitis induced with myelin oligodendrocyte glycoprotein peptide 35­55. Finally, thymocyte development to the prototypic foreign Ag OVA and the self Ag myelin oligodendrocyte glycoprotein (MOG)3 35­55 in ERK1-de

181

?1?1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis  

Microsoft Academic Search

Psoriasis is a common T cell–mediated autoimmune inflammatory disease. We show that blocking the interaction of ?1?1 integrin (VLA-1) with collagen prevented accumulation of epidermal T cells and immunopathology of psoriasis. ?1?1 integrin, a major collagen-binding surface receptor, was exclusively expressed by epidermal but not dermal T cells. ?1?1-positive T cells showed characteristic surface markers of effector memory cells and

Onur Boyman; Giulia Tonel; Adrian Tun-Kyi; Ute Laggner; Antonin de Fougerolles; Victor Kotelianski; Humphrey Gardner; Curdin Conrad; Frank O Nestle

2007-01-01

182

Ablation of ribosomal protein L22 selectively impairs alphabeta T cell development by activation of a p53-dependent checkpoint.  

PubMed

The alphabeta and gammadelta T lineages are thought to arise from a common precursor; however, the regulation of separation and development of these lineages is not fully understood. We report here that development of alphabeta and gammadelta precursors was differentially affected by elimination of ribosomal protein L22 (Rpl22), which is ubiquitously expressed but not essential for translation. Rpl22 deficiency selectively arrested development of alphabeta-lineage T cells at the beta-selection checkpoint by inducing their death. The death was caused by induction of p53 expression, because p53 deficiency blocked death and restored development of Rpl22-deficient thymocytes. Importantly, Rpl22 deficiency led to selective upregulation of p53 in alphabeta-lineage thymocytes, at least in part by increasing p53 synthesis. Taken together, these data indicate that Rpl22 deficiency activated a p53-dependent checkpoint that produced a remarkably selective block in alphabeta T cell development but spared gammadelta-lineage cells, suggesting that some ribosomal proteins may perform cell-type-specific or stage-specific functions. PMID:17555992

Anderson, Stephen J; Lauritsen, Jens Peter Holst; Hartman, Matthew G; Foushee, Ann Marie Digeorge; Lefebvre, Juliette M; Shinton, Susan A; Gerhardt, Brenda; Hardy, Richard R; Oravecz, Tamas; Wiest, David L

2007-06-01

183

Defective thymic progenitor development and mature T-cell responses in a mouse model for Down syndrome  

PubMed Central

In addition to archetypal cognitive defects, Down syndrome (DS) is characterized by altered lymphocyte development and function, including premature thymic involution and increased incidence of infections. However, the potential mechanisms for these changes have not been fully elucidated. The current study used the Ts65Dn mouse model of DS to assess deficiencies in T-cell development and possible molecular alterations. Ts65Dn mice exhibited premature thymic involution and a threefold to fourfold decrease in the number and proportion of immature, double-negative thymocyte progenitors. In addition, there were twofold fewer double-positive and CD4 single-positive thymocytes in Ts65Dn thymuses. Reflecting this deficient thymic function, there were fewer naive T cells in the spleen and polyclonal stimulation of peripheral T cells exhibited a marked reduction in proliferation, suggesting a senescent phenotype. In contrast, B-cell progenitors were unchanged in the bone marrow of Ts65Dn mice, but in the spleen, there were decreased transitional and follicular B cells and these cells proliferated less upon antigen receptor stimulus but not in response to lipopolysaccharide. As a potential mechanism for diminished thymic function, immature thymocyte populations expressed diminished levels of the cytokine receptor interleukin-7R?, which was associated with decreased proliferation and increased apoptosis. Increased oxidative stress and inhibition of the Notch pathway were identified as possible mediators of decreased interleukin-7R? expression in Ts65Dn mice. The data suggest that immature thymocyte defects underlie immune dysfunction in DS and that increased oxidative stress and reduced cytokine signalling may alter lymphocyte development in Ts65Dn mice. PMID:23432468

Lorenzo, Laureanne P E; Shatynski, Kristen E; Clark, Sarah; Yarowsky, Paul J; Williams, Mark S

2013-01-01

184

Development of CD4+CD25+FoxP3+ regulatory T cells from cord blood hematopoietic progenitor cells.  

PubMed

Adult stem cells are capable of generating all of the cells of the hematopoietic system, and this process is orchestrated in part by the interactions between these cells and the stroma. T cell progenitors emerge from the stem cell compartment and migrate to the thymus, where their terminal differentiation and maturation occur, and it is during this phase that selection shapes the immune repertoire. Notch ligands, including Delta-like 1 (DL1), play a critical role in this lymphoid differentiation. To mimic this in vitro, stroma-expressing DL1 have been used to generate CD4(+)CD8(+) double-positive and single-positive T cells from hematopoietic stem/progenitor cells. This system provides a robust tool to investigate thymopoiesis; however, its capacity to generate regulatory T cells (Tregs) has yet to be reported. Natural Tregs (nTregs) develop in the thymus and help maintain immune homeostasis and have potential clinical use as a cell therapy for modulation of autoimmune disease or for transplant tolerization. Here, we describe for the first time the development of a population of CD4(+)CD25(+) CD127(lo)FoxP3(+) cells that emerge in coculture of cord blood (CB) CD34(+) progenitors on OP9-DL1 stroma. These hematopoietic progenitor-derived CD4(+)CD25(+) Tregs have comparable suppressor function with CB nTregs in vitro. The addition of IL-2 to the coculture enhanced the expansion and survival of this population significantly. This manipulable culture system, therefore, generates functional Tregs and provides a system to elucidate the mechanism of Treg development. PMID:19103952

Hutton, Jonathon F; Gargett, Tessa; Sadlon, Timothy J; Bresatz, Suzanne; Brown, Cheryl Y; Zola, Heddy; Shannon, M Frances; D'Andrea, Richard J; Barry, Simon C

2009-03-01

185

Phenotypic changes to the endogenous antigen-specific CD8+ T cell response correlates with the development and resolution of allergic airway disease.  

PubMed

The role of CD8(+) T cells in the pathogenesis of asthma remains controversial, as both pro- and anti-inflammatory functions have been suggested. This study was designed to examine the endogenous CD8(+) T cell response in a biphasic ovalbumin (OVA)-induced model of allergic airway disease (AAD) and its subsequent resolution with the development of local inhalational tolerance (LIT). We observed increases in OVA-specific CD8(+) T cell numbers in the local lung compartments (bronchoalveolar lavage, lung tissue, hilar lymph node) at AAD and LIT; systemic compartments (spleen, inguinal lymph node) displayed no such increases in CD8(+) T cell numbers. OVA-specific CD8(+) T cells appeared to exhibit plasticity both phenotypically and functionally. They possessed pro-inflammatory characteristics at AAD, with high phenotypic expression of CD11a and increased functional expression of granzyme B and interferon-?. In contrast, at LIT they showed increased phenotypic expression of the inhibitory marker NKG2A and functionally did not produce granzyme B or interferon-?. In addition, in a discontinuous model the OVA-specific CD8(+) T cells could be recalled on re-exposure to OVA, demonstrating memory. Finally, confocal microscopy results showed that OVA-specific CD8(+) T cells at AAD are associated with B cell aggregates in lung tissue. These B cell aggregates resembled tertiary ectopic lymphoid tissue and may thus provide a local environment for the salient cellular interactions that contribute to the development of LIT. PMID:22452921

McNamara, Jeffrey T; Schramm, Craig M; Singh, Anurag; Secor, Eric R; Guernsey, Linda A; Lefrançois, Leo; Thrall, Roger S

2012-05-01

186

Phenotypic Changes to the Endogenous Antigen-Specific CD8+ T Cell Response Correlates with the Development and Resolution of Allergic Airway Disease  

PubMed Central

The role of CD8+ T cells in the pathogenesis of asthma remains controversial, as both pro- and anti-inflammatory functions have been suggested. This study was designed to examine the endogenous CD8+ T cell response in a biphasic ovalbumin (OVA)–induced model of allergic airway disease (AAD) and its subsequent resolution with the development of local inhalational tolerance (LIT). We observed increases in OVA-specific CD8+ T cell numbers in the local lung compartments (bronchoalveolar lavage, lung tissue, hilar lymph node) at AAD and LIT; systemic compartments (spleen, inguinal lymph node) displayed no such increases in CD8+ T cell numbers. OVA-specific CD8+ T cells appeared to exhibit plasticity both phenotypically and functionally. They possessed pro-inflammatory characteristics at AAD, with high phenotypic expression of CD11a and increased functional expression of granzyme B and interferon-?. In contrast, at LIT they showed increased phenotypic expression of the inhibitory marker NKG2A and functionally did not produce granzyme B or interferon-?. In addition, in a discontinuous model the OVA-specific CD8+ T cells could be recalled on re-exposure to OVA, demonstrating memory. Finally, confocal microscopy results showed that OVA-specific CD8+ T cells at AAD are associated with B cell aggregates in lung tissue. These B cell aggregates resembled tertiary ectopic lymphoid tissue and may thus provide a local environment for the salient cellular interactions that contribute to the development of LIT. PMID:22452921

McNamara, Jeffrey T.; Schramm, Craig M.; Singh, Anurag; Secor, Eric R.; Guernsey, Linda A.; Lefrançois, Leo; Thrall, Roger S.

2012-01-01

187

Bcl11b prevents the intrathymic development of innate CD8 T cells in a cell intrinsic manner.  

PubMed

If Bcl11b activity is compromised, CD4(+)CD8(+) double-positive (DP) thymocytes produce a greatly increased fraction of innate CD8(+) single-positive (SP) cells highly producing IFN-?, which are also increased in mice deficient of genes such as Itk, Id3 and NF-?B1 that affect TCR signaling. Of interest, the increase in the former two is due to the bystander effect of IL-4 that is secreted by promyelocytic leukemia zinc finger-expressing NKT and ??T cells whereas the increase in the latter is cell intrinsic. Bcl11b zinc-finger proteins play key roles in T cell development and T cell-mediated immune response likely through TCR signaling. We examined thymocytes at and after the DP stage in Bcl11b (F/S826G) CD4cre, Bcl11b (F/+) CD4cre and Bcl11b (+/S826G) mice, carrying the allele that substituted serine for glycine at the position of 826. Here we show that Bcl11b impairment leads to an increase in the population of TCR??(high)CD44(high)CD122(high) innate CD8SP thymocytes, together with two different developmental abnormalities: impaired positive and negative selection accompanying a reduction in the number of CD8SP cells, and developmental arrest of NKT cells at multiple steps. The innate CD8SP thymocytes express Eomes and secrete IFN-? after stimulation with PMA and ionomycin, and in this case their increase is not due to a bystander effect of IL-4 but cell intrinsic. Those results indicate that Bcl11b regulates development of different thymocyte subsets at multiple stages and prevents an excess of innate CD8SP thymocytes. PMID:25422283

Hirose, Satoshi; Touma, Maki; Go, Rieka; Katsuragi, Yoshinori; Sakuraba, Yoshiyuki; Gondo, Yoichi; Abe, Manabu; Sakimura, Kenji; Mishima, Yukio; Kominami, Ryo

2015-04-01

188

Ubiquitination Regulates Expression of the Serine/Arginine-rich Splicing Factor 1 (SRSF1) in Normal and Systemic Lupus Erythematosus (SLE) T Cells*  

PubMed Central

T cells from patients with systemic lupus erythematosus (SLE) exhibit reduced expression of the critical T cell receptor (TCR)-associated CD3? signaling chain and are poor producers of the vital cytokine IL-2. By oligonucleotide pulldown and mass spectrometry discovery approaches, we identified the splicing regulator serine/arginine-rich splicing factor (SRSF) 1 or splicing factor 2/alternative splicing factor (SF2/ASF) to be important in the expression of CD3? chain. Importantly, increases in the expression of SRSF1 rescued IL-2 production in T cells from patients with SLE. In this study, we investigated the regulation of SRSF1 expression in resting and activated human T cells. We found that T cell stimulation induced a rapid and significant increase in mRNA expression of SRSF1; however, protein expression levels did not correlate with this increase. Co-engagement of CD28 induced a similar mRNA induction and reduction in protein levels. Proteasomal but not lysosomal degradation was involved in this down-regulation as evidenced by blocking with specific inhibitors MG132 and bafilomycin, respectively. Immunoprecipitation studies showed increased ubiquitination of SRSF1 in activated T cells. Interestingly, T cells from patients with SLE showed increased ubiquitination of SRSF1 when compared with those from healthy individuals. Our results demonstrate a novel mechanism of regulation of the splicing factor SRSF1 in human T cells and a potential molecular mechanism that controls its expression in SLE. PMID:24368769

Moulton, Vaishali R.; Gillooly, Andrew R.; Tsokos, George C.

2014-01-01

189

Strategy escalation: an emerging paradigm for safe clinical development of T cell gene therapies.  

PubMed

Gene therapy techniques are being applied to modify T cells with chimeric antigen receptors (CARs) for therapeutic ends. The versatility of this platform has spawned multiple options for their application with new permutations in strategies continually being invented, a testimony to the creative energies of many investigators. The field is rapidly expanding with immense potential for impact against diverse cancers. But this rapid expansion, like the Big Bang, comes with a somewhat chaotic evolution of its therapeutic universe that can also be dangerous, as seen by recently publicized deaths. Time-honored methods for new drug testing embodied in Dose Escalation that were suitable for traditional inert agents are now inadequate for these novel "living drugs". In the following, I propose an approach to escalating risk for patient exposures with these new immuno-gene therapy agents, termed Strategy Escalation, that accounts for the molecular and biological features of the modified cells and the methods of their administration. This proposal is offered not as a prescriptive but as a discussion framework that investigators may wish to consider in configuring their intended clinical applications. PMID:20537174

Junghans, Richard Paul

2010-01-01

190

T-Cell-Based Immunosuppressive Therapy Inhibits the Development of Natural Antibodies in Infant Baboons  

PubMed Central

Background We set out to determine whether B-cell tolerance to A/B-incompatible alloantigens and pig xenoantigens could be achieved in infant baboons. Methods Artery patch grafts were implanted in the abdominal aorta in 3-month-old baboons using A/B-incompatible (AB-I) allografts or wild-type pig xenografts (pig). Group 1 (Gp1) (controls, n = 6) received no immunosuppressive therapy (IS) and no graft. Gp2 (n = 2) received an AB-I or pig graft but no IS. Gp3 received AB-I grafts + IS (Gp3A: n = 2) or pig grafts + IS (Gp3B: n = 2). IS consisted of ATG, anti-CD154mAb, and mycophenolate mofetil until age 8 to 12 months. Gp4 (n = 2) received IS only but no graft. Results In Gp1, anti-A/B and cytotoxic anti-pig immunoglobulin-M increased steadily during the first year. Gp2 became sensitized to donor-specific AB-I or pig antigens within 2 weeks. Gp3 and Gp4 infants that received anti-CD154mAb made no or minimal anti-A/B and anti-pig antibodies while receiving IS. Discussion The production of natural anti-A/B and anti-pig antibodies was inhibited by IS with anti-CD154mAb, even in the absence of an allograft or xenograft, suggesting that natural antibodies may not be entirely T-cell independent. These data are in contrast to clinical experience with AB-I allotransplantation in infants, who cease producing only donor-specific antibodies. PMID:22441321

Dons, Eefje M.; Montoya, Claudia; Long, Cassandra E.; Hara, Hidetaka; Echeverri, Gabriel J.; Ekser, Burcin; Ezzelarab, Corin; Medellin, Dasha Roa; van der Windt, Dirk J.; Murase, Noriko; Rigatti, Lora H.; Wagner, Robert; Wolf, Roman F.; Ezzelarab, Mohamed; West, Lori J.; Ijzermans, Jan N. M.; Cooper, David K. C.

2013-01-01

191

Development of ?? T cell subset responses in gnotobiotic pigs infected with human rotaviruses and colonized with probiotic lactobacilli  

PubMed Central

?? T cell responses are induced by various viral and bacterial infections. Different ?? T cells contribute to activation and regulation of the inflammatory response and to epithelial repair. How ?? T cells respond to rotavirus infection and how the colonization of probiotics influences the ?? T cell response were unknown. In this study, we evaluated by multicolor flow cytometry the frequencies and distribution of total ?? T cells and three major subsets (CD2?CD8?, CD2+CD8? and CD2+CD8+) in ileum, spleen and blood of gnotobiotic (Gn) pigs at early (3–5 days) and late phases (28 days) after rotavirus infection. The Gn pigs were inoculated with the virulent human rotavirus Wa strain and colonized with a mixture of two strains of probiotics Lactobacillus acidophilus and Lactobacillus reuteri. In naive pigs, the highest frequency of total ?? T cells was found in blood, followed by spleen and ileum at the early age (8–10 days old) whereas in older pigs (32 days of age) the highest frequency of total ?? T cells was found in ileum and spleen followed by blood. Rotavirus infection significantly increased frequencies of intestinal total ?? T cells and the putatively regulatory CD2+CD8+ ?? T cell subset and decreased frequencies of the putatively proinflammatory CD8? subsets in ileum, spleen and blood at post-infection days (PID) 3 or 5. The three ?? T cell subsets distributed and responded differently after rotavirus infection and/or lactobacilli colonization. The CD2+CD8+ subset contributed the most to the expansion of total ?? T cells after rotavirus infection in ileum because more than 77% of the total ?? T cells there were CD2+CD8+ cells. There was an additive effect between lactobacilli and rotavirus in inducing total ?? T cell expansion in ileum at PID 5. The overall effect of lactobacilli colonization versus rotavirus infection on frequencies of the CD2+CD8+ ?? T cell subset in ileum was similar; however, rotavirus-infected pigs maintained significantly higher frequencies of CD8? subsets in ileum than lactobacilli-colonized pigs. The dynamic ?? T cell responses suggest that ?? T cell subsets may play important roles in different stages of immune responses after rotavirus infection and probiotic colonization. The knowledge on the kinetics and distribution patterns of ?? T cell subsets in naïve pigs and after rotavirus infection or lactobacilli colonization provides the foundation for further mechanistic studies of their functions. PMID:21489639

Wen, Ke; Li, Guohua; Zhang, Wei; Azevedo, Marli SP; Saif, Linda J; Liu, Fangning; Bui, Tammy; Yousef, Ahmed; Yuan, Lijuan

2011-01-01

192

The bone marrow of myeloma patients is steadily inhabited by a normal-sized pool of functional regulatory T cells irrespectiveof the disease status  

PubMed Central

Conflicting data have been reported about the frequency and function of regulatory T cells in multiple myeloma. Most studies have investigated peripheral blood rather than bone marrow Tregs and side-by-side comparisons with bone marrow from healthy donors have still not been made. In this study, we show that regulatory T-cells total count, subset distribution, and expression of chemokine receptors are similar in the bone marrow of myeloma patients and healthy donors. Regulatory T cells are not recruited by myeloma cells in the bone marrow and their counts are unaffected by the tumor burden and the disease status. The diversity of T-cell receptor repertoire is highly preserved ensuring broad reactivity and effective suppressor function. Our results indicate that regulatory T cells may not be the main players of immunological tolerance to myeloma cells under base-line conditions, but their fully preserved immune competence may promote their inadvertent activation and blunt T-cell driven anti-myeloma immune interventions even after myeloma cells have successfully been cleared by chemotherapy. PMID:24972771

Foglietta, Myriam; Castella, Barbara; Mariani, Sara; Coscia, Marta; Godio, Laura; Ferracini, Riccardo; Ruggeri, Marina; Muccio, Vittorio; Omedé, Paola; Palumbo, Antonio; Boccadoro, Mario; Massaia, Massimo

2014-01-01

193

The bone marrow of myeloma patients is steadily inhabited by a normal-sized pool of functional regulatory T cells irrespectiveof the disease status.  

PubMed

Conflicting data have been reported about the frequency and function of regulatory T cells in multiple myeloma. Most studies have investigated peripheral blood rather than bone marrow Tregs and side-by-side comparisons with bone marrow from healthy donors have still not been made. In this study, we show that regulatory T-cells total count, subset distribution, and expression of chemokine receptors are similar in the bone marrow of myeloma patients and healthy donors. Regulatory T cells are not recruited by myeloma cells in the bone marrow and their counts are unaffected by the tumor burden and the disease status. The diversity of T-cell receptor repertoire is highly preserved ensuring broad reactivity and effective suppressor function. Our results indicate that regulatory T cells may not be the main players of immunological tolerance to myeloma cells under base-line conditions, but their fully preserved immune competence may promote their inadvertent activation and blunt T-cell driven anti-myeloma immune interventions even after myeloma cells have successfully been cleared by chemotherapy. PMID:24972771

Foglietta, Myriam; Castella, Barbara; Mariani, Sara; Coscia, Marta; Godio, Laura; Ferracini, Riccardo; Ruggeri, Marina; Muccio, Vittorio; Omedé, Paola; Palumbo, Antonio; Boccadoro, Mario; Massaia, Massimo

2014-10-01

194

Neonatal exposure to antigen primes the immune system to develop responses in various lymphoid organs and promotes bystander regulation of diverse T cell specificities.  

PubMed

Neonatal exposure to Ag has always been considered suppressive for immunity. Recent investigations, however, indicated that the neonatal immune system could be guided to develop immunity. For instance, delivery of a proteolipid protein (PLP) peptide on Ig boosts the neonatal immune system to develop responses upon challenge with the PLP peptide later. Accordingly, mice given Ig-PLP at birth and challenged with the PLP peptide as adults developed proliferative T cells in the lymph node that produced IL-4 instead of the usual Th1 cytokines. However, the spleen was unresponsive unless IL-12 was provided. Herein, we wished to determine whether such a neonatal response is intrinsic to the PLP peptide or could develop with an unrelated myelin peptide as well as whether the T cell deviation is able to confer resistance to autoimmunity involving diverse T cell specificities. Accordingly, the amino acid sequence 87-99 of myelin basic protein was expressed on the same Ig backbone, and the resulting Ig-myelin basic protein chimera was tested for induction of neonatal immunity and protection against experimental allergic encephalomyelitis. Surprisingly, the results indicated that immunity developed in the lymph node and spleen, with deviation of T cells occurring in both organs. More striking, the splenic T cells produced IL-10 in addition to IL-4, providing an environment that facilitated bystander deviation of responses to unrelated epitopes and promoted protection against experimental allergic encephalomyelitis involving diverse T cell specificities. Thus, neonatal exposure to Ag can prime responses in various organs and sustain regulatory functions effective against diverse autoreactive T cells. PMID:11591739

Pack, C D; Cestra, A E; Min, B; Legge, K L; Li, L; Caprio-Young, J C; Bell, J J; Gregg, R K; Zaghouani, H

2001-10-15

195

Large granular lymphocytes provide an accessory function in the in vitro development of influenza A virus-specific cytotoxic T cells.  

PubMed

We report that large granular lymphocytes (LGL) have an accessory function in the development of cytotoxic T cells (Tc) through the production of soluble factor(s). LGL and T cells were separated on Percoll gradients and the ability of the separated and of the recombined LGL and T cells to generate influenza A virus-specific Tc activity was measured. When stimulated by virus-infected, irradiated, adherent cells, neither LGL nor T cells cultured separately produced Tc activity. When they were co-cultured, however, even if separated by a 0.22-micron pore size membrane, Tc responses were readily generated from the small T cell precursors and natural killer activity was maintained in the LGL. Thus, LGL were required as accessory cells for Tc responses to occur and the effect was mediated by a soluble factor(s). alpha-Interferon (IFN) was produced in cultures containing LGL and/or stimulating adherent cells, whereas gamma-IFN was only produced in cultures containing both LGL and T cells. Therefore, neither alpha- nor gamma-IFN appeared to be the LGL produced soluble factor that mediated the accessory effect of LGL on Tc responses. PMID:6202775

Burlington, D B; Djeu, J Y; Wells, M A; Kiley, S C; Quinnan, G V

1984-06-01

196

T cell repertoires and competitive exclusion  

Microsoft Academic Search

Self-renewal is generally thought to play a major role in the maintenance of the T-cell repertoire. Here we develop a set of mathematical models for T-cell activation by peptides on antigen presenting cells (APCs). We show that competition between T cells is inherent to the processes involved in T cells binding APCs. We prove that for each dominant peptide only

R. J. de Boer; A. S. Perelson

1994-01-01

197

Fbw7 Targets GATA3 through Cyclin-Dependent Kinase 2-Dependent Proteolysis and Contributes to Regulation of T-Cell Development  

PubMed Central

Proper development of T cells depends on lineage-specific regulators controlled transcriptionally and posttranslationally to ensure precise levels at appropriate times. Conditional inactivation of F-box protein Fbw7 in mouse T-cell development resulted in reduced thymic CD4 single-positive (SP) and splenic CD4+ and CD8+ cell proportions. Fbw7 deficiency skewed CD8 SP lineage differentiation, which exhibited a higher incidence of apoptosis. Similar perturbations during development of CD8-positive cells were reported with transgenic mice, which enforced GATA3 (T-cell differentiation regulator) expression throughout T-cell development. We observed augmented GATA3 in CD4/CD8 double negative (DN) stage 4, CD4 SP, and CD8 SP lineages in Fbw7-deficient thymocytes. Using overexpressed proteins in cultured cells, we demonstrated that Fbw7 bound to, ubiquitylated, and destabilized GATA3. Two Cdc4 phosphodegron (CPD) candidate sequences, consensus Fbw7 recognition domains, were identified in GATA3, and phosphorylation of Thr-156 in CPD was required for Fbw7-mediated ubiquitylation and degradation. Phosphorylation of GATA3 Thr-156 was detected in mouse thymocytes, and cyclin-dependent kinase 2 (CDK2) was identified as a respondent for phosphorylation at Thr-156. These observations suggest that Fbw7-mediated GATA3 regulation with CDK2-mediated phosphorylation of CPD contributes to the precise differentiation of T-cell lineages. PMID:24820417

Kitagawa, Kyoko; Shibata, Kiyoshi; Matsumoto, Akinobu; Matsumoto, Masaki; Ohhata, Tatsuya; Nakayama, Keiichi I.; Niida, Hiroyuki

2014-01-01

198

Development of an In Vitro Assay and Demonstration of Plasmodium berghei Liver-Stage Inhibition by TRAP-Specific CD8+ T Cells  

PubMed Central

The development of an efficacious vaccine against the Plasmodium parasite remains a top priority. Previous research has demonstrated the ability of a prime-boost virally vectored sub-unit vaccination regimen, delivering the liver-stage expressed malaria antigen TRAP, to produce high levels of antigen-specific T cells. The liver-stage of malaria is the main target of T cell-mediated immunity, yet a major challenge in assessing new T cell inducing vaccines has been the lack of a suitable pre-clinical assay. We have developed a flow-cytometry based in vitro T cell killing assay using a mouse hepatoma cell line, Hepa1-6, and Plasmodium berghei GFP expressing sporozoites. Using this assay, P. berghei TRAP-specific CD8+ T cell enriched splenocytes were shown to inhibit liver-stage parasites in an effector-to-target ratio dependent manner. Further development of this assay using human hepatocytes and P. falciparum would provide a new method to pre-clinically screen vaccine candidates and to elucidate mechanisms of protection in vitro. PMID:25822951

Longley, Rhea J.; Bauza, Karolis; Ewer, Katie J.; Hill, Adrian V. S.; Spencer, Alexandra J.

2015-01-01

199

Disruption of the CD4–major histocompatibility complex class II interaction blocks the development of CD4+ T cells in vivo  

PubMed Central

The experiments presented in this report were designed to specifically examine the role of CD4–major histocompatibility complex (MHC) class II interactions during T cell development in vivo. We have generated transgenic mice expressing class II molecules that cannot interact with CD4 but that are otherwise competent to present peptides to the T cell receptor. MHC class II expression was reconstituted in A? gene knock-out mice by injection of a transgenic construct encoding either the wild-type I-A?b protein or a construct encoding a mutation designed to specifically disrupt binding to the CD4 molecule. We demonstrate that the mutation, EA137 and VA142 in the ?2 domain of I-Ab, is sufficient to disrupt CD4–MHC class II interactions in vivo. Furthermore, we show that this interaction is critical for the efficient selection of a complete repertoire of mature CD4+ T helper cells as evidenced by drastically reduced numbers of conventional CD4+ T cells in animals expressing the EA137/VA142 mutant I-Ab and by the failure to positively select the transgenic AND T cell receptor on the mutated I-Ab. These results underscore the importance of the CD4–class II interaction in the development of mature peripheral CD4+ T cells. PMID:9539765

Riberdy, Janice M.; Mostaghel, Elahe; Doyle, Carolyn

1998-01-01

200

T-Cell Lineage Determination  

PubMed Central

Summary T cells originate from hematopoietic stem cells (HSCs) in the bone marrow but complete their development in the thymus. HSCs give rise to a variety of non-renewing hematopoietic progenitors, among which a rare subset migrates to the thymus via the bloodstream. The earliest T-cell progenitors identified in the thymus are not T-lineage restricted but possess the ability to give rise to cells of many different lineages. Alternative lineage potentials are gradually lost as progenitors progress towards later developmental stages. Here, we review the early developmental events that might be involved in T-cell lineage fate determination, including the properties of possible thymus settling progenitors, their homing into the thymus, and their T-cell lineage specification and commitment. PMID:20969581

Yang, Qi; Bell, J. Jeremiah; Bhandoola, Avinash

2010-01-01

201

Bach2 maintains T cells in a naive state by suppressing effector memory-related genes  

PubMed Central

The transcriptional repressor BTB and CNC homology 2 (Bach2) is thought to be mainly expressed in B cells with specific functions such as class switch recombination and somatic hypermutation, but its function in T cells is not known. We found equal Bach2 expression in T cells and analyzed its function using Bach2-deficient (?/?) mice. Although T-cell development was normal, numbers of peripheral naive T cells were decreased, which rapidly produced Th2 cytokines after TCR stimulation. Bach2?/? naive T cells highly expressed genes related to effector-memory T cells such as CCR4, ST-2 and Blimp-1. Enhanced expression of these genes induced Bach2?/? naive T cells to migrate toward CCR4-ligand and respond to IL33. Forced expression of Bach2 restored the expression of these genes. Using Chromatin Immunoprecipitation (ChIP)-seq analysis, we identified S100 calcium binding protein a, Heme oxigenase 1, and prolyl hydroxylase 3 as Bach2 direct target genes, which are highly expressed in effector-memory T cells. These findings indicate that Bach2 suppresses effector memory-related genes to maintain the naive T-cell state and regulates generation of effector-memory T cells. PMID:23754397

Tsukumo, Shin-ichi; Unno, Midori; Muto, Akihiko; Takeuchi, Arata; Kometani, Kohei; Kurosaki, Tomohiro; Igarashi, Kazuhiko; Saito, Takashi

2013-01-01

202

Dual T cell receptor alpha chain T cells in autoimmunity  

PubMed Central

Allelic exclusion at the T cell receptor alpha locus TCR-alpha is incomplete, as demonstrated by the presence of a number of T lymphocyte clones carrying two expressed alpha chain products. Such dual alpha chain T cells have been proposed to play a role in autoimmunity, for example, because of a second TCR-alpha beta pair having bypassed negative selection by virtue of low expression. We examined this hypothesis by generating mice of various autoimmunity-prone strains carrying a hemizygous targeted disruption of the TCR-alpha locus, therefore unable to produce dual alpha chain T cells. Normal mice have a low but significant proportion of T cells expressing two cell-surface TCR-alpha chains that could be enumerated by comparison to TCR-alpha hemizygotes, which have none. Susceptibility to various autoimmune diseases was analyzed in TCR-alpha hemizygotes that had been backcrossed to disease-prone strains for several generations. The incidence of experimental allergic encephalomyelitis and of lupus is not affected by the absence of dual TCR-alpha cells. In contrast, nonobese diabetic (NOD) TCR alpha hemizygotes are significantly protected from cyclophosphamide-accelerated insulitis and diabetes. Thus, dual alpha T cells may play an important role in some but not all autoimmune diseases. Furthermore, since protected and susceptible NOD mice both show strong spontaneous responses to glutamic acid decarboxylase, responses to this antigen, if necessary for diabetetogenesis, are not sufficient. PMID:7561698

1995-01-01

203

Development of CD8+ T cells expressing two distinct receptors specific for MTB and HIV-1 peptides  

PubMed Central

The immune response in individuals co-infected with Mycobacterium tuberculosis (MTB) and the human immunodeficiency virus (MTB/HIV) gradually deteriorates, particularly in the cellular compartment. Adoptive transfer of functional effector T cells can confer protective immunity to immunodeficient MTB/HIV co-infected recipients. However, few such effector T cells exist in vivo, and their isolation and amplification to sufficient numbers is difficult. Therefore, enhancing immune responses against both pathogens is critical for treating MTB/HIV co-infected patients. One approach is adoptive transfer of T cell receptor (TCR) gene-modified T cells for the treatment of MTB/HIV co-infections because lymphocyte numbers and their functional avidity is significantly increased by TCR gene transfer. To generate bispecific CD8+ T cells, MTB Ag85B199–207 peptide-specific TCRs (MTB/TCR) and HIV-1 Env120–128 peptide-specific TCRs (HIV/TCR) were isolated and introduced into CD8+ T cells simultaneously using a retroviral vector. To avoid mispairing among exogenous and endogenous TCRs, and to improve the function and stability of the introduced TCRs, several strategies were employed, including introducing mutations in the MTB/TCR constant (C) regions, substituting part of the HIV/TCR C regions with CD3?, and linking gene segments with three different 2A peptides. Results presented in this report suggest that the engineered T cells possessed peptide-specific specificity resulting in cytokine production and cytotoxic activity. This is the first report describing the generation of engineered T cells specific for two different pathogens and provides new insights into TCR gene therapy for the treatment of immunocompromised MTB/HIV co-infected patients.

Hao, Pei-Pei; Zhang, Xiao-Bing; Luo, Wei; Zhou, Chao-Ying; Wen, Qian; Yang, Zhi; Liu, Su-Dong; Jiang, Zhen-Min; Zhou, Ming-Qian; Jin, Qi; Ma, Li

2013-01-01

204

Poor Predictive Value of Cytomegalovirus (CMV)–Specific T Cell Assays for the Development of CMV Retinitis in Patients with AIDS  

PubMed Central

Background We examined the potential clinical utility of using a cytomegalovirus (CMV)–specific T cell immunoassay to determine the risk of developing new-onset CMV retinitis (CMVR) in patients with acquired immunodeficiency syndrome (AIDS). Methods CMV-specific T cell assays were performed by multiparameter flow cytometry using stored peripheral blood mononuclear cells that had been obtained in an observational study 2–6 months before new-onset CMVR was diagnosed in case patients (at a study visit during which a dilated ophthalmologic examination revealed no evidence of CMVR) and at the same study visit in control subjects (matched by absolute CD4+ T cell count at entry) who did not subsequently develop retinitis during 1–6 years of study follow-up. Results There were no significant differences in CMV-specific CD4+ or CD8+ T cell interferon-? or interleukin-2 expression in peripheral blood mononuclear cells from case patients and control subjects. Although there were trends toward lower percentages and absolute numbers of CMV-specific, cytokine-expressing CD8+ T cells with a “late memory” phenotype (CD27?CD28?) as well as with an “early memory” phenotype (CD27+CD28+CD45RA+) in case patients than in control subjects, these differences were not statistically significant. Conclusions Many studies have reported that CMV-specific CD4+ and CD8+ T cell responses distinguish patients with active CMVR (i.e., who lack CMV-protective immunity) from those with inactive CMVR after immune restoration by antiretroviral treatment (i.e., who have CMV-protective immunity). However, the multiple CMV-specific immune responses we measured do not appear to have clinical utility for predicting the risk for patients with AIDS of developing new-onset CMVR with sufficient accuracy to be used in guiding therapeutic management. PMID:18173357

Jacobson, Mark A.; Tan, Qi Xuan; Girling, Valerie; Poon, C.; Van Natta, Mark; Jabs, Douglas A.; Inokuma, Margaret; Maecker, Holden T.; Bredt, Barry; Sinclair, Elizabeth

2009-01-01

205

Expression of a single ICAM-1 isoform on T cells is sufficient for development of experimental autoimmune encephalomyelitis.  

PubMed

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in leukocyte trafficking, induction of cellular immune responses, and immunological synapse formation. As a member of the immunoglobulin superfamily of adhesion proteins, ICAM-1 is composed of repeating Ig-like domains, a transmembrane domain, and short cytoplasmic tail that participates in intracellular signaling events. At least seven ICAM-1 protein isoforms are generated by alternative splicing, however little is known regarding their immunobiology. We have previously shown using different lines of ICAM-1 mutant mice (Icam1(tm1Jcgr) and Icam1(tm1Bay) ) that expression of alternatively spliced ICAM-1 isoforms can significantly influence the disease course during the development of EAE. In this study, we show using a newly developed transgenic mouse (CD2-Icam1(D4del) /Icam1(null) ) that T-cell-specific expression of a single ICAM-1 isoform composed of Ig domains 1, 2, 3, and 5 can mediate the initiation and progression of EAE. Our results indicate that the ICAM-1 isoform lacking Ig domain 4 can drive pathogenesis in demyelinating disease and may be a novel therapeutic target for treating multiple sclerosis. PMID:24435747

Bullard, Daniel C; Hu, Xianzhen; Crawford, David; McDonald, Kristin; Ramos, Theresa N; Barnum, Scott R

2014-04-01

206

T-cell clonotypes in cancer  

PubMed Central

Cells of the immune system spontaneously recognize autologous tumor cells and T cells are believed to be the main effector cells for the immune surveillance of cancer. Recent advances in our understanding of basic and tumor immunology together with methodological developments implies that tumor specific T cells can now be studied functionally, phenotypically as well as molecularly. T cells recognize peptide antigens in the context of MHC molecules through the clonally distributed T-cell receptor (TCR), thus, the clonal distribution of the TCR offers the means to detect and track specific T cells based upon detection of the unique TCR. In this review, we present and discuss available data on TCR utilization of tumor specific T cells in murine models as well as spontaneous and treatment induced anti-tumor T-cell responses in humans. PMID:15072580

thor Straten, Per; Schrama, David; Andersen, Mads Hald; Becker, Jürgen C

2004-01-01

207

?? T Cells and Their Potential for Immunotherapy  

PubMed Central

V?9V?2 (also termed V?2V?2) T cells, a major human peripheral blood ?? T cell subset, recognize microbial (E)-4-hydroxy-3-methylbut-2-enyl diphosphate and endogenous isopentenyl diphosphate in a TCR-dependent manner. The recognition does not require specific accessory cells, antigen uptake, antigen processing, or MHC class I, class II, or class Ib expression. This subset of T cells plays important roles in mediating innate immunity against a wide variety of infections and displays potent and broad cytotoxic activity against human tumor cells. Because ??T cells express both natural killer receptors such as NKG2D and ?? T cell receptors, they are considered to represent a link between innate and adaptive immunity. In addition, activated ?? T cells express a high level of antigen-presenting cell-related molecules and can present peptide antigens derived from destructed cells to ?? T cells. Utilizing these antimicrobial and anti-tumor properties of ?? T cells, preclinical and clinical trials have been conducted to develop novel immunotherapies for infections and malignancies. Here, we review the immunological properties of ?? T cells including the underlying recognition mechanism of nonpeptitde antigens and summarize the results of ?? T cell-based therapies so far performed. Based on the results of the reported trials, ?? T cells appear to be a promising tool for novel immunotherapies against certain types of diseases. PMID:24520210

Wu, Yan-Ling; Ding, Yan-Ping; Tanaka, Yoshimasa; Shen, Li-Wen; Wei, Chuan-He; Minato, Nagahiro; Zhang, Wen

2014-01-01

208

T Cell-Dendritic Cell Interaction in Vivo: Random Encounters Favor Development of Long-Lasting Ties  

NSDL National Science Digital Library

Understanding the complexity of the functional communication between cells composing the immune system is central to improving our capacity to manipulate it and conceive better strategies to combat microbial pathogens. So far, these studies have been based on immunohistochemistry of fixed tissues and in vitro attempts to reproduce functional connections between cells. The application of two-photon laser microscopy to the observation of viable immune cells in their natural environment where foreign antigens are carried to trigger an immune response opens a new era for these studies. They reveal exceptional properties of the locomotion of T cells that facilitate encounters with dendritic cells and the receipt of information that promotes T cell survival, death, or initiation of immune responses. These studies also complement in vitro observations addressing the importance of time of stimulation in determining T cell fates.

Oreste Acuto (Institut Pasteur; Molecular Immunology Unit, Department of Immunology REV)

2003-07-22

209

Human MAIT and CD8?? cells develop from a pool of type-17 precommitted CD8+ T cells  

PubMed Central

Human mucosal associated invariant T (MAIT) CD8+ and Tc17 cells are important tissue-homing cell populations, characterized by high expression of CD161 (++) and type-17 differentiation, but their origins and relationships remain poorly defined. By transcriptional and functional analyses, we demonstrate that a pool of polyclonal, precommitted type-17 CD161++CD8??+ T cells exist in cord blood, from which a prominent MAIT cell (TCR V?7.2+) population emerges post-natally. During this expansion, CD8?? T cells appear exclusively within a CD161++CD8+/MAIT subset, sharing cytokine production, chemokine-receptor expression, TCR-usage, and transcriptional profiles with their CD161++CD8??+ counterparts. Our data demonstrate the origin and differentiation pathway of MAIT-cells from a naive type-17 precommitted CD161++CD8+ T-cell pool and the distinct phenotype and function of CD8?? cells in man. PMID:22086415

Walker, Lucy J.; Kang, Yu-Hoi; Smith, Matthew O.; Tharmalingham, Hannah; Ramamurthy, Narayan; Fleming, Vicki M.; Sahgal, Natasha; Leslie, Alistair; Oo, Ye; Geremia, Alessandra; Scriba, Thomas J.; Hanekom, Willem A.; Lauer, Georg M.; Lantz, Olivier; Adams, David H.; Powrie, Fiona; Barnes, Eleanor

2012-01-01

210

Harnessing endogenous miR-181a to segregate transgenic antigen receptor expression in developing versus post-thymic T cells in murine hematopoietic chimeras.  

PubMed

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression by targeting complementary sequences, referred to as miRNA recognition elements (MREs), typically located in the 3' untranslated region of mRNAs. miR-181a is highly expressed in developing thymocytes and markedly downregulated in post-thymic T cells. We investigated whether endogenous miR-181a can be harnessed to segregate expression of chimeric antigen receptors (CARs) and TCRs between developing and mature T cells. Lentiviral-encoded antigen receptors were tagged with a miR-181a-specific MRE and transduced into mouse BM cells that were used to generate hematopoietic chimeras. Expression of a CAR specific for human CD19 (hCD19) was selectively suppressed in late double-negative and double-positive thymocytes, coinciding with the peak in endogenous miR-181a expression. Receptor expression was fully restored in post-thymic resting and activated T cells, affording protection against a subsequent challenge with hCD19+ tumors. Hematopoietic mouse chimeras engrafted with a conalbumin-specific TCR prone to thymic clonal deletion acquired peptide-specific T cell responsiveness only when the vector-encoded TCR transcript was similarly engineered to be subject to regulation by miR-181a. These results demonstrate the potential of miRNA-regulated transgene expression in stem cell-based therapies, including cancer immunotherapy. PMID:19033646

Papapetrou, Eirini P; Kovalovsky, Damian; Beloeil, Laurent; Sant'angelo, Derek; Sadelain, Michel

2009-01-01

211

Bcl-XL displays restricted distribution during T cell development and inhibits multiple forms of apoptosis but not clonal deletion in transgenic mice  

PubMed Central

The survival of T lymphocytes is tightly controlled during development. Here, we show that Bcl-xL, a protein homologue of Bcl-2, is highly regulated in the thymus in a pattern different than that of Bcl-2. The maximum expression was in CD4+CD8+ thymocytes, a developmental stage where Bcl-2 is downregulated. To assess the role of Bcl-xL in thymocyte apoptosis, we generated mice overexpressing an E mu-bcl-x transgene within the T cell compartment. Constitutive expression of Bcl-xL resulted in accumulation of thymocytes and mature T cells in lymphoid organs. Thymocytes overexpressing Bcl-xL exhibited increased viability in vitro and were resistant to apoptosis induced by different signals, including glucocorticoid, gamma irradiation, calcium ionophore, and CD3 cross-linking. However, Bcl-xL was unable to block clonal deletion of thymocytes reactive with self-superantigens or H-Y antigen. These studies demonstrate that Bcl-2 and Bcl-xL, two functionally related proteins, are regulated independently during T cell development. In contrast to Bcl-2, which has been implicated in the maintenance of mature T cells, Bcl-xL appears to provide a survival signal for the maintenance of more immature CD4+CD8+ thymocytes before positive selection. PMID:7500043

1995-01-01

212

The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naïve T cells.  

PubMed

The Mst1 and Mst2 protein kinases are the mammalian homologs of hippo, a major inhibitor of cell proliferation in Drosophila. Mst1 is most abundant in lymphoid tissues. Mice lacking Mst1 exhibit markedly reduced levels of the Mst1 regulatory protein Nore1B/RAPL in lymphoid cells, whereas Mst2 abundance is unaltered. Mst1-null mice exhibit normal T cell development but low numbers of mature naïve T cells with relatively normal numbers of effector/memory T cells. In vitro, the Mst1-deficient naïve T cells exhibit markedly greater proliferation in response to stimulation of the T cell receptor whereas the proliferative responses of the Mst1-null effector/memory T cell cohort is similar to wild type. Thus, elimination of Mst1 removes a barrier to the activation and proliferative response of naïve T cells. The levels of Mst1 and Nore1B/RAPL in wild-type effector/memory T cells are approximately 10% those seen in wild-type naïve T cells, which may contribute to the enhanced proliferative responses of the former. Freshly isolated Mst1-null T cells exhibit high rates of ongoing apoptosis, a likely basis for their low numbers in vivo; they also exhibit defective clustering of LFA-1, as previously observed for Nore1B/RAPL-deficient T cells. Among known Mst1 substrates, only the phosphorylation of the cell cycle inhibitory proteins MOBKL1A/B is lost entirely in TCR-stimulated, Mst1-deficient T cells. Mst1/2-catalyzed MOBKL1A/B phosphorylation slows proliferation and is therefore a likely contributor to the anti-proliferative action of Mst1 in naïve T cells. The Nore1B/RAPL-Mst1 complex is a negative regulator of naïve T cell proliferation. PMID:19073936

Zhou, Dawang; Medoff, Benjamin D; Chen, Lanfen; Li, Lequn; Zhang, Xian-feng; Praskova, Maria; Liu, Matthew; Landry, Aimee; Blumberg, Richard S; Boussiotis, Vassiliki A; Xavier, Ramnik; Avruch, Joseph

2008-12-23

213

SOCS3 deletion in T lymphocytes suppresses development of chronic ocular inflammation via upregulation of CTLA-4 and expansion of regulatory T cells.  

PubMed

Suppressors of cytokine signaling (SOCS) proteins are negative-feedback regulators of the JAK/STAT pathway, and SOCS3 contributes to host immunity by regulating the intensity and duration of cytokine signals and inflammatory responses. Mice with Socs3 deletion in myeloid cells exhibit enhanced STAT3 signaling, expansion of Th1 and Th17 cells, and develop severe experimental autoimmune encephalomyelitis. Interestingly, development of the unique IL-17/IFN-? double-producing (Th17/IFN-? and Tc17/IFN-?) subsets that exhibit strong cytotoxic activities and are associated with pathogenesis of several autoimmune diseases has recently been shown to depend on epigenetic suppression of SOCS3 expression, further suggesting involvement of SOCS3 in autoimmunity and tumor immunity. In this study, we generated mice with Socs3 deletion in the CD4 T cell compartment (CD4-SOCS3 knockout [KO]) to determine in vivo effects of the loss of Socs3 in the T cell-mediated autoimmune disease, experimental autoimmune uveitis (EAU). In contrast to the exacerbation of experimental autoimmune encephalomyelitis in myeloid-specific SOCS3-deleted mice, CD4-SOCS3KO mice were protected from acute and chronic uveitis. Protection from EAU correlated with enhanced expression of CTLA-4 and expansion of IL-10-producing regulatory T cells with augmented suppressive activities. We further show that SOCS3 interacts with CTLA-4 and negatively regulates CTLA-4 levels in T cells, providing a mechanistic explanation for the expansion of regulatory T cells in CD4-SOCS3 during EAU. Contrary to in vitro epigenetic studies, Th17/IFN-? and Tc17/IFN-? populations were markedly reduced in CD4-SOCS3KO, suggesting that SOCS3 promotes expansion of the Th17/IFN-? subset associated with development of severe uveitis. Thus, SOCS3 is a potential therapeutic target in uveitis and other autoinflammatory diseases. PMID:24101549

Yu, Cheng-Rong; Kim, Sung-Hye; Mahdi, Rashid M; Egwuagu, Charles E

2013-11-15

214

Development of CD4+CD25+FoxP3+ regulatory T cells from cord blood hematopoietic progenitor cells  

Microsoft Academic Search

Adult stem cells are capable of gener- ating all of the cells of the hematopoietic system, and this process is orchestrated in part by the interactions between these cells and the stroma. T cell progenitors emerge from the stem cell com- partment and migrate to the thymus, where their terminal differentiation and maturation occur, and it is during this phase

Jonathon F. Hutton; Tessa Gargett; Timothy J. Sadlon; Suzanne Bresatz; Cheryl Y. Brown; Heddy Zola; M. Frances Shannon; Richard J. D'Andrea; Simon C. Barry

2008-01-01

215

Development and characterization of T cell leukemia cell lines established from SCL\\/LMO1 double transgenic mice  

Microsoft Academic Search

We have established a panel of nine immortal cell lines from T cell malignancies which arose in mice transgenic for the SCL and LMO1 genes. Cells from the primary malignancies initially grew very slowly in vitro, loosely attached to a stromal layer, before gaining the ability to proliferate independently. Upon gaining the ability to proliferate in the absence of a

DS Chervinsky; DH Lam; X-F Zhao; MP Melman; PD Aplan

2001-01-01

216

Immune system modelling: competition and T cell repertoire maintenance  

E-print Network

and negative selection Memory T cellSelf antigen (Survival signal) Immature thymocyte Mature thymocyte Naive nodes + lymphoid vessels = peripheral lymphoid organs bone marrow T cell development 1 Precursor T cellsImmune system modelling: competition and T cell repertoire maintenance Hugo van den Berg1 Emily

Wirosoetisno, Djoko

217

Normal Development of Brain Circuits  

Microsoft Academic Search

Spanning functions from the simplest reflex arc to complex cognitive processes, neural circuits have diverse functional roles. In the cerebral cortex, functional domains such as visual processing, attention, memory, and cognitive control rely on the development of distinct yet interconnected sets of anatomically distributed cortical and subcortical regions. The developmental organization of these circuits is a remarkably complex process that

Gregory Z Tau; Bradley S Peterson

2010-01-01

218

T Cell Expansion Is the Limiting Factor of Virus Control in Mice with Attenuated TCR Signaling: Implications for Human Immunodeficiency.  

PubMed

Defining the minimal thresholds for effective antiviral T cell immunity is important for clinical decisions in immunodeficient patients. TCR signaling is critical for T cell development, activation, and effector functions. In this article, we analyzed which of these TCR-mediated processes is limiting for antiviral immunity in a mouse strain with reduced expression of SLP-76 (twp mice). Despite severe T cell activation defects in vitro, twp mice generated a normal proportion of antiviral effector T cells postinfection with lymphocytic choriomeningitis virus (LCMV). Twp CD8(+) T cells showed impaired polyfunctional cytokine production, whereas cytotoxicity as the crucial antiviral effector function for LCMV control was normal. The main limiting factor in the antiviral response of twp mice was impaired T cell proliferation and survival, leading to a 5- to 10-fold reduction of antiviral T cells at the peak of the immune response. This was still sufficient to control infection with the LCMV Armstrong strain, but the more rapidly replicating LCMV-WE induced T cell exhaustion and viral persistence. Thus, under conditions of impaired TCR signaling, reduced T cell expansion was the limiting factor in antiviral immunity. These findings have implications for understanding antiviral immunity in patients with T cell deficiencies. PMID:25672755

Hillen, Kristina M; Gather, Ruth; Enders, Anselm; Pircher, Hanspeter; Aichele, Peter; Fisch, Paul; Blumenthal, Britta; Schamel, Wolfgang W; Straub, Tobias; Goodnow, Christopher C; Ehl, Stephan

2015-03-15

219

The role of regulatory T-cells in glioma immunology.  

PubMed

Despite recent advances in treatment, the prognosis for glioblastoma multiforme (GBM) remains poor. The lack of response to treatment in GBM patients may be attributed to the immunosuppressed microenvironment that is characteristic of invasive glioma. Regulatory T-cells (Tregs) are immunosuppressive T-cells that normally prevent autoimmunity when the human immune response is evoked; however, there have been strong correlations between glioma-induced immunosuppression and Tregs. In fact, induction of Treg activity has been correlated with glioma development in both murine models and patients. While the exact mechanisms by which regulatory T-cells function require further elucidation, various cytokines such as interleukin-10 (IL-10) and transforming growth factor-? (TFG-?) have been implicated in these processes and are currently under investigation. In addition, hypoxia is characteristic of tumor development and is also correlated with downstream induction of Tregs. Due to the poor prognosis associated with immunosuppression in glioma patients, Tregs remain a promising area for immunotherapeutic research. PMID:24582432

Ooi, Yinn Cher; Tran, Patrick; Ung, Nolan; Thill, Kimberly; Trang, Andy; Fong, Brendan M; Nagasawa, Daniel T; Lim, Michael; Yang, Isaac

2014-04-01

220

EmTIP, a T-Cell Immunomodulatory Protein Secreted by the Tapeworm Echinococcus multilocularis Is Important for Early Metacestode Development  

PubMed Central

Background Alveolar echinococcosis (AE), caused by the metacestode of the tapeworm Echinococcus multilocularis, is a lethal zoonosis associated with host immunomodulation. T helper cells are instrumental to control the disease in the host. Whereas Th1 cells can restrict parasite proliferation, Th2 immune responses are associated with parasite proliferation. Although the early phase of host colonization by E. multilocularis is dominated by a potentially parasitocidal Th1 immune response, the molecular basis of this response is unknown. Principal Findings We describe EmTIP, an E. multilocularis homologue of the human T-cell immunomodulatory protein, TIP. By immunohistochemistry we show EmTIP localization to the intercellular space within parasite larvae. Immunoprecipitation and Western blot experiments revealed the presence of EmTIP in the excretory/secretory (E/S) products of parasite primary cell cultures, representing the early developing metacestode, but not in those of mature metacestode vesicles. Using an in vitro T-cell stimulation assay, we found that primary cell E/S products promoted interferon (IFN)-? release by murine CD4+ T-cells, whereas metacestode E/S products did not. IFN-? release by T-cells exposed to parasite products was abrogated by an anti-EmTIP antibody. When recombinantly expressed, EmTIP promoted IFN-? release by CD4+ T-cells in vitro. After incubation with anti-EmTIP antibody, primary cells showed an impaired ability to proliferate and to form metacestode vesicles in vitro. Conclusions We provide for the first time a possible explanation for the early Th1 response observed during E. multilocularis infections. Our data indicate that parasite primary cells release a T-cell immunomodulatory protein, EmTIP, capable of promoting IFN-? release by CD4+ T-cells, which is probably driving or supporting the onset of the early Th1 response during AE. The impairment of primary cell proliferation and the inhibition of metacestode vesicle formation by anti-EmTIP antibodies suggest that this factor fulfills an important role in early E. multilocularis development within the intermediate host. PMID:24392176

Nono, Justin Komguep; Lutz, Manfred B.; Brehm, Klaus

2014-01-01

221

Engineering T cells for cancer therapy  

Microsoft Academic Search

It is generally accepted that the immune system plays an important role in controlling tumour development. However, the interplay between tumour and immune system is complex, as demonstrated by the fact that tumours can successfully establish and develop despite the presence of T cells in tumour. An improved understanding of how tumours evade T-cell surveillance, coupled with technical developments allowing

W Mansoor; D E Gilham; F C Thistlethwaite; R E Hawkins

2005-01-01

222

Antigen-specific regulatory T cells develop via the ICOS–ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity  

Microsoft Academic Search

Asthma is caused by T-helper cell 2 (Th2)-driven immune responses, but the immunological mechanisms that protect against asthma development are poorly understood. T-cell tolerance, induced by respiratory exposure to allergen, can inhibit the development of airway hyperreactivity (AHR), a cardinal feature of asthma, and we show here that regulatory T (TR) cells can mediate this protective effect. Mature pulmonary dendritic

Omid Akbari; Gordon J. Freeman; Everett H. Meyer; Edward A. Greenfield; Tammy T. Chang; Arlene H. Sharpe; Gerald Berry; Rosemarie H. DeKruyff; Dale T. Umetsu

2002-01-01

223

miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when  

E-print Network

miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when. Several miR- NAs are specifically expressed in hematopoietic cells. Here we show that one such miRNA, miR the development of mature T and B cells; expression of miR-150 is sharply up-regulated at the immature B cell

Bartel, David

224

IL-12 activates IFN-gamma production through the preferential activation of CD30+ T cells.  

PubMed

CD30 is normally expressed by a subset (15 to 20%) of CD45RO+ T cells after activation by a variety of T cell stimuli and defines the principal IFN-gamma-producing T cells subset. Inasmuch as the production of IFN-gamma is regulated by IL-2 and IL-12, we have examined the effects of these cytokines on the proliferation, induction, and function of CD30+ and CD30- T cell subsets. Upon isolation, CD30+CD25+ T cells exhibit high levels of baseline proliferation compared with CD30-CD25+ T cells. Neutralizing Abs specific for IL-2, IL-4, IL-6, or IL-12 had no effect on basal levels of proliferation in CD30+CD25+ T cells, whereas anti-IL-2 inhibited the basal proliferative activity of CD30-CD25+ T cells. The addition of exogenous rIL-12 to purified CD30+CD25+ and CD30-CD25+ T cells subsets induced significantly higher maximal levels of proliferation in the CD30+ subset, whereas rIL-2 supported comparable levels of maximal proliferation in each subset. The addition of rIL-2 to anti-CD3-activated PBMC increased the relative numbers of CD30+ T cells by expansion of CD30+ T cells, as opposed to recruitment of CD30+ T cells from the CD30- population. Furthermore, the development of the CD30+ T cell subset was inhibited by either anti-IL-2, anti-IL-12, or rIL-10. Inhibition by anti-IL-2 and rIL-10 was overcome by the addition of rIL-12, but not IL-2, to the cultures. Finally, rIL-12 increased IFN-gamma production by CD30+ T cells, yet had little effect on IFN-gamma production by CD30- T cells. Thus, CD30+ T cells are preferentially regulated by IL-12, and the effects of IL-12 on T cell IFN-gamma production are mediated largely through its effects on the CD30+ subset. PMID:7995963

Alzona, M; Jäck, H M; Fisher, R I; Ellis, T M

1995-01-01

225

Involvement of Ca/sup 2 +//phospholipid-dependent C-kinase in phorbol ester-mediated activation of normal human T cell  

SciTech Connect

C-kinase appears to be involved in biological responses of T cells, and phorbol myristate acetate (PMA) is a direct activator of this enzyme. In this study, reaction of T cells with PMA (0.1-50 ng/ml) showed a dose-dependent increase in /sup 3/H-thymidine incorporation; higher concentrations were toxic. C-kinase assays performed in parallel demonstrated sustained translocation of >99% of C-kinase activity from the cytosol to the detergent-soluble membrane fraction. Experiments were done in the presence of cyclosporine (CSA), and of polymyxin B (PMB) which also inhibits C-kinase. Both PMA and CSA caused profound and dose-dependent reduction in proliferation, with maximal inhibition of >70% and >90% respectively. Moreover, addition of PMB showed coordinate inhibition of C-kinase activity (>80% at 10 ..mu..M), whereas at similar concentrations inhibiting cell proliferation CSA had no detectable effect. These results indicate that PMA initiates activation and proliferation by stimulation of at least two distinct pathways, one of which involves C-kinase activation and is inhibited by PMB.

Dirienzo, W.; Nel, A.E.; Lattanze, G.R.; Galbraith, R.M.

1986-03-01

226

ADAM17 Deletion in Thymic Epithelial Cells Alters Aire Expression without Affecting T Cell Developmental Progression  

PubMed Central

Background Cellular interactions between thymocytes and thymic stromal cells are critical for normal T cell development. Thymic epithelial cells (TECs) are important stromal niche cells that provide essential growth factors, cytokines, and present self-antigens to developing thymocytes. The identification of genes that mediate cellular crosstalk in the thymus is ongoing. One candidate gene, Adam17, encodes a metalloprotease that functions by cleaving the ectodomain of several transmembrane proteins and regulates various developmental processes. In conventional Adam17 knockout mice, a non-cell autonomous role for ADAM17 in adult T cell development was reported, which strongly suggested that expression of ADAM17 in TECs was required for normal T cell development. However, knockdown of Adam17 results in multisystem developmental defects and perinatal lethality, which has made study of the role of Adam17 in specific cell types difficult. Here, we examined T cell and thymic epithelial cell development using a conditional knockout approach. Methodology/Principal Findings We generated an Adam17 conditional knockout mouse in which floxed Adam17 is deleted specifically in TECs by Cre recombinase under the control of the Foxn1 promoter. Normal T cell lineage choice and development through the canonical ?? T cell stages was observed. Interestingly, Adam17 deficiency in TECs resulted in reduced expression of the transcription factor Aire. However, no alterations in the patterns of TEC phenotypic marker expression and thymus morphology were noted. Conclusions/Significance In contrast to expectation, our data clearly shows that absence of Adam17 in TECs is dispensable for normal T cell development. Differentiation of TECs is also unaffected by loss of Adam17 based on phenotypic markers. Surprisingly, we have uncovered a novel genetic link between Adam17and Aire expression in vivo. The cell type in which ADAM17 mediates its non-cell autonomous impact and the mechanisms by which it regulates intrathymic T cell development remain to be identified. PMID:20976004

Gravano, David M.; McLelland, Bryce T.; Horiuchi, Keisuke; Manilay, Jennifer O.

2010-01-01

227

Engineered T cells for cancer treatment.  

PubMed

Adoptively transferred T cells have the capacity to traffic to distant tumor sites, infiltrate fibrotic tissue and kill antigen-expressing tumor cells. Various groups have investigated different genetic engineering strategies designed to enhance tumor specificity, increase T cell potency, improve proliferation, persistence or migratory capacity and increase safety. This review focuses on recent developments in T cell engineering, discusses the clinical application of these engineered cell products and outlines future prospects for this therapeutic modality. PMID:24239105

Anurathapan, Usanarat; Leen, Ann M; Brenner, Malcolm K; Vera, Juan F

2014-06-01

228

E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination.  

PubMed

CD28 costimulation is essential for the development of thymic-derived CD4(+)CD25(+)Foxp3(+) regulatory T cells ("tTregs"). E3 ubiquitin ligase Cbl-b has been shown to regulate CD28 dependence of T cell activation. In this paper, we report that the loss of Cbl-b partially but significantly rescues the defective development of tTregs in Cd28(-/-) mice. This partial rescue is independent of IL-2. Mechanistically, Cbl-b binds to Foxp3 upon TCR stimulation and, together with Stub1, targets Foxp3 for ubiquitination and subsequently degradation in the proteasome. As Cbl-b self-ubiquitination and proteasomal degradation is impaired in Cd28(-/-) T cells, the defective development of tTregs in Cd28(-/-) mice may in part be due to increased Foxp3 ubiquitination and degradation targeted by Stub1 and Cbl-b. Treating Cd28(-/-) mice with a proteasome inhibitor completely rescues defective tTreg development in these mice. Therefore, Cbl-b, together with Stub1, ubiquitinate Foxp3, and regulate tTreg development. PMID:25560411

Zhao, Yixia; Guo, Hui; Qiao, Guilin; Zucker, Mark; Langdon, Wallace Y; Zhang, Jian

2015-02-15

229

Development and characterization of T cell leukemia cell lines established from SCL/LMO1 double transgenic mice.  

PubMed

We have established a panel of nine immortal cell lines from T cell malignancies which arose in mice transgenic for the SCL and LMO1 genes. Cells from the primary malignancies initially grew very slowly in vitro, loosely attached to a stromal layer, before gaining the ability to proliferate independently. Upon gaining the ability to proliferate in the absence of a stromal layer, these cell lines grew rapidly, doubling every 14-23 h, to a very high density, approaching 10(7) cells/ml. Whereas the tumors which arise in SCL/LMO1 double transgenic mice are typically diploid or pseudodiploid, the cell lines were all grossly aneuploid, suggesting the possibility that additional genetic events were selected for in vitro. Given that SCL and LMO1 gene activation are both commonly seen in human patients with T cell acute lymphoblastic leukemia, these cell lines may be a useful in vitro model for the human disease. PMID:11243382

Chervinsky, D S; Lam, D H; Zhao, X F; Melman, M P; Aplan, P D

2001-01-01

230

The MAR-binding protein SATB1 orchestrates temporal and spatial expression of multiple genes during T-cell development  

Microsoft Academic Search

SATB1 is expressed primarily in thymocytes and can act as a transcriptional repressor. SATB1 binds in vivo to the matrix attachment regions (MARs) of DNA, which are implicated in the loop domain organization of chromatin. The role of MAR-binding proteins in specific cell lineages is unknown. We generated SATB1-null mice to determine how SATB1 functions in the T-cell lineage. SATB1-null

John D. Alvarez; Dag H. Yasui; Hiroyuki Niida; Tadashi Joh; Dennis Y. Loh; Terumi Kowhi-Shigematsu

2000-01-01

231

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays  

Microsoft Academic Search

Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing\\u000a of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology.\\u000a The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs\\u000a and other animal species to assess their sensitizing

Stefan F. Martin; Philipp R. Esser; Sonja Schmucker; Lisa Dietz; Dean J. Naisbitt; B. Kevin Park; Marc Vocanson; Jean-Francois Nicolas; Monika Keller; Werner J. Pichler; Matthias Peiser; Andreas Luch; Reinhard Wanner; Enrico Maggi; Andrea Cavani; Thomas Rustemeyer; Anne Richter; Hermann-Josef Thierse; Federica Sallusto

2010-01-01

232

Screening for CMV-specific T cell proliferation to identify patients at risk of developing late onset CMV disease  

Microsoft Academic Search

Thirty patients undergoing allogeneic BMT were screened post-transplant together with their marrow donors for CMV-specific T cell proliferation and the occurrence of CMV disease. Twenty-one of these patients received a marrow transplant from an HLA-matched sibling donor, and nine from an HLA-matched unrelated donor. All these patients were either CMV seropositive and\\/or had received a transplant from a CMV-seropositive donor.

H Krause; H Hebart; G Jahn; CA Müller; H Einsele

1997-01-01

233

?? T Cell Immunotherapy-A Review.  

PubMed

Cancer immunotherapy utilizing V?9V?2 T cells has been developed over the past decade. A large number of clinical trials have been conducted on various types of solid tumors as well as hematological malignancies. V?9V?2 T cell-based immunotherapy can be classified into two categories based on the methods of activation and expansion of these cells. Although the in vivo expansion of V?9V?2 T cells by phosphoantigens or nitrogen-containing bisphosphonates (N-bis) has been translated to early-phase clinical trials, in which the safety of the treatment was confirmed, problems such as activation-induced V?9V?2 T cell anergy and a decrease in the number of peripheral blood V?9V?2 T cells after infusion of these stimulants have not yet been solved. In addition, it is difficult to ex vivo expand V?9V?2 T cells from advanced cancer patients with decreased initial numbers of peripheral blood V?9V?2 T cells. In this article, we review the clinical studies and reports targeting V?9V?2 T cells and discuss the development and improvement of V?9V?2 T cell-based cancer immunotherapy. PMID:25686210

Kobayashi, Hirohito; Tanaka, Yoshimasa

2015-01-01

234

Expansion of CD4+CD25+ helper T cells without regulatory function in smoking and COPD  

PubMed Central

Background Regulatory T cells have been implicated in the pathogenesis of COPD by the increased expression of CD25 on helper T cells along with enhanced intracellular expression of FoxP3 and low/absent CD127 expression on the cell surface. Method Regulatory T cells were investigated in BALF from nine COPD subjects and compared to fourteen smokers with normal lung function and nine never-smokers. Results In smokers with normal lung function, the expression of CD25+CD4+ was increased, whereas the proportions of FoxP3+ and CD127+ were unchanged compared to never-smokers. Among CD4+ cells expressing high levels of CD25, the proportion of FoxP3+ cells was decreased and the percentage of CD127+ was increased in smokers with normal lung function. CD4+CD25+ cells with low/absent CD127 expression were increased in smokers with normal lung function, but not in COPD, when compared to never smokers. Conclusion The reduction of FoxP3 expression in BALF from smokers with normal lung function indicates that the increase in CD25 expression is not associated with the expansion of regulatory T cells. Instead, the high CD127 and low FoxP3 expressions implicate a predominantly non-regulatory CD25+ helper T-cell population in smokers and stable COPD. Therefore, we suggest a smoking-induced expansion of predominantly activated airway helper T cells that seem to persist after COPD development. PMID:21651772

2011-01-01

235

Developmental exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin attenuates later-life Notch1-mediated T cell development and leukemogenesis.  

PubMed

Over half of T cell acute lymphoblastic leukemia (T-ALL) patients have activating mutations in the Notch gene. Moreover, the contaminant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is a known carcinogen that mediates its toxicity through the aryl hydrocarbon receptor (AHR), and crosstalk between activated AHR and Notch signaling pathways has previously been observed. Given the importance of Notch signaling in thymocyte development and T-ALL disease progression, we hypothesized that the activated AHR potentiates disease initiation and progression in an in vivo model of Notch1-induced thymoma. This hypothesis was tested utilizing adult and developmental exposure paradigms to TCDD in mice expressing a constitutively active Notch1 transgene (Notch(ICN-TG)). Following exposure of adult Notch(ICN-TG) mice to a single high dose of TCDD, we observed a significant increase in the efficiency of CD8 thymocyte generation. We next exposed pregnant mice to 3?g/kg of TCDD throughout gestation and lactation to elucidate effects of developmental AHR activation on later-life T cell development and T-ALL-like thymoma susceptibility induced by Notch1. We found that the vehicle-exposed Notch(ICN-TG) offspring have a peripheral T cell pool heavily biased toward the CD4 lineage, while TCDD-exposed Notch(ICN-TG) offspring were biased toward the CD8 lineage. Furthermore, while the vehicle-exposed NotchICN-TG mice showed increased splenomegaly and B to T cell ratios indicative of disease, mice developmentally exposed to TCDD were largely protected from disease. These studies support a model where developmental AHR activation attenuates later-life Notch1-dependent impacts on thymocyte development and disease progression. PMID:25585350

Ahrenhoerster, Lori S; Leuthner, Tess C; Tate, Everett R; Lakatos, Peter A; Laiosa, Michael D

2015-03-01

236

Epithelial Defence by ?? T Cells  

Microsoft Academic Search

?? T cells constitute a separate lineage of T lymphocytes which differ from conventional ?? T cells with regard to T cell receptor (TCR) repertoire and tissue localization. In murine skin, ?? T cells expressing a canonical V?5 TCR are abundant and contribute as so-called dendritic epidermal T cells to local immune surveillance. In humans, major subsets of ?? T

Dieter Kabelitz; Lothar Marischen; Hans-Heinrich Oberg; Wolfgang Holtmeier; Daniela Wesch

2005-01-01

237

T cell repertoires and competitive exclusion.  

PubMed

Self-renewal is generally thought to play a major role in the maintenance of the T-cell repertoire. Here we develop a set of mathematical models for T-cell activation by peptides on antigen presenting cells (APCs). We show that competition between T cells is inherent to the processes involved in T cells binding APCs. We prove that for each dominant peptide only one T-cell clone can ultimately survive the competition. This is analogous to a classical result from theoretical ecology known as the principle of "competitive exclusion". These findings allow for three main results. First, competitive exclusion during an immune response to antigen implies that the clone(s) with the highest affinity for the dominant peptide(s) will outcompete all others. This allows for a form of "affinity selection". Second, the competition for binding antigen gives rise to regulation of T-cell numbers within a single clone. This allows for a regulated form of T-cell memory when T cells are continuously activated by a persisting antigen. Third, competitive exclusion implies that for each peptide only one T-cell specificity can be maintained in the repertoire. If the T-cell repertoire is largely maintained owing to cross-reactivities with various antigens, competitive exclusion means that the diversity of the T-cell repertoire is limited by the number of antigens stimulating the system. If the cross-reactivities were to involve activation by self antigens this would confirm an earlier result suggesting that the T-cell repertoire is diverse owing to the diversity of the self environment. PMID:7967629

De Boer, R J; Perelson, A S

1994-08-21

238

Insulinoma-released exosomes or microparticles are immunostimulatory and can activate autoreactive T cells spontaneously developed in non-obese diabetes mice1  

PubMed Central

Exosomes (EXO) are secreted intracellular microparticles that can trigger inflammation and induce antigen-specific immune responses. To test possible roles of EXO in autoimmunity, we isolated small microparticles, mainly EXO, from mouse insulinoma and examined their activities to stimulate the autoimmune responses in non-obese diabetic (NOD) mice, a model for human type 1 diabetes. We demonstrate that the EXO contains strong innate stimuli and expresses candidate diabetes autoantigens. They can induce secretion of inflammatory cytokines through MyD88-dependent pathways, and activate purified APC and result in T cell proliferation. To address whether EXO or the secreted microparticles are possible autoimmune targets causing islet-specific inflammation, we monitored the T cell responses spontaneously developed in prediabetic NOD mice for their reactivity to the EXO, and compared this reactivity between diabetes-susceptible and -resistant congenic mouse strains. We found that older NOD females, which have advanced islet destruction, accumulated more EXO-reactive, IFN-gamma-producing lymphocytes than younger females or age-matched males, and that pancreatic lymph nodes from the prediabetic NOD, but not from the resistant mice, were also enriched with EXO-reactive Th1 cells. In vivo, immunization with the EXO accelerates insulitis development in diabetes-resistant NOR mice. Thus, EXO or small microparticles can be recognized by the diabetes-associated autoreactive T cells, supporting that EXO might be a possible autoimmune target and/or insulitis trigger in NOD or congenic mouse strains. PMID:21734072

Sheng, Huiming; Hassanali, Saleema; Nugent, Courtney; Wen, Li; Hamilton-Williams, Emma; Dias, Peter; Dai, Yang D.

2011-01-01

239

Severe atherosclerosis of the aorta and development of peripheral T-cell lymphoma in an adolescent with angiolymphoid hyperplasia with eosinophilia.  

PubMed

We report an adolescent girl with a history of angiolymphoid hyperplasia with eosinophilia (ALHE) diagnosed at the age of 10 years. The patient also suffered from chronic persistent multiresistant herpes simplex virus infection. Atherosclerotic occlusive disease of the abdominal aorta and its major branches was observed at the age of 17 years, necessitating vascular surgical intervention 1 year later because of disease progression. Histological examination of the aorta disclosed widespread atherosclerosis and high levels of gene expression of both T-helper cell type (Th) 1- and Th2-derived cytokines. This suggests that a highly stimulated systemic immune response including increased production of both Th1- and Th2-derived cytokines such as interferon-gamma and interleukin-4 may result in severe atherosclerotic lesions at a very young age. In addition, the patient developed a peripheral T-cell lymphoma at the age of 18 years. Neither systemic atherosclerosis nor T-cell lymphoma has been reported in association with ALHE. It is suggested that a highly stimulated dysfunctional immune response may play a key role in persistent inflammatory disease and premature development of atherosclerosis as well as malignant transformation of T cells. PMID:15888166

Andreae, J; Galle, C; Magdorf, K; Staab, D; Meyer, L; Goldman, M; Querfeld, U

2005-05-01

240

Role of Neuronal Interferon-? in the Development of Myelopathy in Rats Infected with Human T-Cell Leukemia Virus Type 1  

PubMed Central

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of not only adult T-cell leukemia but also HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Among the rat strains infected with HTLV-1, chronic progressive myelopathy, named HAM rat disease, occurs exclusively in WKAH rats. In the present study, we found that HTLV-1 infection induces interferon (IFN)-? production in the spinal cords of HAM-resistant strains but not in those of WKAH rats. Neurons were the major cells that produced IFN-? in HTLV-1-infected, HAM-resistant strains. Administration of IFN-? suppressed expression of pX, the gene critically involved in the onset of HAM rat disease, in an HTLV-1-immortalized rat T-cell line, indicating that IFN-? protects against the development of HAM rat disease. The inability of WKAH spinal cord neurons to produce IFN-? after infection appeared to stem from defects in signaling through the interleukin (IL)-12 receptor. Specifically, WKAH-derived spinal cord cells were unable to up-regulate the IL-12 receptor ?2 gene in response to IL-12 stimulation. We suggest that the failure of spinal cord neurons to produce IFN-? through the IL-12 pathway is involved in the development of HAM rat disease. PMID:16816372

Miyatake, Yukiko; Ikeda, Hitoshi; Ishizu, Akihiro; Baba, Tomohisa; Ichihashi, Toru; Suzuki, Akira; Tomaru, Utano; Kasahara, Masanori; Yoshiki, Takashi

2006-01-01

241

T Cell Therapies  

Microsoft Academic Search

\\u000a T cell therapies are increasingly used for the treatment of\\u000a \\u0009 malignancies and viral-associated diseases. Initial studies\\u000a \\u0009 focused on the use of unmanipulated T cell populations after\\u000a \\u0009 allogeneic stem cell transplantation. More recently, the use of\\u000a \\u0009 antigen-specific T cells has been explored. This chapter reviews\\u000a \\u0009 the clinical experience with polyclonal Epstein-Barr virus\\u000a \\u0009 (EBV)-specific cytotoxic T cells (CTL) for the treatment of\\u000a \\u0009 EBV-associated malignancies.

S. Gottschalk; C. M. Bollard; K. C. Straathof; C. U. Louis; B. Savoldo; G. Dotti; M. K. Brenner; H. E. Heslop; C. M. Rooney

242

Generation of T-cell memory  

Microsoft Academic Search

Recent studies of T-cell memory have suggested that the persistent presence of the priming antigen is not necessary for maintenance of CD8 memory. Factors contributing to the development of memory from activated T cells reman ill defined but accumulating data suggest that cytokines play a key role in this process. There has also been recent progress in undestanding turnover of

Peter CL Beverly

1996-01-01

243

Chimeric antigen receptor T Cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo.  

PubMed

Adoptive immunotherapy using T lymphocytes genetically modified to express a chimeric antigen receptor (CAR-T) holds considerable promise for the treatment of cancer. However, CAR-based therapies may involve on-target toxicity against normal tissues expressing low amounts of the targeted tumor-associated antigen (TAA). To specify T cells for robust effector function that is selective for tumor but not normal tissue, we developed a trans-signaling CAR strategy, whereby T-cell activation signal 1 (CD3z) is physically dissociated from costimulatory signal 2 (CD28) in two CARs of differing antigen specificity: mesothelin and a-folate receptor (FRa). Human T cells were genetically modified to coexpress signal 1 (anti-Meso scFv-CD3z) and signal 2 (anti-FRa scFv-CD28) CARs in trans. Trans-signaling CAR-T cells showed weak cytokine secretion against target cells expressing only one TAA in vitro, similar to first-generation CAR-T cells bearing CD3z only, but showed enhanced cytokine secretion upon encountering natural or engineered tumor cells coexpressing both antigens, equivalent to that of second-generation CAR-T cells with dual signaling in cis. CAR-T cells with dual specificity also showed potent anticancer activity and persistence in vivo, which was superior to first-generation CAR-T cells and equivalent to second-generation CARs. Importantly, second-generation CAR-T cells exhibited potent activity against cells expressing mesothelin alone, recapitulating normal tissue, whereas trans-signaling CAR-T cells did not. Thus, a dual specificity, trans-signaling CAR approach can potentiate the therapeutic efficacy of CAR-T cells against cancer while minimizing parallel reactivity against normal tissues bearing single antigen. PMID:24409448

Lanitis, Evripidis; Poussin, Mathilde; Klattenhoff, Alex W; Song, Degang; Sandaltzopoulos, Raphael; June, Carl H; Powell, Daniel J

2013-07-01

244

T cell lipid peroxidation induces ferroptosis and prevents immunity to infection.  

PubMed

The selenoenzyme glutathione peroxidase 4 (Gpx4) is a major scavenger of phospholipid hydroperoxides. Although Gpx4 represents a key component of the reactive oxygen species-scavenging network, its relevance in the immune system is yet to be defined. Here, we investigated the importance of Gpx4 for physiological T cell responses by using T cell-specific Gpx4-deficient mice. Our results revealed that, despite normal thymic T cell development, CD8(+) T cells from T(?Gpx4/?Gpx4) mice had an intrinsic defect in maintaining homeostatic balance in the periphery. Moreover, both antigen-specific CD8(+) and CD4(+) T cells lacking Gpx4 failed to expand and to protect from acute lymphocytic choriomeningitis virus and Leishmania major parasite infections, which were rescued with diet supplementation of high dosage of vitamin E. Notably, depletion of the Gpx4 gene in the memory phase of viral infection did not affect T cell recall responses upon secondary infection. Ex vivo, Gpx4-deficient T cells rapidly accumulated membrane lipid peroxides and concomitantly underwent cell death driven by ferroptosis but not necroptosis. These studies unveil an essential role of Gpx4 for T cell immunity. PMID:25824823

Matsushita, Mai; Freigang, Stefan; Schneider, Christoph; Conrad, Marcus; Bornkamm, Georg W; Kopf, Manfred

2015-04-01

245

T cells promote the regeneration of neural precursor cells in the hippocampus of Alzheimer's disease mice  

PubMed Central

Alzheimer's disease is closely associated with disorders of neurogenesis in the brain, and growing evidence supports the involvement of immunological mechanisms in the development of the disease. However, at present, the role of T cells in neuronal regeneration in the brain is unknown. We injected amyloid-beta 1–42 peptide into the hippocampus of six BALB/c wild-type mice and six BALB/c-nude mice with T-cell immunodeficiency to establish an animal model of Alzheimer's disease. A further six mice of each genotype were injected with same volume of normal saline. Immunohistochemistry revealed that the number of regenerated neural progenitor cells in the hippocampus of BALB/c wild-type mice was significantly higher than that in BALB/c-nude mice. Quantitative fluorescence PCR assay showed that the expression levels of peripheral T cell-associated cytokines (interleukin-2, interferon-?) and hippocampal microglia-related cytokines (interleukin-1?, tumor necrosis factor-?) correlated with the number of regenerated neural progenitor cells in the hippocampus. These results indicate that T cells promote hippocampal neurogenesis in Alzheimer's disease and T-cell immunodeficiency restricts neuronal regeneration in the hippocampus. The mechanism underlying the promotion of neuronal regeneration by T cells is mediated by an increased expression of peripheral T cells and central microglial cytokines in Alzheimer's disease mice. Our findings provide an experimental basis for understanding the role of T cells in Alzheimer's disease. PMID:25317172

Liu, Jing; Ma, Yuxin; Tian, Sumin; Zhang, Li; Zhao, Mengmeng; Zhang, Yaqiong; Xu, Dachuan

2014-01-01

246

Development of angioimmunoblastic T-cell lymphoma after treatment of diffuse large B-cell lymphoma: a case report and review of literature  

PubMed Central

Cases of diffuse large B-cell lymphoma (DLBCL) arising after the initial diagnosis of angioimmunoblastic T-cell lymphoma (AITL) and DLBCL synchronous with AITL have been reported. To date, there is no report on the subsequent development of AITL in patients with DLBCL. Here we presented a rare case of AITL developing six months after the initial diagnosis of DLBCL. In order to investigate the clinical and molecular features of patients with AITL and DLBCL, we also reviewed the literature on AITL patients developing DLBCL, and patients with composite AITL and DLBCL. PMID:25031772

Wang, Yaya; Xie, Bailu; Chen, Yu; Huang, Zhenqian; Tan, Huo

2014-01-01

247

Prenatal exposure to radiofrequencies: effects of WiFi signals on thymocyte development and peripheral T cell compartment in an animal model.  

PubMed

Wireless local area networks are an increasing alternative to wired data networks in workplaces, homes, and public areas. Concerns about possible health effects of this type of signal, especially when exposure occurs early in life, have been raised. We examined the effects of prenatal (in utero) exposure to wireless fidelity (WiFi) signal-associated electromagnetic fields (2450?MHz center-frequency band) on T cell development and function. Pregnant mice were exposed whole body to a specific absorption rate of 4?W/kg, 2?h per day, starting 5 days after mating and ending 1 day before the expected delivery. Sham-exposed and cage control groups were used as controls. No effects on cell count, phenotype, and proliferation of thymocytes were observed. Also, spleen cell count, CD4/CD8 cell frequencies, T cell proliferation, and cytokine production were not affected by the exposure. These findings were consistently observed in the male and female offspring at early (5 weeks of age) and late (26 weeks of age) time points. Nevertheless, the expected differences associated with aging and/or gender were confirmed. In conclusion, our results do not support the hypothesis that the exposure to WiFi signals during prenatal life results in detrimental effects on the immune T cell compartment. PMID:22556007

Laudisi, Federica; Sambucci, Manolo; Nasta, Francesca; Pinto, Rosanna; Lodato, Rossella; Altavista, Pierluigi; Lovisolo, Giorgio Alfonso; Marino, Carmela; Pioli, Claudio

2012-12-01

248

Neonatal testosterone imprinting affects thymus development and leads to phenotypic rejuvenation and masculinization of the peripheral blood T-cell compartment in adult female rats.  

PubMed

Exposure of female rodents to testosterone in the critical neonatal period produces defeminization/masculinization of the hypothalamo-pituitary-gonadal (HPG) axis, i.e. neonatal androgenization and postpones axis maturation. To address the hypothesis that HPG axis signaling is involved in the programming of thymic maturation/involution and sexual differentiation we studied the impact of neonatal androgenization on thymic cellularity, development of effector and regulatory T cells, and phenotypic characteristics of peripheral blood T lymphocytes in adult rats. A single injection of testosterone on postnatal day 2 postponed thymic maturation/involution as revealed by organ hypercellularity, increased cellularity of the most mature (CD4+CD8- and CD4-CD8+) TCRalphabeta(high) thymocyte and both recent thymic emigrant (RTE) subsets and caused phenotypic defeminization/masculinization of thymic (decreased CD4+CD8-TCRalphabeta(high)/CD4-CD8+TCRalphabeta(high) cell ratio) and peripheral blood T-cell compartments (decreased CD4+RTE/CD8+RTE and CD4+/CD8+ cell ratio). In addition, neonatal androgenization increased the relative and absolute numbers of both CD4+CD25+Foxp3+ and natural killer (NK) regulatory T cells in peripheral blood. These findings, in conjunction with thymocyte overexpression of Thy-1 that is assumed to reduce negative selection affecting self-reactive cell generation, suggest a new relationship between self-reactive and regulatory T cells. In conclusion, our study provides additional evidence for a role of HPG signals (i.e. sex steroids and gonadotropins) in programming the kinetics of thymic maturation/involution and in establishing immunological sexual dimorphism. PMID:19028560

Leposavi?, Gordana; Perisi?, Milica; Kosec, Dusko; Arsenovi?-Ranin, Nevena; Radojevi?, Katarina; Stoji?-Vukani?, Zorica; Pilipovi?, Ivan

2009-02-01

249

Bovine ?? T Cells Are a Major Regulatory T Cell Subset  

PubMed Central

In humans and mice, ?? T cells represent <5% of the total circulating lymphocytes. In contrast, the ?? T cell compartment in ruminants accounts for 15–60% of the total circulating mononuclear lymphocytes. Despite the existence of CD4+CD25high Foxp3+ T cells in the bovine system, these are neither anergic nor suppressive. We present evidence showing that bovine ?? T cells are the major regulatory T cell subset in peripheral blood. These ?? T cells spontaneously secrete IL-10 and proliferate in response to IL-10, TGF-?, and contact with APCs. IL-10–expressing ?? T cells inhibit Ag-specific and nonspecific proliferation of CD4+ and CD8+ T cells in vitro. APC subsets expressing IL-10 and TFG-? regulate proliferation of ?? T cells producing IL-10. We propose that ?? T cells are a major regulatory T cell population in the bovine system. PMID:24890724

Hope, Jayne; Taylor, Geraldine; Smith, Adrian L.; Cubillos-Zapata, Carolina; Charleston, Bryan

2014-01-01

250

The Retinoic Acid-Metabolizing Enzyme Cyp26b1 Regulates CD4 T Cell Differentiation and Function  

PubMed Central

The vitamin A metabolite retinoic acid (RA) has potent immunomodulatory properties that affect T cell differentiation, migration and function. However, the precise role of RA metabolism in T cells remains unclear. Catabolism of RA is mediated by the Cyp26 family of cytochrome P450 oxidases. We examined the role of Cyp26b1, the T cell-specific family member, in CD4+ T cells. Mice with a conditional knockout of Cyp26b1 in T cells (Cyp26b1?/? mice) displayed normal lymphoid development but showed an increased sensitivity to serum retinoids, which led to increased differentiation under both inducible regulatory T (iTreg) cell- and TH17 cell-polarizing conditions in vitro. Further, Cyp26b1 expression was differentially regulated in iTreg and TH17 cells. Transfer of naïve Cyp26b1?/? CD4+ T cells into Rag1?/? mice resulted in significantly reduced disease in a model of T cell-dependent colitis. Our results show that T cell-specific expression of Cyp26b1 is required for the development of T cell-mediated colitis and may be applicable to the development of therapeutics that target Cyp26b1 for the treatment of inflammatory bowel disease. PMID:23991089

Chenery, Alistair; Burrows, Kyle; Antignano, Frann; Underhill, T. Michael; Petkovich, Martin; Zaph, Colby

2013-01-01

251

Smad4 promotes differentiation of effector and circulating memory CD8 T cells but is dispensable for tissue-resident memory CD8 T cells.  

PubMed

Tissue-resident memory CD8 T cells are a unique subset of virus-specific CTLs that bolster local immune responses after becoming lodged in previously infected tissues. These cells provide enhanced protection by intercepting returning pathogens before a new infection gets established. In contrast, central memory CD8 T cells circulate in the bloodstream and proliferate in secondary lymphoid organs before replenishing effector and memory CD8 T cell populations in remote parts of the body. Both populations of virus-specific memory CD8 T cells participate in immunity to influenza virus infection; however, the signaling pathways that instruct developing memory CD8 T cells to distribute to specific tissues are poorly defined. We show that TGF-? promotes the development of pulmonary tissue-resident memory T cells via a signaling pathway that does not require the downstream signaling intermediate Sma- and Mad-related protein (Smad)4. In contrast, circulating memory CD8 T cells have no requirement for TGF-? but show signs of arrested development in the absence of Smad4, including aberrant CD103 expression. These signaling pathways alter the distribution of virus-specific CTLs in the lungs but do not prevent robust cytokine responses. Our data show that Smad4 is required for normal differentiation of multiple subsets of virus-specific CD8 T cells. In normal circumstances, Smad4 may be activated via a pathway that bypasses the TGF-? receptor. Improved understanding of these signaling pathways could be used to augment vaccine-induced immunity. PMID:25637015

Hu, Yinghong; Lee, Young-Tae; Kaech, Susan M; Garvy, Beth; Cauley, Linda S

2015-03-01

252

Clonal expansions and loss of receptor diversity in the naive CD8 T cell repertoire of aged mice.  

PubMed

There are well-characterized age-related changes in the peripheral repertoire of CD8 T cells characterized by reductions in the ratio of naive:memory T cells and the development of large clonal expansions in the memory pool. In addition, the TCR repertoire of naive T cells is reduced with aging. Because a diverse repertoire of naive T cells is essential for a vigorous response to new infections and vaccinations, there is much interest in understanding the mechanisms responsible for declining repertoire diversity. It has been proposed that one reason for declining repertoire diversity in the naive T cell pool is an increasing dependence on homeostatic proliferation in the absence of new thymic emigrants for maintenance of the naive peripheral pool. In this study, we have analyzed the naive CD8 T cell repertoire in young and aged mice by DNA spectratype and sequence analysis. Our data show that naive T cells from aged mice have perturbed spectratype profiles compared with the normally Gaussian spectratype profiles characteristic of naive CD8 T cells from young mice. In addition, DNA sequence analysis formally demonstrated a loss of diversity associated with skewed spectratype profiles. Unexpectedly, we found multiple repeats of the same sequence in naive T cells from aged but not young mice, consistent with clonal expansions previously described only in the memory T cell pool. Clonal expansions among naive T cells suggests dysregulation in the normal homeostatic proliferative mechanisms that operate in young mice to maintain diversity in the naive T cell repertoire. PMID:19124721

Ahmed, Mushtaq; Lanzer, Kathleen G; Yager, Eric J; Adams, Pamela S; Johnson, Lawrence L; Blackman, Marcia A

2009-01-15

253

Mice Deficient in STAT1 but Not STAT2 or IRF9 Develop a Lethal CD4+ T-Cell-Mediated Disease following Infection with Lymphocytic Choriomeningitis Virus  

PubMed Central

Interferon (IFN) signaling is crucial for antiviral immunity. While type I IFN signaling is mediated by STAT1, STAT2, and IRF9, type II IFN signaling requires only STAT1. Here, we studied the roles of these signaling factors in the host response to systemic infection with lymphocytic choriomeningitis virus (LCMV). In wild-type (WT) mice and mice lacking either STAT2 or IRF9, LCMV infection was nonlethal, and the virus either was cleared (WT) or established persistence (STAT2 knockout [KO] and IRF9 KO). However, in the case of STAT1 KO mice, LCMV infection was lethal and accompanied by severe multiorgan immune pathology, elevated expression of various cytokine genes in tissues, and cytokines in the serum. This lethal phenotype was unaltered by the coabsence of the gamma interferon (IFN-?) receptor and hence was not dependent on IFN-?. Equally, the disease was not due to a combined defect in type I and type II IFN signaling, as IRF9 KO mice lacking the IFN-? receptor survived infection with LCMV. Clearance of LCMV is mediated normally by CD8+ T cells. However, the depletion of these cells in LCMV-infected STAT1 KO mice was delayed, but did not prevent, lethality. In contrast, depletion of CD4+ T cells prevented lethality in LCMV-infected STAT1 KO mice and was associated with a reduction in tissue immune pathology. These studies highlight a fundamental difference in the role of STAT1 versus STAT2 and IRF9. While all three factors are required to limit viral replication and spread, only STAT1 has the unique function of preventing the emergence of a lethal antiviral CD4+ T-cell response. PMID:22496215

Hofer, Markus J.; Li, Wen; Manders, Peter; Terry, Rachael; Lim, Sue Ling; King, Nicholas J. C.

2012-01-01

254

Reduction of T Cell Receptor Diversity in NOD Mice Prevents Development of Type 1 Diabetes but Not Sjögren’s Syndrome  

PubMed Central

Non-obese diabetic (NOD) mice are well-established models of independently developing spontaneous autoimmune diseases, Sjögren’s syndrome (SS) and type 1 diabetes (T1D). The key determining factor for T1D is the strong association with particular MHCII molecule and recognition by diabetogenic T cell receptor (TCR) of an insulin peptide presented in the context of I-Ag7 molecule. For SS the association with MHCII polymorphism is weaker and TCR diversity involved in the onset of the autoimmune phase of SS remains poorly understood. To compare the impact of TCR diversity reduction on the development of both diseases we generated two lines of TCR transgenic NOD mice. One line expresses transgenic TCR? chain originated from a pathogenically irrelevant TCR, and the second line additionally expresses transgenic TCR?mini locus. Analysis of TCR sequences on NOD background reveals lower TCR diversity on Treg cells not only in the thymus, but also in the periphery. This reduction in diversity does not affect conventional CD4+ T cells, as compared to the TCRmini repertoire on B6 background. Interestingly, neither transgenic TCR? nor TCRmini mice develop diabetes, which we show is due to lack of insulin B:9–23 specific T cells in the periphery. Conversely SS develops in both lines, with full glandular infiltration, production of autoantibodies and hyposalivation. It shows that SS development is not as sensitive to limited availability of TCR specificities as T1D, which suggests wider range of possible TCR/peptide/MHC interactions driving autoimmunity in SS. PMID:25379761

Kern, Joanna; Drutel, Robert; Leanhart, Silvia; Bogacz, Marek; Pacholczyk, Rafal

2014-01-01

255

Effect of passive administration of alloantiserum containing antibody against putative acceptor(s) for T cell-replacing factor (TRF) in the neonatal stage on development of B cell activity responsive to TRF.  

PubMed

Previously, we showed that the antiserum raised in male (DBA/2Ha X BALB/c)F1(DCF1) mice (T cell-replacing factor [TRF]-low response animals) by immunizing them with activated B cells from BALB/c mice (TRF-high-responders) contained antibodies against putative TRF-acceptor site(s). We have now evaluated the hypothesis that neonatal treatment of mice with the above antiserum suppresses the development of B cells responsive to TRF. Male DCF1 mouse anti-BALB/c B-cell antiserum or normal DCF1 mouse serum as a control was injected into BALB/c mice within 24 hr after birth. In the antiserum-treated mice, no augmented primary immunoglobulin M (IgM) antibody responses to sheep red blood cells (SRBC) were observed under the conditions in which markedly augmented IgM anti-SRBC responses were induced in control BALB/c mice, suggesting that development of B cells reacting with male DCF1 mouse anti-BALB/c B-cell antiserum is suppressed by the neonatal treatment with the antiserum. Furthermore, the development of B cell activity responsible for helper factors derived from T cells, such as TRF, was markedly suppressed in the neonatally antiserum-treated mice, whereas activity of B cells capable of interacting directly with helper T cells through antigen-bridges was not significantly affected by the same treatment. Such suppression of the B cell activity could be induced only when the antiserum was administered within 48 hr after birth. Moreover, neonatal treatment of mice with the antiserum induced suppressed responsiveness of B cells to a T-independent type 2 antigen, TNP-Ficoll. Neither serum-borne suppressive serum components nor suppressor cells were detected by the system employed. These results support the hypothesis that TRF responsive B cells constitute a subpopulation distinct from the other B cells capable of cooperating with helper T cells via cognate interaction. PMID:2939324

Hashimoto, Y; Tsukada, S; Hamaoka, T; Sano, Y; Koyama, N; Takatsu, K

1986-01-01

256

The highway code of T cell trafficking.  

PubMed

Coordinated migratory events are required for the development of effective and regulated immunity. Naïve T lymphocytes are programmed to recirculate predominantly in secondary lymphoid tissue by non-specific stimuli. In contrast, primed T cells must identify specific sites of antigen location in non-lymphoid tissue to exert targeted effector responses. Following priming, T cells acquire the ability to establish molecular interactions mediated by tissue-selective integrins and chemokine receptors (homing receptors) that allow their access to specific organs, such as the skin and the gut. Recent studies have shown that an additional level of specificity is provided by the induction of specific T cell migration into the tissue following recognition of antigen displayed by the endothelium. In addition, co-stimulatory signals (such as those induced by CD28 and CTLA-4 molecules) have been shown not only to regulate T cell activation and differentiation, but also to orchestrate the anatomy of the ensuing T cell response. PMID:18161751

Marelli-Berg, F M; Cannella, L; Dazzi, F; Mirenda, V

2008-01-01

257

Cytotoxic T lymphocyte responses by chimeric thymocytes. Self-recognition is determined early in T cell development  

SciTech Connect

In this study the cytotoxic T lymphocyte (CTL) recognition pattern of thymocytes from recently reconstituted parent leads to F1 and F1 leads to parent radiation bone marrow chimeras was investigated. Chimeric thymocytes were entirely of donor origin approximately 4 weeks after irradiation and reconstitution but were not capable of autonomously generating either alloreactive or trinitrophenyl (TNP)-modified-self-reactive CTL responses. These experiments demonstrte that even at the earliest time CTL effectors of donor origin from the thymuses of chimeras can be studied, their self-receptor repertoire has already been restricted to recognition of host MHC determinants. These results support the cocept that the host environment influences the self-recognition capacity of T cells at the pre- or intrathymic stage of differentation.

Kruisbeek, A.M.; Hodes, R.J.; Singer, A.

1981-01-01

258

Visualizing T Cell Migration in situ  

PubMed Central

Mounting a protective immune response is critically dependent on the orchestrated movement of cells within lymphoid tissues. The structure of secondary lymphoid organs regulates immune responses by promoting optimal cell–cell and cell–extracellular matrix interactions. Naïve T cells are initially activated by antigen presenting cells in secondary lymphoid organs. Following priming, effector T cells migrate to the site of infection to exert their functions. Majority of the effector cells die while a small population of antigen-specific T cells persists as memory cells in distinct anatomical locations. The persistence and location of memory cells in lymphoid and non-lymphoid tissues is critical to protect the host from re-infection. The localization of memory T cells is carefully regulated by several factors including the highly organized secondary lymphoid structure, the cellular expression of chemokine receptors and compartmentalized secretion of their cognate ligands. This balance between the anatomy and the ordered expression of cell surface and soluble proteins regulates the subtle choreography of T cell migration. In recent years, our understanding of cellular dynamics of T cells has been advanced by the development of new imaging techniques allowing in situ visualization of T cell responses. Here, we review the past and more recent studies that have utilized sophisticated imaging technologies to investigate the migration dynamics of naïve, effector, and memory T cells. PMID:25120547

Benechet, Alexandre P.; Menon, Manisha; Khanna, Kamal M.

2014-01-01

259

Normal development but differentially altered proliferative responses of lymphocytes in mice lacking CD81.  

PubMed Central

CD81 (TAPA-1) is a member of the transmembrane 4 superfamily (TM4SF) which is expressed on the cell surface of most cells of the body throughout their cellular differentiation. It has been recognized in several cell surface complexes of lymphocytes, suggesting that it may have diverse roles in lymphocyte development and activation regulation. Mice with a CD81 null mutation revealed normal T- and conventional B-cell development, although CD19 expression on B cells was dull and B-1 cells were reduced in number. However, both T and B cells of mutant mice exhibited strikingly enhanced proliferation in response to various types of stimuli. Interestingly, while proliferative responses of T cells following T-cell antigen receptor (TCR) engagement was enhanced in the absence of CD81, B-cell proliferation in response to B-cell antigen-receptor (BCR) cross-linking was severely impaired. Despite these altered proliferative responses, both tyrosine phosphorylation and intracellular calcium flux in response to cross-linking of cell surface antigen receptors were normal in mutant mice, reflecting apparently normal initial signaling of antigen receptors. In conclusion, though CD81 is not essential for normal T- and conventional B-cell development, it plays key roles in controlling lymphocyte homeostasis by regulating lymphocyte proliferation in distinct manners, dependent on the context of stimulation. PMID:9250665

Miyazaki, T; Müller, U; Campbell, K S

1997-01-01

260

SOCS3 Deletion in T-Lymphocytes Suppresses Development of Chronic Ocular Inflammation Via Up-regulation of CTLA-4 and Expansion of Regulatory T cells  

PubMed Central

Suppressors of cytokine signaling (SOCS) proteins are negative-feedback regulators of JAK/STAT pathway and SOCS3 contributes to host immunity by regulating the intensity/duration of cytokine signals and inflammatory responses. Mice with Socs3 deletion in myeloid cells exhibit enhanced STAT3-signaling, expansion of Th1 and Th17 cells and developed severe experimental autoimmune encephalomyelitis (EAE). Interestingly, development of the unique IL-17/IFN-?-double producing (Th17/IFN-? and Tc17/IFN-?) subsets that exhibit strong cytotoxic activities and associated with pathogenesis of several autoimmune diseases, has recently been shown to depend on epigenetic suppression of SOCS3 expression, further suggesting involvement of SOCS3 in autoimmunity and tumor immunity. In this study, we generated mice with Socs3 deletion in CD4 T cell compartment (CD4-SOCS3KO) to determine in vivo effects of the loss of Socs3 in the T cell-mediated autoimmune disease, experimental autoimmune uveitis (EAU). In contrast to the exacerbation of EAE in myeloid-specific SOCS3-deleted mice, CD4-SOCS3KO mice were protected from acute and chronic uveitis. Protection from EAU correlated with enhanced expression of CTLA4 and expansion of IL-10 producing Tregs with augmented suppressive activities. We further show that SOCS3 interacts with CTLA4 and negatively regulates CTLA4 levels in T cells, providing mechanistic explanation for the expansion of Tregs in CD4-SOCS3 during EAU. Contrary to in vitro epigenetic studies, Th17/IFN-? and Tc17/IFN-? populations were markedly reduced in CD4-SOCS3KO, suggesting that SOCS3 promotes expansion of Th17/IFN-? subset associated with development of severe uveitis. Thus, SOCS3 is a potential therapeutic target in uveitis and other auto-inflammatory diseases. PMID:24101549

Yu, Cheng-Rong; Kim, Sung-Hye; Mahdi, Rashid M.; Egwuagu, Charles E.

2013-01-01

261

Harnessing the antibacterial and immunological properties of mucosal-associated invariant T cells in the development of novel oral vaccines against enteric infections.  

PubMed

Enteric infections are a major cause of mortality and morbidity with significant social and economic implications worldwide and particularly in developing countries. An attractive approach to minimizing the impact of these diseases is via the development of oral vaccination strategies. However, oral vaccination is challenging due to the tolerogenic and hyporesponsive nature of antigen presenting cells resident in the gastrointestinal tract. The inclusion of adjuvants in oral vaccine formulations has the potential to overcome this challenge. To date no oral adjuvants have been licenced for human use and thus oral adjuvant discovery remains a key goal in improving the potential for oral vaccine development. Mucosal-associated invariant T (MAIT) cells are a recently discovered population of unconventional T cells characterized by an evolutionarily conserved ?? T cell receptor (TCR) that recognizes antigens presented by major histocompatibility complex (MHC) class I-related (MR1) molecule. MAIT cells are selected intra-thymically by MR1 expressing double positive thymocytes and enter the circulation with a naïve phenotype. In the circulation they develop a memory phenotype and are programmed to home to mucosal tissues and the liver. Once resident in these tissues, MAIT cells respond to bacterial and yeast infections through the production of chemokines and cytokines that aid in the induction of an adaptive immune response. Their abundance in the gastrointestinal tract and ability to promote adaptive immunity suggests that MAIT cell activators may represent attractive novel adjuvants for use in oral vaccination. PMID:25173989

Abautret-Daly, Aine E; Davitt, Christopher J H; Lavelle, Ed C

2014-11-15

262

T Cell Apoptosis in Human Heart Allografts  

PubMed Central

It is unclear whether the intracardial immune reactivity after heart transplantation influences the peripheral immunological status (activation or nonresponsiveness) of the patient. Co-stimulation and activation-induced cell death (AICD) or apoptosis play an important role in determining the balance between lymphocyte reactivity and nonreactivity. Therefore, we studied the expression of co-stimulatory molecules and the process of apoptosis in biopsies of human heart allografts, using immunohistochemistry. Although a normal expression of co-stimulatory molecules on antigen-presenting cells was observed, the expression of their counter-structures on T cells was absent. This may be due to chronic T cell activation, which can lead to the induction of apoptosis via the Fas/Fas ligand pathway. In the infiltrates, a considerable percentage of the lymphocytes, but not the macrophages, were apoptotic. Apoptosis was confirmed by DNA fragmentation analysis. Increased numbers of Bax-expressing versus decreased numbers of Bcl2-expressing lymphocytes in comparison with normal lymphoid tissue confirmed a imbalance in favor of apoptosis. Apoptosis was biased towards CD4+ T cells (65.7% versus 26.6% in CD8+ T cells). Fas was expressed on most of the infiltrating cells. Fas ligand expression was also observed, not only on most of the T cells but also on all macrophages. Because macrophages were often detected in close contact with T cells, they may play a role in T cell regulation via the Fas/Fas ligand pathway. This study indicates that, during rejection, not only is tissue damage induced by infiltrating T cells, but also the infiltrating lymphocytes themselves are actively down-regulated (eg, AICD) by one another and by macrophages in the infiltrate. This regulatory process may affect the immunological status of the patient after heart transplantation. PMID:9846972

Van Hoffen, Els; Van Wichen, Dick F.; Leemans, Jaklien C.; Broekhuizen, Richard A.J.F.; Bruggink, Annette H.; De Boer, Mark; De Jonge, Nicolaas; Kirkels, Hans; Slootweg, Piet J.; Gmelig-Meyling, Frits H.J.; De Weger, Roel A.

1998-01-01

263

The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia.  

PubMed

Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting a role as an essential driver for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34(+) thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from ex vivo isolated Notch active CD34(+) and Notch inactive CD4(+)CD8(+) thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publicly available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T cells. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way for the development of novel therapeutic strategies that target hyperactive Notch signaling in human T-cell acute lymphoblastic leukemia. PMID:25344525

Durinck, Kaat; Wallaert, Annelynn; Van de Walle, Inge; Van Loocke, Wouter; Volders, Pieter-Jan; Vanhauwaert, Suzanne; Geerdens, Ellen; Benoit, Yves; Van Roy, Nadine; Poppe, Bruce; Soulier, Jean; Cools, Jan; Mestdagh, Pieter; Vandesompele, Jo; Rondou, Pieter; Van Vlierberghe, Pieter; Taghon, Tom; Speleman, Frank

2014-12-01

264

The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia  

PubMed Central

Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting a role as an essential driver for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34+ thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from ex vivo isolated Notch active CD34+ and Notch inactive CD4+CD8+ thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publicly available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T cells. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way for the development of novel therapeutic strategies that target hyperactive Notch signaling in human T-cell acute lymphoblastic leukemia. PMID:25344525

Durinck, Kaat; Wallaert, Annelynn; Van de Walle, Inge; Van Loocke, Wouter; Volders, Pieter-Jan; Vanhauwaert, Suzanne; Geerdens, Ellen; Benoit, Yves; Van Roy, Nadine; Poppe, Bruce; Soulier, Jean; Cools, Jan; Mestdagh, Pieter; Vandesompele, Jo; Rondou, Pieter; Van Vlierberghe, Pieter; Taghon, Tom; Speleman, Frank

2014-01-01

265

Human immunodeficiency virus-infected adherent cell-derived inhibitory factor (p29) inhibits normal T cell proliferation through decreased expression of high affinity interleukin-2 receptors and production of interleukin-2.  

PubMed Central

Adherent cells from HIV-infected subjects as well as in vitro HIV-infected normal adherent cells produce spontaneously a 29-kD (p29) factor that inhibits mitogen-induced proliferation of normal T cells. p29 mediates a partial dose-dependent inhibition of total protein synthesis in both nonstimulated and PHA-activated cells that is associated with impaired PHA-induced expression of IL-2 receptor (IL-2R)alpha chain, HLA-class II molecules, and production of IL-2 by these cells; conversely, p29 does not modify the expression of IL-2R beta chain, 4F2, CD9, or transferrin receptor, or the production of IL-1 and TNF alpha by the cells. 1 h preincubation of the cells with p29 is sufficient to detect its biologic activity and added rIL-2 abrogates p29-induced inhibition of IL-2R alpha chain expression; however, p29 does not display any biologic effect on already expressed IL-2R alpha chains. The impaired expression of IL-2R alpha chain mediated by p29 is not due to a decreased accumulation of the corresponding mRNA transcripts, but is associated with a two-fold increase of intracellular cAMP. Binding experiments with 125I-rIL-2 reveals that p29 induces a 50% decrease in the number of both high and low affinity IL-2R per cell. p29 also inhibits alloantigen-induced proliferation of PBMC, whereas it does not modify IL-2-dependent proliferation of 48-h PHA-blasts that already express high affinity IL-2R. These findings indicate that p29 mediates its biologic activity during early stages of T cell activation affecting the expression of high affinity IL-2R and production of IL-2, through a nontranscriptional mechanism involving an increase of intracellular cAMP. Images PMID:1321845

Ammar, A; Sahraoui, Y; Tsapis, A; Bertoli, A M; Jasmin, C; Georgoulias, V

1992-01-01

266

Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice  

PubMed Central

Tim-1, a type I transmembrane glycoprotein, consists of an IgV domain and a mucin domain. The IgV domain is essential for binding Tim-1 to its ligands, but little is known about the role of the mucin domain, even though genetic association of TIM-1 with atopy/asthma has been linked to the length of mucin domain. We generated a Tim-1–mutant mouse (Tim-1?mucin) in which the mucin domain was deleted genetically. The mutant mice showed a profound defect in IL-10 production from regulatory B cells (Bregs). Associated with the loss of IL-10 production in B cells, older Tim-1?mucin mice developed spontaneous autoimmunity associated with hyperactive T cells, with increased production of IFN-? and elevated serum levels of Ig and autoantibodies. However, Tim-1?mucin mice did not develop frank systemic autoimmune disease unless they were crossed onto the Fas-mutant lpr mice on a C57BL/6 background. Tim-1?mucinlpr mice developed accelerated and fulminant systemic autoimmunity with accumulation of abnormal double-negative T cells and autoantibodies to a number of lupus-associated autoantigens. Thus, Tim-1 plays a critical role in maintaining suppressive Breg function, and our data also demonstrate an unexpected role of the Tim-1 mucin domain in regulating Breg function and maintaining self-tolerance. PMID:22773818

Xiao, Sheng; Brooks, Craig R.; Zhu, Chen; Wu, Chuan; Sweere, Johanna M.; Petecka, Sonia; Yeste, Ada; Quintana, Francisco J.; Ichimura, Takaharu; Sobel, Raymond A.; Bonventre, Joseph V.; Kuchroo, Vijay K.

2012-01-01

267

Double Negative (DN) ?? T Cells: misperception and overdue recognition  

PubMed Central

CD4?CD8? double negative (DN) ?? T cells are legitimate components of the normal immune system. However, they are poorly understood and largely ignored by immunologists because of their historical association with the lymphoproliferation that occurs in mice (lpr and gld) and humans (ALPS patients) with impaired Fas-mediated apoptosis where they are considered abnormal T cells. We believe that the traditional view that DN T cells that cause lymphoproliferation (hereafter referred to as lpr DN T cells) are CD4 and CD8 T cells that lost their coreceptor, conceived more than two decades ago, is flawed and that conflating lpr DN T cells with DN T cells found in normal immune system (hereafter referred to as nDN T cells) is unnecessarily dampening interest of this potentially important cell type. To begin rectifying these misperceptions, we will revisit the traditional view of lpr DN T cells and show that it does not hold true in light of recent immunological advances. In lieu of it, we offer a new model proposing that Fas-mediated apoptosis actively removes normally existing DN T cells from the periphery and that impaired Fas-mediated apoptosis leads to accumulation of these cells rather than de novo generation of DN T cells from activated CD4 or CD8 T cells. By doing so, we hope to provoke a new discussion that may lead to a consensus about the origin of lpr DN T cells and regulation of their homeostasis by the Fas pathway and reignite wider interest in nDN T cells. PMID:25420721

Martina, Maria N; Noel, Sanjeev; Saxena, Ankit; Rabb, Hamid; Hamad, Abdel Rahim A

2015-01-01

268

Therapeutic regulatory T cells subvert effector T cell function in inflamed islets to halt autoimmune diabetes.  

PubMed

Therapeutic regulatory T cells (Tregs) can reverse pre-established autoimmune pathology. In this study, using a mouse model of autoimmune diabetes, we aimed to determine the means by which therapeutic Tregs control islet inflammation. Islet Ag-specific Tregs infiltrated inflamed islets soon after infusion into prediabetic mice, which was quickly followed by a selective reduction of mRNA associated with effector T cells in the islets. This change was partially due to decreased CD8(+) T cell accumulation in the tissue. CD8(+) T cells that remained in the islets after Treg treatment were able to engage dendritic cells in a manner similar to that found in untreated mice, consistent with the retention of an activated phenotype by islet dendritic cells shortly after Treg treatment. Nonetheless, Treg treatment abrogated IFN-? production by intraislet CD8(+) and CD4(+) T cells at the protein level with minimal effect on IFN-? mRNA. Sustained expression of IFN-? protein by effector T cells was dependent on common ?-chain cytokine activation of the mTOR pathway, which was suppressed in islet CD8(+) T cells in vivo after Treg treatment. These multifaceted mechanisms underlie the efficacy of therapeutic Treg subversion of effector T cell functions at the site of inflammation to restore normal tissue homeostasis. PMID:25732730

Mahne, Ashley E; Klementowicz, Joanna E; Chou, Annie; Nguyen, Vinh; Tang, Qizhi

2015-04-01

269

Breaking the co-operation between bystander T-cells and natural killer cells prevents the development of immunosuppression after traumatic skeletal muscle injury in mice.  

PubMed

Nosocomial infections represent serious complications after traumatic or surgical injuries in intensive care units. The pathogenesis of the underlying immunosuppression is only incompletely understood. In the present study, we investigated whether injury interferes with the function of the adaptive immune system in particular with the differentiation of antigen-specific T helper (Th)-cell responses in vivo. We used a mouse model for traumatic gastrocnemius muscle injury. Ovalbumin (OVA), which served as a foreign model antigen, was injected into the hind footpads for determination of the differentiation of OVA-specific Th-cells in the draining popliteal lymph node (pLN). The release of interferon (IFN)-? from OVA-specific Th-cells was impaired within 24 h after injury and this impairment persisted for at least 7 days. In contrast, the proliferation of OVA-specific Th-cells remained unaffected. Injury did not modulate the function of antigen-presenting cells (APCs) in the pLN. Adoptive transfer of total T-cells from pLNs of injured mice inhibited IFN-? production by OVA-specific Th-cells in naive mice. Suppressed Th1 priming did not occur in lymphocyte-deficient mice after injury but was restored by administration of T-cells before injury. Moreover, the suppression of Th1 differentiation required the presence of natural killer (NK) cells that were recruited to the pLN after injury; this recruitment was dependent on lymphocytes, toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). In summary, upon traumatic skeletal muscle injury T-cells and NK cells together prevent the development of protective Th1 immunity. Breaking this co-operation might be a novel approach to reduce the risk of infectious complications after injury. PMID:25609031

Wirsdörfer, Florian; Bangen, Jörg M; Pastille, Eva; Hansen, Wiebke; Flohé, Stefanie B

2015-06-01

270

Notch3 and pre-TCR interaction unveils distinct NF-?B pathways in T-cell development and leukemia  

PubMed Central

Notch signaling plays a critical role in T-cell differentiation and leukemogenesis. We previously demonstrated that, while pre-TCR is required for thymocytes proliferation and leukemogenesis, it is dispensable for thymocyte differentiation in Notch3-transgenic mice. Notch3-transgenic premalignant thymocytes and T lymphoma cells overexpress pT?/pre-TCR and display constitutive activation of NF-?B, providing survival signals for immature thymocytes. We provide genetic and biochemical evidence that Notch3 triggers multiple NF-?B activation pathways. A pre-TCR-dependent pathway preferentially activates NF-?B via IKK?/IKK?/NIK complex, resulting in p50/p65 heterodimer nuclear entry and recruitment onto promoters of Cyclin D1, Bcl2-A1 and IL7-receptor-? genes. In contrast, upon pT? deletion, Notch3 binds IKK? and maintains NF-?B activation through an alternative pathway, depending on an NIK-independent IKK? homodimer activity. The consequent NF-?B2/p100 processing allows nuclear translocation of p52/RelB heterodimers, which only trigger transcription from Bcl2-A1 and IL7-receptor-? genes. Our data suggest that a finely tuned interplay between Notch3 and pre-TCR pathways converges on regulation of NF-?B activity, leading to differential NF-?B subunit dimerization that regulates distinct gene clusters involved in either cell differentiation or proliferation/leukemogenesis. PMID:16498412

Vacca, Alessandra; Felli, Maria Pia; Palermo, Rocco; Di Mario, Giuseppina; Calce, Angelica; Di Giovine, Monica; Frati, Luigi; Gulino, Alberto; Screpanti, Isabella

2006-01-01

271

Antigen-specific T cell receptors and factors  

Microsoft Academic Search

This book provides recent developments in molecular biology, molecular immunology, protein chemistry of antigen-binding T cell receptors and factors, and of the clonotype-specific receptors of helper and cytotoxic T cells that are restricted by the major histocompatability complex. The relationship of T cell receptors to one another and to immunoglobulins is explored, and the expression of allotypy idiotypy by these

Marchalonis

1987-01-01

272

Genetically Engineered Antigen Specificity in T Cells for Adoptive Immunotherapy  

Microsoft Academic Search

\\u000a Antigen specificity has been genetically conferred to human T cells for therapy through the transfer of sequences encoding\\u000a antigen-specific T-cell receptors (TCRs) or through the antigen-specific antibody-based chimeric antigen receptors (CARs).\\u000a By either method, the advantage of the adoptive transfer of modified T cells over immunotherapies developed to date such as\\u000a vaccines or cytokines alone is that T cells have

Bruce L. Levine

273

The role of the T cell in autoimmune inflammation  

Microsoft Academic Search

T cells, in particular CD4+ T cells, have been implicated in mediating many aspects of autoimmune inflammation. However, current evidence suggests that the role played by CD4+ T cells in the development of rheumatoid inflammation exceeds that of activated proinflammatory T-helper (Th)1 effector cells that drive the chronic autoimmune response. Subsets of CD4+ T cells with regulatory capacity, such as

Alla Skapenko; Jan Leipe; Peter E Lipsky; Hendrik Schulze-Koops

2005-01-01

274

Obesity Impairs ?? T Cell Homeostasis and Antiviral Function in Humans  

PubMed Central

Obese patients are susceptible to increased morbidity and mortality associated with infectious diseases such as influenza A virus. ?? T cells and memory ?? T cells play key roles in reducing viral load by rapidly producing IFN-? and lysing infected cells. In this article we analyze the impact of obesity on T lymphocyte antiviral immunity. Obese donors exhibit a reduction in ?? T cells in the peripheral blood. The severity of obesity negatively correlates with the number of ?? T cells. The remaining ?? T cells have a skewed maturation similar to that observed in aged populations. This skewed ?? T cell population exhibits a blunted antiviral IFN-? response. Full ?? T cell function can be restored by potent stimulation with 1-Hydroxy-2-methyl-buten-4yl 4-diphosphate (HDMAPP), suggesting that ?? T cells retain the ability to produce IFN-?. Additionally, ?? T cells from obese donors have reduced levels of IL-2R?. IL-2 is able to restore ?? T cell antiviral cytokine production, which suggests that ?? T cells lack key T cell specific growth factor signals. These studies make the novel finding that the ?? T cell antiviral immune response to influenza is compromised by obesity. This has important implications for the development of therapeutic strategies to improve vaccination and antiviral responses in obese patients. PMID:25785862

Dutt, Shelley; Han, Peggy P.; Fujioka, Ken; Jameson, Julie M.

2015-01-01

275

Obesity Impairs ?? T Cell Homeostasis and Antiviral Function in Humans.  

PubMed

Obese patients are susceptible to increased morbidity and mortality associated with infectious diseases such as influenza A virus. ?? T cells and memory ?? T cells play key roles in reducing viral load by rapidly producing IFN-? and lysing infected cells. In this article we analyze the impact of obesity on T lymphocyte antiviral immunity. Obese donors exhibit a reduction in ?? T cells in the peripheral blood. The severity of obesity negatively correlates with the number of ?? T cells. The remaining ?? T cells have a skewed maturation similar to that observed in aged populations. This skewed ?? T cell population exhibits a blunted antiviral IFN-? response. Full ?? T cell function can be restored by potent stimulation with 1-Hydroxy-2-methyl-buten-4yl 4-diphosphate (HDMAPP), suggesting that ?? T cells retain the ability to produce IFN-?. Additionally, ?? T cells from obese donors have reduced levels of IL-2R?. IL-2 is able to restore ?? T cell antiviral cytokine production, which suggests that ?? T cells lack key T cell specific growth factor signals. These studies make the novel finding that the ?? T cell antiviral immune response to influenza is compromised by obesity. This has important implications for the development of therapeutic strategies to improve vaccination and antiviral responses in obese patients. PMID:25785862

Costanzo, Anne E; Taylor, Kristen R; Dutt, Shelley; Han, Peggy P; Fujioka, Ken; Jameson, Julie M

2015-01-01

276

CD8 T Cell Tolerance to a Tumor-Associated Self-Antigen Is Reversed by CD4 T Cells Engineered To Express the Same T Cell Receptor  

PubMed Central

Ag receptors used for cancer immunotherapy are often directed against tumor-associated Ags also expressed in normal tissues. Targeting of such Ags can result in unwanted autoimmune attack of normal tissues or induction of tolerance in therapeutic T cells. We used a murine model to study the phenotype and function of T cells redirected against the murine double minute protein 2 (MDM2), a tumor-associated Ag that shows low expression in many normal tissues. Transfer of MDM2-TCR–engineered T cells into bone marrow chimeric mice revealed that Ag recognition in hematopoietic tissues maintained T cell function, whereas presentation of MDM2 in nonhematopoietic tissues caused reduced effector function. TCR-engineered CD8+ T cells underwent rapid turnover, downmodulated CD8 expression, and lost cytotoxic function. We found that MDM2-TCR–engineered CD4+ T cells provided help and restored cytotoxic function of CD8+ T cells bearing the same TCR. Although the introduction of the CD8 coreceptor enhanced the ability of CD4+ T cells to recognize MDM2 in vitro, the improved self-antigen recognition abolished their ability to provide helper function in vivo. The data indicate that the same class I–restricted TCR responsible for Ag recognition and tolerance induction in CD8+ T cells can, in the absence of the CD8 coreceptor, elicit CD4 T cell help and partially reverse tolerance. Thus MHC class I–restricted CD4+ T cells may enhance the efficacy of therapeutic TCR-engineered CD8+ T cells and can be readily generated with the same TCR. PMID:25539815

Ghorashian, Sara; Veliça, Pedro; Chua, Ignatius; McNicol, Anne-Marie; Carpenter, Ben; Holler, Angelika; Nicholson, Emma; Ahmadi, Maryam; Zech, Mathias; Xue, Shao-An; Uckert, Wolfgang; Morris, Emma; Chakraverty, Ronjon

2015-01-01

277

CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor.  

PubMed

Ag receptors used for cancer immunotherapy are often directed against tumor-associated Ags also expressed in normal tissues. Targeting of such Ags can result in unwanted autoimmune attack of normal tissues or induction of tolerance in therapeutic T cells. We used a murine model to study the phenotype and function of T cells redirected against the murine double minute protein 2 (MDM2), a tumor-associated Ag that shows low expression in many normal tissues. Transfer of MDM2-TCR-engineered T cells into bone marrow chimeric mice revealed that Ag recognition in hematopoietic tissues maintained T cell function, whereas presentation of MDM2 in nonhematopoietic tissues caused reduced effector function. TCR-engineered CD8(+) T cells underwent rapid turnover, downmodulated CD8 expression, and lost cytotoxic function. We found that MDM2-TCR-engineered CD4(+) T cells provided help and restored cytotoxic function of CD8(+) T cells bearing the same TCR. Although the introduction of the CD8 coreceptor enhanced the ability of CD4(+) T cells to recognize MDM2 in vitro, the improved self-antigen recognition abolished their ability to provide helper function in vivo. The data indicate that the same class I-restricted TCR responsible for Ag recognition and tolerance induction in CD8(+) T cells can, in the absence of the CD8 coreceptor, elicit CD4 T cell help and partially reverse tolerance. Thus MHC class I-restricted CD4(+) T cells may enhance the efficacy of therapeutic TCR-engineered CD8(+) T cells and can be readily generated with the same TCR. PMID:25539815

Ghorashian, Sara; Veliça, Pedro; Chua, Ignatius; McNicol, Anne-Marie; Carpenter, Ben; Holler, Angelika; Nicholson, Emma; Ahmadi, Maryam; Zech, Mathias; Xue, Shao-An; Uckert, Wolfgang; Morris, Emma; Chakraverty, Ronjon; Stauss, Hans J

2015-02-01

278

Anticancer agent xanthohumol inhibits IL-2 induced signaling pathways involved in T cell proliferation.  

PubMed

Xanthohumol (XN), a prenylated chalcone present in hops exhibits anti-inflammatory, antioxidant and anticancer activity. In the present study we show that XN inhibits the proliferation of mouse lymphoma cells and IL-2 induced proliferation and cell cycle progression in mouse splenic T cells. The suppression of T cell proliferation by XN was due to the inhibition of IL-2 induced Janus kinase/signal transducers and activators of transcription (Jak/STAT) and extracellular signal-regulated kinase 1 and 2 (Erk1/2) signaling pathways. XN also inhibited proliferation-related cellular proteins such as c-Myc, c-Fos and NF-kappaB and cyclin D1. Thus, understanding of IL-2 induced cell signaling pathways in normal T cells, which are constitutively turned on in T cell lymphomas may facilitate development of XN for the treatment of hematologic cancers. PMID:22946339

Liu, Yongbo; Gao, Xiaohua; Deeb, Dorrah; Arbab, Ali S; Dulchavsky, Scott A; Gautam, Subhash C

2012-01-01

279

Designer T cells by T cell receptor replacement.  

PubMed

T cell receptor (TCR) gene transfer is a convenient method to produce antigen-specific T cells for adoptive therapy. However, the expression of two TCR in T cells could impair their function or cause unwanted effects by mixed TCR heterodimers. With five different TCR and four different T cells, either mouse or human, we show that some TCR are strong--in terms of cell surface expression--and replace weak TCR on the cell surface, resulting in exchange of antigen specificity. Two strong TCR are co-expressed. A mouse TCR replaces human TCR on human T cells. Even though it is still poorly understood why some TCRalpha/beta combinations are preferentially expressed on T cells, our data suggest that, in the future, designer T cells with exclusive tumor reactivity can be generated by T cell engineering. PMID:17051621

Sommermeyer, Daniel; Neudorfer, Julia; Weinhold, Monika; Leisegang, Matthias; Engels, Boris; Noessner, Elfriede; Heemskerk, Mirjam H M; Charo, Jehad; Schendel, Dolores J; Blankenstein, Thomas; Bernhard, Helga; Uckert, Wolfgang

2006-11-01

280

Role of CD4 T Cell Help and Costimulation in CD8 T Cell Responses During Listeria monocytogenes Infection1  

E-print Network

pathways play in the development of CD8 T cell responses during bacterial infection. In this study, we. Furthermore, these epitope-specific CD8 T cells established long-term memory in CD4 / mice that was capable in the early control of a primary infection. Upon rein- fection, Ag-specific memory T cells mount a prompt

Maizels, Rick

281

Increased Expression of Phosphorylated FADD in Anaplastic Large Cell and Other T-Cell Lymphomas  

PubMed Central

FAS-associated protein with death domain (FADD) is a major adaptor protein involved in extrinsic apoptosis, embryogenesis, and lymphocyte homeostasis. Although abnormalities of the FADD/death receptor apoptotic pathways have been established in tumorigenesis, fewer studies have analyzed the expression and role of phosphorylated FADD (pFADD). Our identification of FADD as a lymphoma-associated autoantigen in T-cell lymphoma patients raises the possibility that pFADD, with its correlation with cell cycle, may possess role(s) in human T-cell lymphoma development. This immunohistochemical study investigated pFADD protein expression in a range of normal tissues and lymphomas, particularly T-cell lymphomas that require improved therapies. Whereas pFADD was expressed only in scattered normal T cells, it was detected at high levels in T-cell lymphomas (eg, 84% anaplastic large cell lymphoma and 65% peripheral T cell lymphomas, not otherwise specified). The increased expression of pFADD supports further study of its clinical relevance and role in lymphomagenesis, highlighting phosphorylation of FADD as a potential therapeutic target. PMID:25232277

Patel, Suketu; Murphy, Derek; Haralambieva, Eugenia; Abdulla, Zainalabideen A; Wong, Kah Keng; Chen, Hong; Gould, Edith; Roncador, Giovanna; Hatton, Chris SR; Anderson, Amanda P; Banham, Alison H; Pulford, Karen

2014-01-01

282

4-1BB ligand signaling to T cells limits T cell activation.  

PubMed

4-1BB ligand (4-1BBL) and its receptor, 4-1BB, are both induced on T cells after activation, but little is known about the role of 4-1BBL. In this study we show that 4-1BBL can transmit signals that limit T cell effector activity under tolerogenic conditions. Cross-linking 4-1BBL inhibited IL-2 production in vitro, primarily with suboptimal TCR stimulation. Furthermore, naive 4-1BBL-deficient OT-II transgenic T cells displayed a greater conversion to effector T cells in vivo when responding to soluble OVA peptide in wild-type hosts, whereas development of Foxp3(+) regulatory T cells was not altered. A greater number of effector T cells also differentiated from naive wild-type OT-II T cells when transferred into 4-1BB-deficient hosts, suggesting that APC-derived 4-1BB is likely to trigger 4-1BBL. Indeed, effector T cells that could not express 4-1BBL accumulated in larger numbers in vitro when stimulated with 4-1BB-expressing mesenteric lymph node dendritic cells. 4-1BBL was expressed on T cells when Ag presentation was limiting, and 4-1BBL was aberrantly expressed at very high levels on T cells that could not express 4-1BB. Trans-ligation, Ab capture, and endocytosis experiments additionally showed that T cell-intrinsic 4-1BB regulated internalization of membrane 4-1BBL, implying that the strong induction of 4-1BB on T cells may counteract the suppressive function of 4-1BBL by limiting its availability. These data suggest that 4-1BBL expressed on T cells can restrain effector T cell development, creating a more favorable regulatory T cell to effector cell balance under tolerogenic conditions, and this may be particularly active in mucosal barrier tissues where 4-1BB-expressing regulatory dendritic cells present Ag. PMID:25404362

Eun, So-Young; Lee, Seung-Woo; Xu, Yanfei; Croft, Michael

2015-01-01

283

SELECTION OF MACROPHAGE-RESIS TANT PROGRESSOR TUMOR VARIANTS BY THE NORMAL HOST Requirement for Concomitant T Cell-mediated Immunity  

Microsoft Academic Search

The evolutionary progression from an initial carcinogen-expos ed target cell to a cancer cell is characterized by a series of alterations in heritable phenotypic properties of the cells (1). Obviously, malignant cells that succeed in forming progressive tumors must have developed some means of subverting relevant host defenses and homeostatic control mechanisms. Thus, an analysis of how potentialiy malignant ceils

JAMES L. URBAN; HANS SCHREIBER

284

T-cell intrinsic and extrinsic mechanisms of p27Kip1 in the regulation of CD8 T-cell memory.  

PubMed

CD8 T cells exhibit dynamic alterations in proliferation and apoptosis during various phases of the CD8 T-cell response, but the mechanisms that regulate cellular proliferation from the standpoint of CD8 T-cell memory are not well defined. The cyclin-dependent kinase inhibitor p27(Kip1) functions as a negative regulator of the cell cycle in T cells, and it has been implicated in regulating cellular processes, including differentiation, transcription and migration. Here, we investigated whether p27(Kip1) regulates CD8 T-cell memory by T-cell-intrinsic or T-cell-extrinsic mechanisms, by conditional ablation of p27(Kip1) in T cells or non-T cells. Studies of T-cell responses to an acute viral infection show that p27(Kip1) negatively regulates the proliferation of CD8 T cells by T-cell-intrinsic mechanisms. However, the enhanced proliferation of CD8 T cells induced by T-cell-specific p27(Kip1) deficiency minimally affects the primary expansion or the magnitude of CD8 T-cell memory. Unexpectedly, p27(Kip1) ablation in non-T cells markedly augmented the number of high-quality memory CD8 T cells by enhancing the accumulation of memory precursor effector cells without increasing their proliferation. Further studies show that p27(Kip1) deficiency in immunizing dendritic cells fail to enhance CD8 T-cell memory. Nevertheless, we have delineated the T-cell-intrinsic, anti-proliferative activities of p27(Kip1) in CD8 T cells from its role as a factor in non-T cells that restricts the development of CD8 T-cell memory. These findings have implications in vaccine development and understanding the mechanisms that maintain T-cell homeostasis. PMID:23207280

Jatzek, Anna; Marie Tejera, Melba; Plisch, Erin H; Fero, Matthew L; Suresh, M

2013-02-01

285

Recent Developments in Nonlinear Normal Mode Initialization  

NASA Technical Reports Server (NTRS)

The importance of a balanced initial condition upon GLAS GCM forecasts and assimilation cycles was assessed. An effort to combine previous work on normal mode initialization at GLA is underway to develop an initialization process for the production version of the GLAS 4th order GCM. The major aspects of this work fall into two parts: vectorization of the linear projector code and the insertion of the mode projector and Machenhauer iteration algorithm into the full GLAS GCM. Memory and paging constraints place restrictions on the number of horizontal modes stored for initialization purposes, and on the manner in which they are stored. Only the first five vertical structures of the gravity modes are used. Differing phase and normalization conventions provided many elusive coding errors. A Machenhauer nonlinear normal mode initialization technique is used. This method entails the insertion of a modified version of the mode projector into the full GCM, and the modification of the GCM to allow for iterative calls to the projector.

Bloom, S. C.

1985-01-01

286

Memory CD8+ T cell differentiation  

PubMed Central

In response to infection or effective vaccination, naive antigen-specific CD8+ T cells undergo a dramatic highly orchestrated activation process. Initial encounter with an appropriately activated antigen-presenting cell leads to blastogenesis and an exponential increase in antigen-specific CD8+ T cell numbers. Simultaneously, a dynamic differentiation process occurs, resulting in formation of both primary effector and long-lived memory cells. Current findings have emphasized the heterogeneity of effector and memory cell populations with the description of multiple cellular subsets based on phenotype, function, and anatomic location. Yet, only recently have we begun to dissect the underlying factors mediating the temporal control of the development of distinct effector and memory CD8+ T cell sublineages. In this review we will focus on the requirements for mounting an effective CD8+ T cell response and highlight the elements regulating the differentiation of effector and memory subsets. PMID:20146720

Obar, Joshua J.; Lefrançois, Leo

2010-01-01

287

Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia  

Microsoft Academic Search

Interleukin 7 (IL-7) and its receptor, formed by IL-7R? (encoded by IL7R) and ?c, are essential for normal T-cell development and homeostasis. Here we show that IL7R is an oncogene mutated in T-cell acute lymphoblastic leukemia (T-ALL). We find that 9% of individuals with T-ALL have somatic gain-of-function IL7R exon 6 mutations. In most cases, these IL7R mutations introduce an

Priscila P Zenatti; Daniel Ribeiro; Wenqing Li; Linda Zuurbier; Milene C Silva; Maddalena Paganin; Julia Tritapoe; Julie A Hixon; André B Silveira; Bruno A Cardoso; Leonor M Sarmento; Nádia Correia; Maria L Toribio; Jörg Kobarg; Martin Horstmann; Rob Pieters; Silvia R Brandalise; Adolfo A Ferrando; Jules P Meijerink; Scott K Durum; J Andrés Yunes; João T Barata

2011-01-01

288

A sharp T-cell antigen receptor signaling threshold for T-cell proliferation  

PubMed Central

T-cell antigen receptor (TCR) signaling is essential for activation, proliferation, and effector function of T cells. Modulation of both intensity and duration of TCR signaling can regulate these events. However, it remains unclear how individual T cells integrate such signals over time to make critical cell-fate decisions. We have previously developed an engineered mutant allele of the critical T-cell kinase zeta-chain-associated protein kinase 70 kDa (Zap70) that is catalytically inhibited by a small molecule inhibitor, thereby blocking TCR signaling specifically and efficiently. We have also characterized a fluorescent reporter Nur77–eGFP transgenic mouse line in which T cells up-regulate GFP uniquely in response to TCR stimulation. The combination of these technologies unmasked a sharp TCR signaling threshold for commitment to cell division both in vitro and in vivo. Further, we demonstrate that this threshold is independent of both the magnitude of the TCR stimulus and Interleukin 2. Similarly, we identify a temporal threshold of TCR signaling that is required for commitment to proliferation, after which T cells are able to proliferate in a Zap70 kinase-independent manner. Taken together, our studies reveal a sharp threshold for the magnitude and duration of TCR signaling required for commitment of T cells to proliferation. These results have important implications for understanding T-cell responses to infection and optimizing strategies for immunomodulatory drug delivery. PMID:25136127

Au-Yeung, Byron B.; Zikherman, Julie; Mueller, James L.; Ashouri, Judith F.; Matloubian, Mehrdad; Cheng, Debra A.; Chen, Yiling; Shokat, Kevan M.; Weiss, Arthur

2014-01-01

289

The T-Cell Response to HIV  

PubMed Central

HIV is a disease in which the original clinical observations of severe opportunistic infections gave the first clues regarding the underlying pathology, namely that HIV is essentially an infection of the immune system. HIV infects and deletes CD4+ T cells that normally coordinate the adaptive T- and B-cell response to defend against intracellular pathogens. The immune defect is immediate and profound: At the time of acute infection with an AIDS virus, typically more than half of the gut-associated CD4+ T cells are depleted, leaving a damaged immune system to contend with a life-long infection. PMID:23002014

Walker, Bruce; McMichael, Andrew

2012-01-01

290

An Exhaustion-Like Phenotype Constrains the Activity of CD4+ T Cells Specific for a Self and Melanoma Antigen  

PubMed Central

While the immune system has the capacity to recognize and destroy melanoma, tolerance mechanisms often hinder the development of effective anti-tumor immune responses. Since many melanoma antigens are self proteins expressed in normal melanocytes, self antigen exposure before tumor development can negatively impact the function of T cells specific for these self/tumor antigens. However, the contribution of self tolerance to anti-melanoma T cell dysfunction remains largely unexplored. We have previously described a TCR transgenic (Tg) mouse model in which T cells specific for the self/melanoma antigen, tyrosinase-related protein 1 (TRP1), develop in the presence of endogenous TRP1 expression (Ag+) and diminished antigen presentation due to the absence of gamma-interferon-inducible lysosomal thiol reductase (GILT-/-). We show that TRP1-specific T cells from these Ag+GILT-/-Tg mice do not protect from melanoma tumor growth, fail to induce autoimmune vitiligo, and undergo diminished proliferation compared to T cells from Ag-GILT+/+Tg mice. Despite an increased frequency of TRP1-specific Treg cells in Ag+GILT-/-Tg mice compared to Ag-GILT+/+Tg animals, Treg cell depletion only partially rescues the proliferative capacity of T cells from TRP1-expressing mice, suggesting the involvement of additional suppressive mechanisms. An increased percentage of melanoma-specific T cells from Ag+GILT-/-Tg animals express PD-1, an inhibitory receptor associated with the maintenance of T cell exhaustion. Antibody blockade of PD-1 partially improves the ability of TRP1-specific T cells from Ag+GILT-/-Tg mice to produce IL-2. These findings demonstrate that melanoma-specific T cells exposed to a self/melanoma antigen in healthy tissue develop an exhaustion-like phenotype characterized by PD-1-mediated immunosuppression prior to encounter with tumor. PMID:25875653

Rausch, Matthew P.; Hastings, Karen Taraszka

2015-01-01

291

T Cell Receptor Signaling Kinetics Takes the Stage  

NSDL National Science Digital Library

It has been long surmised that the strength of stimulation of the T cell receptor (TCR) determines the robustness of TCR-mediated signaling and the magnitude of a T cell response. However, it is becoming evident that the signal from the TCR develops over time to approach its steady-state, affinity-determined maximal extent and that variations in this time have a substantial effect on the responsiveness of T cells. Here, I discuss data that show that the kinetics of signal propagation in various segments of the TCR signaling network can influence the spatiotemporal regulation of the effector functions of T cells and the quality of the T cell response.

Yuri Sykulev (Thomas Jefferson University; Department of Microbiology and Immunology and Kimmel Cancer Center REV)

2010-12-21

292

CD4 downregulation by memory CD4+ T cells in vivo renders African green monkeys resistant to progressive SIVagm infection.  

PubMed

African green monkeys (genus Chlorocebus) can be infected with species-specific simian immunodeficiency virus (SIVagm) but do not develop AIDS. These natural hosts of SIV, like sooty mangabeys, maintain high levels of SIV replication but have evolved to avoid immunodeficiency. Elucidating the mechanisms that allow natural hosts to coexist with SIV without overt disease may provide crucial information for understanding AIDS pathogenesis. Here we show that many CD4(+) T cells from African green monkeys downregulate CD4 in vivo as they enter the memory pool; that downregulation of CD4 by memory T cells is independent of SIV infection; that the CD4(-) memory T cells maintain functions that are normally attributed to CD4(+) T cells, including production of interleukin-2 (IL-2), production of IL-17, expression of forkhead box P3 and expression of CD40 ligand; that loss of CD4 expression protects these T cells from infection by SIVagm in vivo; and that these CD4(-) T cells can maintain major histocompatibility complex class II restriction. These data show that the absence of SIV-induced disease progression in natural host species may be partially explained by preservation of a subset of T cells that maintain CD4(+) T cell function while being resistant to SIV infection in vivo. PMID:19525963

Beaumier, Coreen M; Harris, Levelle D; Goldstein, Simoy; Klatt, Nichole R; Whitted, Sonya; McGinty, John; Apetrei, Cristian; Pandrea, Ivona; Hirsch, Vanessa M; Brenchley, Jason M

2009-08-01

293

CXCR6 is expressed on T cells in both T helper type 1 (Th1) inflammation and allergen-induced Th2 lung inflammation but is only a weak mediator of chemotaxis  

PubMed Central

Numerous chemokine receptors are increased in number on T cells in inflamed tissues. Our objective was to examine CXCR6 expression on lymphocytes during immune and inflammatory reactions and its potential for mediating T-cell recruitment. The cDNA for rat CXCR6 was cloned and monoclonal antibodies (mAbs) to CXCR6 were developed. CXCR6 was present on 4–6% of CD4 and CD8 T cells in blood, normal lymph nodes (LNs) and the spleen, primarily on memory T cells. In vitro antigen re-stimulation of LN T cells from animals with autoimmune arthritis and experimental autoimmune encephalomyelitis (EAE) increased the proportion of CXCR6+ T cells to 35–50% and anti-T-cell receptor (TCR) activation to 60–80%. In vivo, after antigen challenge of LNs there was only a small increase in CXCR6+ T cells on the lymphoblasts in the LNs, and a much higher percentage of T cells were CXCR6+ in virus-induced peritoneal exudates (?47%) and in allergen-induced lung inflammation (33%). Chemotaxis of CXCR6-expressing inflammatory T cells to CXCL16 was poor, but that to CXCL10 was robust. We conclude that few T cells in normal and antigen-challenged LNs are CXCR6+, whereas a high proportion of in vitro activated T cells and T cells from inflammatory sites are CXCR6+, but these cells migrate poorly to CXCL16. This suggests that CXCR6 may contribute to T-cell positioning and activation, rather than recruitment. CXCR6 is also expressed on T cells not only in T helper type 1 (Th1) inflammation (arthritis and EAE) but also, as shown here, in Th2 inflammation, where it is increased after allergen challenge. PMID:17437534

Latta, Markus; Mohan, Karkada; Issekutz, Thomas B

2007-01-01

294

?? T Cells in HIV Disease: Past, Present, and Future.  

PubMed

Human immunodeficiency virus (HIV) type 1 dysregulates ?? T cells as part of an immune evasion mechanism. Nearly three decades of research defined the effects of HIV on ?? T cells and how this impacts disease. With highly effective antiretroviral therapy providing virus suppression and longer survival, we expected a return to normal for ?? T cells. This is not the case. Even in patients with CD4 T cell reconstitution, normal ?? T cell levels and function are not recovered. The durable damage to V?2 T cells is paralleled by defects in NK, CD8 T cells, and dendritic cells. Whether these consequences of HIV stem from similar or distinct mechanisms are not known and effective means for recovering the full range of cellular immunity have not been discovered. These unanswered questions receive too little attention in the overall program of efforts to cure HIV this disease. Approved drugs capable of increasing V?2 T cell function are being tested in clinical trials for cancer and hold promise for restoring normal function in patients with HIV disease. The impetus for conducting clinical trials will come from understanding the significance of ?? T cells in HIV disease and what might be gained from targeted immunotherapy. This review traces the history and current progress of AIDS-related research on ?? T cells. We emphasize the damage to ?? T cells that persists despite effective virus suppression. These chronic immune deficits may be linked to the comorbidities of AIDS (cancer, cardiovascular disease, metabolic disease, and others) and will hinder efforts to eradicate HIV by cytotoxic T or NK cell killing. Here, we focus on one subset of T cells that may be critical in the pathogenesis of HIV and an attractive target for new immune-based therapies. PMID:25688241

Pauza, C David; Poonia, Bhawna; Li, Haishan; Cairo, Cristiana; Chaudhry, Suchita

2014-01-01

295

Surface molecules that drive T cell development in vitro in the absence of thymic epithelium and in the absence of lineage-specific signals.  

PubMed

Differentiation of immature double positive (DP) CD4+ CD8+ thymocytes into single positive (SP) CD4+ and CD8+ T cells is referred to as positive selection and requires physical contact with thymic cortical epithelium. We now have identified "coinducer" molecules on DP thymocytes that, together with TCR, signal DP thymocytes to differentiate into SP T cells in vitro in the absence of thymic epithelium. A remarkable number of different molecules on DP thymocytes possessed "coinducing" activity, including CD2, CD5, CD24, CD28, CD49d, CD81, and TSA-1. Interestingly, in vitro differentiation occurred in the absence of lineage-specific signals, yet resulted in the selective generation of CD4+CD8- T cells. Thus, the present study has identified surface molecules that can signal DP thymocytes to differentiate into SP T cells in the absence of thymic epithelium and has characterized a default pathway for CD4+ T cell differentiation. PMID:9075925

Cibotti, R; Punt, J A; Dash, K S; Sharrow, S O; Singer, A

1997-03-01

296

Glucocorticoids Attenuate T Cell Receptor Signaling  

PubMed Central

Glucocorticoids (GCs) affect peripheral immune responses by inhibiting T cell immunity at several stages of the activation cascade, causing impaired cytokine production and effector function. The recent demonstration that the thymic epithelium and possibly thymocytes themselves produce steroids suggests that endogenous GCs also play a role in the control of T cell development. As both peripheral responsiveness and thymic differentiation appear to be regulated by the quantity and quality of intracellular signals issued by antigen–major histocompatibility complex-engaged T cell receptor (TCR) complexes, we investigated the effects of GCs on the signaling properties of T cells stimulated by anti-CD3 monoclonal antibodies or agonist peptides. We demonstrate in this work that dexamethasone, a synthetic GC, inhibits the early signaling events initiated upon TCR ligation, such as tyrosine phosphorylation of several TCR-associated substrates including the ? chain, the ZAP70 kinase, and the transmembrane adapter molecule linker for activation of T cells. Hypophosphorylation was not a consequence of reduced kinase activity of src protein tyrosine kinases, but was correlated with an altered- membrane compartmentalization of these molecules. These observations indicate that in addition to their well-described ability to interfere with the transcription of molecules involved in peripheral responses, GCs inhibit T cell activation by affecting the early phosphorylating events induced after TCR ligation. PMID:11283153

Van Laethem, François; Baus, Erika; Smyth, Lesley A.; Andris, Fabienne; Bex, Françoise; Urbain, Jacques; Kioussis, Dimitris; Leo, Oberdan

2001-01-01

297

Memory T Cells in Transplantation.  

PubMed

Following infections and environmental exposures, memory T cells are generated that provide long-term protective immunity. Compared to their naïve T cell counterparts, memory T cells possess unique characteristics that endow them with the ability to quickly and robustly respond to foreign antigens. While such memory T cells are beneficial in protecting their hosts from recurrent infection, memory cells reactive to donor antigens pose a major barrier to successful transplantation and tolerance induction. Significant progress has been made over the past several decades contributing to our understanding of memory T cell generation, their distinct biology, and their detrimental impact in clinical and animal models of transplantation. This review focuses on the unique features which make memory T cells relevant to the transplant community and discusses potential therapies targeting memory T cells which may ameliorate allograft rejection. PMID:25435071

Su, Charles A; Fairchild, Robert L

2014-09-01

298

PTPN2 attenuates T-cell lymphopenia-induced proliferation  

NASA Astrophysics Data System (ADS)

When the peripheral T-cell pool is depleted, T cells undergo homoeostatic expansion. This expansion is reliant on the recognition of self-antigens and/or cytokines, in particular interleukin-7. The T cell-intrinsic mechanisms that prevent excessive homoeostatic T-cell responses and consequent overt autoreactivity remain poorly defined. Here we show that protein tyrosine phosphatase N2 (PTPN2) is elevated in naive T cells leaving the thymus to restrict homoeostatic T-cell proliferation and prevent excess responses to self-antigens in the periphery. PTPN2-deficient CD8+ T cells undergo rapid lymphopenia-induced proliferation (LIP) when transferred into lymphopenic hosts and acquire the characteristics of antigen-experienced effector T cells. The enhanced LIP is attributed to elevated T-cell receptor-dependent, but not interleukin-7-dependent responses, results in a skewed T-cell receptor repertoire and the development of autoimmunity. Our results identify a major mechanism by which homoeostatic T-cell responses are tuned to prevent the development of autoimmune and inflammatory disorders.

Wiede, Florian; La Gruta, Nicole L.; Tiganis, Tony

2014-01-01

299

T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness.  

PubMed

Therapy with autologous T cells that have been gene-engineered to express chimeric antigen receptors (CAR) or T cell receptors (TCR) provides a feasible and broadly applicable treatment for cancer patients. In a clinical study in advanced renal cell carcinoma (RCC) patients with CAR T cells specific for carbonic anhydrase IX (CAIX), we observed toxicities that (most likely) indicated in vivo function of CAR T cells as well as low T cell persistence and clinical response rates. The latter observations were confirmed by later clinical trials in other solid tumor types and other gene-modified T cells. To improve the efficacy of T cell therapy, we have redefined in vitro conditions to generate T cells with young phenotype, a key correlate with clinical outcome. For their impact on gene-modified T cell phenotype and function, we have tested various anti-CD3/CD28 mAb-based T cell activation and expansion conditions as well as several cytokines prior to and/or after gene transfer using two different receptors: CAIX CAR and MAGE-C2(ALK)/HLA-A2 TCR. In a total set of 16 healthy donors, we observed that T cell activation with soluble anti-CD3/CD28 mAbs in the presence of both IL15 and IL21 prior to TCR gene transfer resulted in enhanced proportions of gene-modified T cells with a preferred in vitro phenotype and better function. T cells generated according to these processing methods demonstrated enhanced binding of pMHC, and an enhanced proportion of CD8+, CD27+, CD62L+, CD45RA+T cells. These new conditions will be translated into a GMP protocol in preparation of a clinical adoptive therapy trial to treat patients with MAGE-C2-positive tumors. PMID:25423330

Lamers, Cor H J; van Steenbergen-Langeveld, Sabine; van Brakel, Mandy; Groot-van Ruijven, Corrien M; van Elzakker, Pascal M M L; van Krimpen, Brigitte; Sleijfer, Stefan; Debets, Reno

2014-12-01

300

T cells induce terminal differentiation of transformed B cells to mature plasma cell tumors.  

PubMed Central

Major interest in the analysis of mature plasma cell neoplasias of mice and humans has focused on identification of precursor cells that give rise to mature malignant plasma cells. Although several laboratories have recently suggested that such cells are present in the granulomas of pristane-treated mice and the bone marrow of some multiple myeloma patients, the in vivo cellular interactions required for their differentiation into mature plasma cell tumors remains unclear. Given the extensive interactions of peripheral T cells and normal B cells, we assessed the potential role of T cells in plasma-cell tumor development, by using a myc, raf-containing retrovirus, J3V1, to induce plasmacytomas in normal BALB/c mice, T-cell-deficient nude mice, and T-cell-reconstituted nude mice. The B-lineage tumors arising in normal BALB/c mice were uniformly mature plasmacytomas, most of which secreted immunoglobulin. In contrast, nude mice yielded predominantly non-immunoglobulin-secreting B-cell lymphomas with a phenotype characteristic of peripheral B cells. T-cell reconstitution of nude mice prior to tumor induction resulted in a shift from B-cell lymphomas to plasmacytomas. These results imply that transformation can occur prior to terminal differentiation of B cells and that such transformed cells can be driven to terminal differentiation by peripheral T cells. These findings further suggest that, in human multiple myeloma, the ability of T cells to influence the differentiation state of transformed B cells may provide a mechanism by which malignant plasma cells found in the bone marrow could arise from clonotypically related less-mature B cells found in both the bone marrow and periphery. Images Fig. 2 Fig. 4 PMID:7846031

Hilbert, D M; Shen, M Y; Rapp, U R; Rudikoff, S

1995-01-01

301

Polyclonal type II natural killer T cells require PLZF and SAP for their development and contribute to CpG-mediated antitumor response  

PubMed Central

CD1d-restricted natural killer T (NKT) cells are innate-like T cells with potent immunomodulatory function via rapid production of both Th1 and Th2 cytokines. NKT cells comprise well-characterized type I NKT cells, which can be detected by ?-galactosylceramide-loaded CD1d tetramers, and less-studied type II NKT cells, which do not recognize ?-galactosylceramide. Here we characterized type II NKT cells on a polyclonal level by using a J?18-deficient IL-4 reporter mouse model. This model allows us to track type II NTK cells by the GFP+TCR?+ phenotype in the thymus and liver. We found type II NKT cells, like type I NKT cells, exhibit an activated phenotype and are dependent on the transcriptional regulator promyelocytic leukemia zinc finger (PLZF) and the adaptor molecule signaling lymphocyte activation molecule-associated protein (SAP) for their development. Type II NKT cells are potently activated by ?-D-glucopyranosylceramide (?-GlcCer) but not sulfatide or phospholipids in a CD1d-dependent manner, with the stimulatory capacity of ?-GlcCer influenced by acyl chain length. Compared with type I NKT cells, type II NKT cells produce lower levels of IFN-? but comparable amounts of IL-13 in response to polyclonal T-cell receptor stimulation, suggesting they may play different roles in regulating immune responses. Furthermore, type II NKT cells can be activated by CpG oligodeoxynucletides to produce IFN-?, but not IL-4 or IL-13. Importantly, CpG-activated type II NKT cells contribute to the antitumor effect of CpG in the B16 melanoma model. Taken together, our data reveal the characteristics of polyclonal type II NKT cells and their potential role in antitumor immunotherapy. PMID:24550295

Zhao, Jie; Weng, Xiufang; Bagchi, Sreya; Wang, Chyung-Ru

2014-01-01

302

Impaired T cell function in argininosuccinate synthetase deficiency.  

PubMed

ASS1 is a cytosolic enzyme that plays a role in the conversion of citrulline to arginine. In human and mouse tissues, ASS1 protein is found in several components of the immune system, including the thymus and T cells. However, the role of ASS1 in these tissues remains to be defined. Considerable attention has been focused recently on the role of metabolism in T cell differentiation and function. Based on the expression of ASS1 in the immune system, we hypothesized that ASS1 deficiency would result in T cell defects. To evaluate this question, we characterized immune function in hypomorphic fold/fold mice. Analysis of splenic T cells by flow cytometry showed a marked reduction in T cell numbers with normal expression of activation surface markers. Gene therapy correction of liver ASS1 to enhance survival resulted in a partial recovery of splenic T cells for characterization. In vitro and in vivo studies demonstrated the persistence of the ASS1 enzyme defect in T cells and abnormal T cell differentiation and function. Overall, our work suggests that ASS1 plays a role in T cell function, and deficiency produces primary immune dysfunction. In addition, these data suggest that patients with ASS1 deficiency (citrullinemia type I) may have T cell dysfunction. PMID:25492936

Tarasenko, Tatyana N; Gomez-Rodriguez, Julio; McGuire, Peter J

2015-02-01

303

[Psychomotor development and its disorders: between normal and pathological development].  

PubMed

This article discusses some aspects of psychomotor development and its disorders, with special emphasis on psychomotor retardation. Diagnostic classifications of psychomotor problems, such as DSM-IV and CIE-10, are referred to and their advantages and disadvantages are analyzed. The concept of normality as a synonym for the statistical mean in the context of psychomotor disorders is also analyzed in order to consider its dynamic and variability, thereby avoiding the normality/pathology opposition, while some issues, such as the social and cultural aspects, are highlighted, making it possible to rethink the universality and relativity of psychomotor development. PMID:24061024

Vericat, Agustina; Bibiana Orden, Alicia

2013-10-01

304

Self-recognition specificity expressed by T cells from nude mice. Absence of detectable Ia-restricted T cells in nude mice that do exhibit self-K/D-restricted T cell responses  

SciTech Connect

The presence in athymic nude mice of precursor T cells with self-recognition specificity for either H-2 K/D or H-2 I region determinants was investigated. Chimeras were constructed of lethally irradiated parental mice receiving a mixture of F1 nude mouse (6-8 wk old) spleen and bone marrow cells. The donor inoculum was deliberately not subjected to any T cell depletion procedure, so that any potential major histocompatibility complex-committed precursor T cells were allowed to differentiate and expand in the normal parental recipients. 3 mo after reconstitution, the chimeras were immunized with several protein antigens in complete Freund's adjuvant in the footpads and their purified draining lymph node T cells tested 10 d later for ability to recognize antigen on antigen-presenting cells of either parental haplotype. Also, their spleen and lymph node cells were tested for ability to generate a cytotoxic T lymphocyte (CTL) response to trinitrophenyl (TNP)-modified stimulator cells of either parental haplotype. It was demonstrated that T cell proliferative responses of these F1(nude)----parent chimeras were restricted solely to recognizing parental host I region determinants as self and expressed the Ir gene phenotype of the host. In contrast, CTL responses could be generated (in the presence of interleukin 2) to TNP-modified stimulator cells of either parental haplotype. Thus these results indicate that nude mice which do have CTL with self-specificity for K/D region determinants lack proliferating T cells with self-specificity for I region determinants. These results provide evidence for the concepts that development of the I region-restricted T cell repertoire is strictly an intrathymically determined event and that young nude mice lack the unique thymic elements responsible for edu

Kruisbeek, A.M.; Davis, M.L.; Matis, L.A.; Longo, D.L.

1984-09-01

305

Aged-Related Shifts in T cell Homeostasis Lead to Intrinsic T Cell Defects  

PubMed Central

Our recent studies indicate that the longer peripheral persistence of naive CD4 T cells that occurs with age is necessary for the development of the key aging defects that lead to compromised responses to vaccination and to new pathogens or new strains of circulating infectious agents. This longer persistence is in turn is linked to the decrease in development of new thymic emigrants and thymic involution that occur at adolescence. Therefore the process of development of naïve CD4 aging defects, is closely tied to the homeostasis of T cells and the shifts that occur in their homeostasis with age. Here we review this connection between age-related changes in T cell homeostasis and the development of T cell defects and discuss the implication for approaches to better vaccinating the elderly. PMID:22564707

Haynes, Laura; Swain, Susan L.

2012-01-01

306

Genome Expression during Normal Leaf Development 1  

PubMed Central

Changes in genome expression during normal cellular and plastid development in the first leaf of young (7-day-old) wheat (Triticum aestivum var. Maris Dove) were investigated by examining homogeneous populations of leaf cells and plastids of several developmental ages present in the same leaf. The cells were characterized over a period immediately following the last cell division. All of the leaf cells had cytoplasmic contents and nuclei, and between 44% (young tissue) and 54% (older tissue) of the leaf cells were mesophyll cells. Chloroplast development was complete 36 hours after the chloroplasts had ceased dividing. Extremely large changes occurred in cellular constituents over a very short period of leaf development. Maximum rates of accumulation of ribulose bisphosphate carboxylase per mesophyll cell (80 picograms/hour), chlorophyll per mesophyll cell (9 picograms/hour), and 70S ribosomes per mesophyll cell (19 × 105/hour) were recorded. Total cellular DNA varied from 40 to 60 picograms/cell, reflecting the changes in nuclear and chloroplast DNA synthesis during different phases of cellular and chloroplast division. The period of maximum accumulation of protein, total RNA, and both 80S and 70S ribosomes occurred between 36 and 48 hours after the last cell division. Between 48 and 60 hours, 70S rRNA per cell and protein content per cell continued to increase as 80S rRNA per cell declined. Ribulose bisphosphate carboxylase per cell increased 20-fold between 15 and 60 hours. PMID:16662317

Dean, Caroline; Leech, Rachel M.

1982-01-01

307

The tumor suppressor Ikaros shapes the repertoire of notch target genes in T cells.  

PubMed

The Notch signaling pathway is activated in many cell types, but its effects are cell type- and stage-specific. In the immune system, Notch activity is required for the differentiation of T cell progenitors, but it is reduced in more mature thymocytes, in which Notch is oncogenic. Studies based on single-gene models have suggested that the tumor suppressor protein Ikaros plays an important role in repressing the transcription of Notch target genes. We used genome-wide analyses, including chromatin immunoprecipitation sequencing, to identify genes controlled by Notch and Ikaros in gain- and loss-of-function experiments. We found that Ikaros bound to and directly repressed the expression of most genes that are activated by Notch. Specific deletion of Ikaros in thymocytes led to the persistent expression of Notch target genes that are essential for T cell maturation, as well as the rapid development of T cell leukemias in mice. Expression of Notch target genes that are normally silent in T cells, but are activated by Notch in other cell types, occurred in T cells of mice genetically deficient in Ikaros. We propose that Ikaros shapes the timing and repertoire of the Notch transcriptional response in T cells through widespread targeting of elements adjacent to Notch regulatory sequences. These results provide a molecular framework for understanding the regulation of tissue-specific and tumor-related Notch responses. PMID:24643801

Geimer Le Lay, Anne-Solen; Oravecz, Attila; Mastio, Jérôme; Jung, Claudia; Marchal, Patricia; Ebel, Claudine; Dembélé, Doulaye; Jost, Bernard; Le Gras, Stéphanie; Thibault, Christelle; Borggrefe, Tilman; Kastner, Philippe; Chan, Susan

2014-03-18

308

The death receptor 3/TL1A pathway is essential for efficient development of antiviral CD4+ and CD8+ T-cell immunity  

PubMed Central

Death receptor 3 (DR3, TNFRSF25), the closest family relative to tumor necrosis factor receptor 1, promotes CD4+ T-cell-driven inflammatory disease. We investigated the in vivo role of DR3 and its ligand TL1A in viral infection, by challenging DR3-deficient (DR3KO) mice and their DR3WT littermates with the ?-herpesvirus murine cytomegalovirus or the poxvirus vaccinia virus. The phenotype and function of splenic T-cells were analyzed using flow cytometry and molecular biological techniques. We report surface expression of DR3 by naive CD8+ T cells, with TCR activation increasing its levels 4-fold and altering the ratio of DR3 splice variants. T-cell responses were reduced up to 90% in DR3KO mice during acute infection. Adoptive transfer experiments indicated this was dependent on T-cell-restricted expression of DR3. DR3-dependent CD8+ T-cell expansion was NK and CD4 independent and due to proliferation, not decreased cell death. Notably, impaired immunity in DR3KO hosts on a C57BL/6 background was associated with 4- to 7-fold increases in viral loads during the acute phase of infection, and in mice with suboptimal NK responses was essential for survival (37.5%). This is the first description of DR3 regulating virus-specific T-cell function in vivo and uncovers a critical role for DR3 in mediating antiviral immunity. PMID:22593543

Twohig, Jason P.; Marsden, Morgan; Cuff, Simone M.; Ferdinand, John R.; Gallimore, Awen M.; Perks, William V.; Al-Shamkhani, Aymen; Humphreys, Ian R.; Wang, Eddie C. Y.

2012-01-01

309

T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production  

PubMed Central

T-cell exhaustion, originally described in chronic viral infections, was recently reported in solid and hematologic cancers. It is not defined whether exhaustion contributes to T-cell dysfunction observed in chronic lymphocytic leukemia (CLL). We investigated the phenotype and function of T cells from CLL patients and age-matched controls. CD8+ and CD4+ T cells from CLL patients had increased expression of exhaustion markers CD244, CD160, and PD1, with expansion of a PD1+BLIMP1HI subset. These molecules were most highly expressed in the expanded population of effector T cells in CLL. CLL CD8+ T cells showed functional defects in proliferation and cytotoxicity, with the cytolytic defect caused by impaired granzyme packaging into vesicles and nonpolarized degranulation. In contrast to virally induced exhaustion, CLL T cells showed increased production of interferon-? and TNF? and increased expression of TBET, and normal IL2 production. These defects were not restricted to expanded populations of cytomegalovirus (CMV)–specific cells, although CMV seropositivity modulated the distribution of lymphocyte subsets, the functional defects were present irrespective of CMV serostatus. Therefore, although CLL CD8+ T cells exhibit features of T-cell exhaustion, they retain the ability to produce cytokines. These findings also exclude CMV as the sole cause of T-cell defects in CLL. PMID:23247726

Davies, Jeffrey K.; McClanahan, Fabienne; Fatah, Rewas; Iqbal, Sameena; Agrawal, Samir; Ramsay, Alan G.; Gribben, John G.

2013-01-01

310

T cell avidity and tumor recognition: implications and therapeutic strategies  

PubMed Central

In the last two decades, great advances have been made studying the immune response to human tumors. The identification of protein antigens from cancer cells and better techniques for eliciting antigen specific T cell responses in vitro and in vivo have led to improved understanding of tumor recognition by T cells. Yet, much remains to be learned about the intricate details of T cell – tumor cell interactions. Though the strength of interaction between T cell and target is thought to be a key factor influencing the T cell response, investigations of T cell avidity, T cell receptor (TCR) affinity for peptide-MHC complex, and the recognition of peptide on antigen presenting targets or tumor cells reveal complex relationships. Coincident with these investigations, therapeutic strategies have been developed to enhance tumor recognition using antigens with altered peptide structures and T cells modified by the introduction of new antigen binding receptor molecules. The profound effects of these strategies on T cell – tumor interactions and the clinical implications of these effects are of interest to both scientists and clinicians. In recent years, the focus of much of our work has been the avidity and effector characteristics of tumor reactive T cells. Here we review concepts and current results in the field, and the implications of therapeutic strategies using altered antigens and altered effector T cells. PMID:16174302

McKee, Mark D; Roszkowski, Jeffrey J; Nishimura, Michael I

2005-01-01

311

Regulatory T cells in infection.  

PubMed

Infectious agents have intimately co-evolved with the host immune system, acquiring a portfolio of highly sophisticated mechanisms to modulate immunity. Among the common strategies developed by viruses, bacteria, protozoa, helminths, and fungi is the manipulation of the regulatory T cell network in order to favor pathogen survival and transmission. Treg activity also benefits the host in many circumstances by controlling immunopathogenic reactions to infection. Interestingly, some pathogens are able to directly induce the conversion of naive T cells into suppressive Foxp3-expressing Tregs, while others activate pre-existing natural Tregs, in both cases repressing pathogen-specific effector responses. However, Tregs can also act to promote immunity in certain settings, such as in initial stages of infection when effector cells must access the site of infection, and subsequently in ensuring generation of effector memory. Notably, there is little current information on whether infections selectively drive pathogen-specific Tregs, and if so whether these cells are also reactive to self-antigens. Further analysis of specificity, together with a clearer picture of the relative dynamics of Treg subsets over the course of disease, should lead to rational strategies for immune intervention to optimize immunity and eliminate infection. PMID:22118407

Maizels, Rick M; Smith, Katherine A

2011-01-01

312

Stochastic processes in T-cell signaling  

E-print Network

T cells are orchestrators for adaptive immunity. Antigen recognition by T cells is mediated by the interactions between T-cell receptors (TCRs) and peptide-MHC (pMHC) molecules. How T cells can translate stimulatory external ...

Yang, Ming, Ph. D. Massachusetts Institute of Technology

2012-01-01

313

The Role of LMO2 in Development and in T Cell Leukemia After Chromosomal Translocation or Retroviral Insertion  

Microsoft Academic Search

Chromosomal translocations are primary events in the development of leukemias, representing at least one genetic feature of the putative cancer stem cell. Studies of genes influenced by chromosomal translocations have yielded a vast amount of information about how cancer is initiated and maintained. In particular, acute leukemias have demonstrated that chromosomal translocations often involve transcription regulators that function by interacting

Chang-Hoon Nam; Terence H. Rabbitts

2006-01-01

314

Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function  

PubMed Central

The mechanisms that control invariant natural killer T (iNKT)-cell development and function are still poorly understood. The mechanistic or mammalian target of rapamycin (mTOR) integrates various environmental signals/cues to regulate cell growth, proliferation, metabolism, and survival. We report here that ablation of mTOR complex 1 (mTORC1) signaling by conditionally deleting Raptor causes severe defects in iNKT-cell development at early stages, leading to drastic reductions in iNKT-cell numbers in the thymus and periphery. In addition, loss of Raptor impairs iNKT-cell proliferation and production of cytokines upon ?-galactosylceramide stimulation in vitro and in vivo, and inhibits liver inflammation in an iNKT cell-mediated hepatitis model. Furthermore, Raptor deficiency and rapamycin treatment lead to aberrant intracellular localization and functional impairment of promyelocytic leukemia zinc-finger, a transcription factor critical for iNKT-cell development and effector programs. Our findings define an essential role of mTORC1 to direct iNKT-cell lineage development and effector function. PMID:24516149

Shin, Jinwook; Wang, Shang; Deng, Wenhai; Wu, Jinhong; Gao, Jimin; Zhong, Xiao-Ping

2014-01-01

315

Modulation of T cell activation by localized K+ accumulation at the immunological synapse – a mathematical model  

PubMed Central

The response of T cells to antigens (T cell activation) is marked by an increase in intracellular Ca2+ levels. Voltage-gated and Ca2+-dependent K+ channels control the membrane potential of human T cells and regulate Ca2+ influx. This regulation is dependent on proper accumulation of K+ channels at the immunological synapse (IS) a signaling zone that forms between a T cell and antigen presenting cell. It is believed that the IS provides a site for regulation of the activation response and that K+ channel inhibition occurs at the IS, but the underlying mechanisms are unknown. A mathematical model was developed to test whether K+ efflux through K+ channels leads to an accumulation of K+ in the IS cleft, ultimately reducing K+ channel function and intracellular Ca2+ concentration ([Ca2+]i). Simulations were conducted in models of resting and activated T cell subsets, which express different levels of K+ channels, by varying the K+ diffusion constant and the spatial localization of K+ channels at the IS. K+ accumulation in the IS cleft was calculated to increase K+ concentration ([K+]) from its normal value of 5.0 mM to 5.2–10.0 mM. Including K+ accumulation in the model of the IS reduced calculated K+ current by 1–12% and consequently, reduced calculated [Ca2+]i by 1–28%. Significant reductions in K+ current and [Ca2+]i only occurred in activated T cell simulations when most K+ channels were centrally clustered at the IS. The results presented show that the localization of K+ channels at the IS can produce a rise in [K+] in the IS cleft and lead to a substantial decrease in K+ currents and [Ca2+]i in activated T cells thus providing a feedback inhibitory mechanism during T cell activation. PMID:22285786

Martin, Geoffrey V.; Yun, Yeoheung; Conforti, Laura

2012-01-01

316

Actin-Bundling Protein L-Plastin Regulates T Cell Activation  

PubMed Central

Engagement of T cell receptors induces actin rearrangements, which are critical for T cell activation. T cell responses require new actin polymerization, but the significance of higher order actin structures, such as microfilament bundles, is unknown. To determine the role of the actin-bundling protein leukocyte-plastin (L-plastin; LPL) in this process, T cells from LPL?/? mice were studied. LPL?/? T cells were markedly defective in TCR-mediated cytokine production and proliferation. LPL?/? T cells also spread inefficiently on surface with immobilized TCR ligands and formed smaller immunological synapses with APCs, likely due to defective formation of lamellipodia. LPL?/? mice showed delayed rejection of skin allografts after release from immunosuppression. Moreover, LPL?/? mice developed much less severe neurological symptoms in experimental autoimmune encephalomyelitis, which correlated with impaired T cell responses to antigen, manifested by reduced proliferation and production of IFN-? and IL-17. Thus, LPL-dependent actin bundling facilitates the formation of lamellipodia and normal immunological synapses, and thereby enables T cell activation. This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publisher of The JI, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org. PMID:21076065

Wang, Chen; Morley, Sharon Celeste; Donermeyer, David; Peng, Ivan; Lee, Wyne P.; Devoss, Jason; Danilenko, Dimitry M.; Lin, Zhonghua; Zhang, Juan; Zhou, Jie; Allen, Paul M.; Brown, Eric J.

2010-01-01

317

The Challenges and Opportunities for Development of a T-Cell Epitope-Based Herpes Simplex Vaccine  

PubMed Central

The infections with herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) have been prevalent since the ancient Greek times. To this day, they still affect a staggering number of over a half billion individuals worldwide. HSV-2 infections cause painful genital herpes, encephalitis, and death in newborns. HSV-1 infections are more prevalent than HSV-2 infections and cause potentially blinding ocular herpes, oro-facial herpes and encephalitis. While genital herpes in mainly caused by HSV-2 infections, in recent years, there is an increase in the proportion of genital herpes caused by HSV-1 infections in young adults, which reach 50% in some western societies. While prophylactic and therapeutic HSV vaccines remain urgently needed for centuries their development has been notoriously difficult. During the most recent National Institute of Health (NIH) workshop titled "Next Generation Herpes Simplex Virus Vaccines: The Challenges and Opportunities", basic researchers, funding agencies, and pharmaceutical representatives gathered: (i) to assess the status of herpes vaccine research; and (ii) to identify the gaps and propose alternative approaches in developing a safe and efficient herpes vaccine. One “common denominator” among previously failed clinical herpes vaccine trials is that they either used a whole virus or whole viral proteins, which contain both pathogenic “symptomatic” and protective “asymptomatic” antigens/epitopes. In this report, we continue to advocate that using an “asymptomatic” epitope-based vaccine strategy that selectively incorporates protective epitopes which: (i) are exclusively recognized, in vitro, by effector memory CD4+ and CD8+ TEM cells from “naturally” protected seropositive asymptomatic individuals; and (ii) protect, in vivo, human leukocyte antigen (HLA) transgenic animal models from ocular and genital herpes infections and diseases, could be the answer to many of the scientific challenges facing HSV vaccine development. We review the role of animal models in herpes vaccine development and discuss its current status, challenges, and prospects. PMID:25446827

Kuo, Tiffany; Wang, Christine; Badakhshan, Tina; Chilukuri, Sravya; BenMohamed, Lbachir

2014-01-01

318

A T cell receptor beta chain polymorphism is associated with patients developing insulin-dependent diabetes after the age of 20 years.  

PubMed Central

We have studied the BglII polymorphism near the T cell receptor beta chain constant region (TcR-C beta) gene, HLA-DR genotypes and certain autoimmune features in 102 patients with type I (insulin-dependent) diabetes. There was a significant decrease in the frequency of the 1:1 genotype (P = 0.008) and an increase in the 1:2 genotype (P = 0.03) of the BglII TcR polymorphism in the group of patients who developed type-I diabetes after the age of 20 years. This group of patients also showed an increased incidence of autoantibodies (especially islet cell antibody), a family history of diabetes and the presence of other autoimmune diseases. The frequency of this polymorphism in patients who developed type I diabetes before the age of 20 years was similar to a non-diabetic group. These results suggest that there are two genetically distinct groups of patients with type I diabetes. HLA-DR3 and HLA-DR4 genotypes were also increased in the diabetic patients but no significant difference was observed between HLA-DR genotypes, the TcR-C beta genotypes, the age of diagnosis or with other autoimmune features. Patients developing type I (insulin-dependent) diabetes after the age of 20 years have an additional genetic susceptibility for diabetes associated with the TcR-C beta gene. PMID:1979939

McMillan, S A; Graham, C A; Hart, P J; Hadden, D R; McNeill, T A

1990-01-01

319

Regulation of the development of asthmatic inflammation by in situ CD4(+)Foxp3 (+) T cells in a mouse model of late allergic asthma.  

PubMed

CD4(+)Foxp3(+)T cells (Tregs) mediate homeostatic peripheral tolerance by suppressing helper T2 cells in allergy. However, the regulation of asthmatic inflammation by local (in situ) Tregs in asthma remains unclear. BALB/c mice sensitized and challenged with ovalbumin (OVA) (asthma group) developed asthmatic inflammation with eosinophils and lymphocytes, but not mast cells. The number of Tregs in the circulation, pulmonary lymph nodes (pLNs), and thymi significantly decreased in the asthma group compared to the control group without OVA sensitization and challenge in the effector phase. The development of asthmatic inflammation is inversely related to decreased Tregs with reduced mRNA expression such as interleukin (IL)-4, transforming growth factor-?1, and IL-10, but not interferon-?, in pLNs. Moreover, M2 macrophages increased in the local site. The present study suggests that Tregs, at least in part, may regulate the development of asthmatic inflammation by cell-cell contact and regional cytokine productions. PMID:24854160

Nakashima, Tomomi; Hayashi, Toshiharu; Mizuno, Takuya

2014-10-01

320

The fragile environments of inexpensive CD4+ T-cell enumeration in the least developed countries: strategies for accessible support.  

PubMed

With the advent of affordable antiretroviral treatment (ART), flow cytometry has ventured out of the exclusive realms of First World research to the resource-strapped clinical environment of developing countries (DCs). Flow cytometric instrumentation for ART has become more cost-efficient, thanks to simplified, yet accurate protocols and smart technologies. These positive developments have, however, not taken shape without problems, as health care in DCs remains weak due to chronic underfunding of their primary health systems. In addition, the multiplicity of donors has created parallel infrastructures that are difficult to manage and may undermine the responsibilities of public services. Hence, there is a prevailing lack of attention to maintenance, support, and human resource development. Not uncommonly, the procurement of high-value equipment is guided by nontechnical interests with mixed results. As conventional service contracts are unpopular, the sustainability of equipment is under serious threat after warranty periods, with environmental factors such as dust and unreliable power supplies being well-known culprits. Reagent supplies and servicing constitute further challenges, where a combination of short reagent shelf life, cold-box shipping, huge distances across poor infrastructures, rigid accounting procedures, and erratic customs requirements cause significant delays and extra costs. Although excellent, highly trained or trainable local staff is available, it is frequently diverted by brain drain from the government sector to privately funded hospitals, research facilities, and overseas postings. Despite these challenges, corporate service management has commonly remained loyal to its roots in the developed world.A number of propositions address the current situation: "Reagent-rental" agreements represent an attractive alternative to service contracts, while smart instrument design has started to make inroads into more robust device concepts. To avoid logistical bottlenecks, reagents call for lyophilization and increased heat stability. Newly designed remote diagnostic tools are expected to save costs on service visits. Furthermore, web-based customer-relationship management and enterprise resource planning software is expected to ease the existing complex communication- and logistics issues. In addition, a public-private partnership is proposed that involves government, manufacturers, and local distributors with field application specialists. The latter operate crossbrand as independent subcontractors to manufacturers under a nationally endorsed cost-capping and quality assurance agreement to service all cytometric devices common in the region. These locally run networks may serve as "templates" for improved laboratory services in general, in collaboration with CD4 counting, haematology and infectious disease diagnostics. PMID:18228565

Larsen, Christoph H

2008-01-01

321

Regulation of house dust mite responses by intranasally administered peptide: transient activation of CD4 + T cells precedes the development of tolerance in vivo  

Microsoft Academic Search

We have previously demonstrated that intranasal (l.n.) administration of an immunodomlnant peptide (p1 111-139) derived from the house dust mite (HDM) allergen Der p 1 Inhibits antigen- specific CD4+ T cell responses in H-2b mice. Here we report that i.n. peptide induced a rapid but transient activation of MHC class II restricted CD4+ T cells that peaked 4 days after

Gerard F. Hoyne; Brigitte A. Askonas; Charlotte Hetzel; Wayne R. Thomas; Jonathan R. Lamb

1996-01-01

322

Preapoptotic phenotype of viral epitope-specific CD8 T cells precludes memory development and is an intrinsic property of the epitope  

Microsoft Academic Search

Virus-specific CD8 T cells after clearance of infection reduce their number in lymphoid organs by apoptotic death and by migration into peripheral tissues. During and after infection, many lymphocytic choriomeningitis virus (LCMV)-specific CD8 T cells in lymphoid but not peripheral tissues are in a preapoptotic state, as detected by the early apoptosis marker annexin V. In this report, we investigated

Xiaoting Z. Wang; Michael A. Brehm; Raymond M. Welsh

2004-01-01

323

Unbalanced Neonatal CD4+ T-Cell Immunity  

PubMed Central

In comparison to adults, newborns display a heightened susceptibility to pathogens and a propensity to develop allergic diseases. Particular properties of the neonatal immune system can account for this sensitivity. Indeed, a defect in developing protective Th1-type responses and a skewing toward Th2 immunity characterize today the neonatal T-cell immunity. Recently, new findings concerning Th17, regulatory helper T-cell, and follicular helper T-cell subsets in newborns have emerged. In some circumstances, development of effector inflammatory Th17-type responses can be induced in neonates, while differentiation in regulatory T-cells appears to be a default program of neonatal CD4+ T-cells. Poor antibody production, affinity maturation, and germinal center reaction in vaccinated neonates are correlated with a limiting expansion of TFH lymphocytes. We review herein the factors accounting for and the implications of the unbalanced neonatal helper T-cell immunity. PMID:25221551

Debock, Isabelle; Flamand, Véronique

2014-01-01

324

Suppressor T-cell factor(s) display an altered pattern of Igh (immunoglobulin heavy chain locus) genetic restriction when developed in an Igh-congeneic host.  

PubMed Central

Suppressor T-cell factor(s) (TsF1) inhibit the in vivo priming of azobenzenearsonate-specific cytotoxic T-cell responses. The activity of TsF1 is restricted by genes linked to Igh-1 allotypic markers. TsF1 obtained from B6.Igh-1n mice was unable to suppress the immune response in B6.Igh-1b mice and vice versa. However, TsF1 prepared from B6.Igh-1n T cells "parked" in an Igh-congeneic B6.Igh-1b environment displays an additional restriction specificity of the host. Thus, TsF1 prepared from these Igh-chimeric mice suppressed immune responses in both B6.Igh-1n (donor) and B6.Igh-1b (recipient) mice but not in mice of the unrelated strain BALB/c.Igh-1a. The results indicate that the establishment of the suppressor T-cell repertoire is dependent not only upon the genetic background of the individual T cell but also upon the influence of Igh-linked determinants present when T-cell clones are selected during the response. PMID:3920661

HayGlass, K T; Naides, S J; Benacerraf, B; Sy, M S

1985-01-01

325

Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast  

Microsoft Academic Search

For long, T-cell acute lymphoblastic leukemia (T-ALL) remained in the shadow of precursor B-ALL because it was more seldom, and showed a normal karyotype in more than 50% of cases. The last decennia, intense research has been carried out on different fronts. On one side, development of normal thymocyte and its regulation mechanisms have been studied in multiple mouse models

C Graux; J Cools; L Michaux; P Vandenberghe; A Hagemeijer

2006-01-01

326

Established Thymic Epithelial Progenitor/Stem Cell-Like Cell Lines Differentiate into Mature Thymic Epithelial Cells and Support T Cell Development  

PubMed Central

Common thymic epithelial progenitor/stem cells (TEPCs) differentiate into cortical and medullary thymic epithelial cells (TECs), which are required for the development and selection of thymocytes. Mature TEC lines have been widely established. However, the establishment of TEPC lines is rarely reported. Here we describe the establishment of thymic epithelial stomal cell lines, named TSCs, from fetal thymus. TSCs express some of the markers present on tissue progenitor/stem cells such as Sca-1. Gene expression profiling verifies the thymic identity of TSCs. RANK stimulation of these cells induces expression of autoimmune regulator (Aire) and Aire-dependent tissue-restricted antigens (TRAs) in TSCs in vitro. TSCs could be differentiated into medullary thymic epithelial cell-like cells with exogenously expressed NF-?B subunits RelB and p52. Importantly, upon transplantation under the kidney capsules of nude mice, TSCs are able to differentiate into mature TEC-like cells that can support some limited development of T cells in vivo. These findings suggest that the TSC lines we established bear some characteristics of TEPC cells and are able to differentiate into functional TEC-like cells in vitro and in vivo. The cloned TEPC-like cell lines may provide useful tools to study the differentiation of mature TEC cells from precursors. PMID:24086471

Zhan, Yu; Su, Juanjuan; Du, Yarui; Xu, Guoliang; Shi, Yufang; Siebenlist, Ulrich; Zhang, Xiaoren

2013-01-01

327

Relationship between circulating levels of RANTES (regulated on activation, normal T-cell expressed, and secreted) and carotid plaque characteristics: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study  

PubMed Central

Aims To assess the relationship between regulated on activation, normal T-cell expressed and secreted (RANTES) and carotid atherosclerotic plaque burden and plaque characteristics. Methods and results Gadolinium-enhanced magnetic resonance imaging (MRI) of the carotid artery was performed in 1901 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Wall thickness and volume, lipid-core volume, and fibrous cap thickness (by MRI) and plasma RANTES levels (by ELISA) were measured. Regression analysis was performed to study the associations between MRI variables and RANTES. Among 1769 inclusive participants, multivariable regression analysis revealed that total wall volume [beta-coefficient (?) = 0.09, P = 0.008], maximum wall thickness (? = 0.08, P = 0.01), vessel wall area (? = 0.07, P = 0.02), mean minimum fibrous cap thickness (? = 0.11, P = 0.03), and high-sensitivity C-reactive protein (? = 0.09, P = 0.01) were positively associated with RANTES. Total lipid-core volume showed positive association in unadjusted models (? = 0.18, P = 0.02), but not in fully adjusted models (? = 0.13, P = 0.09). RANTES levels were highest in Caucasian females followed by Caucasian males, African-American females, and African-American males (P < 0.0001). Statin use attenuated the relationship between RANTES and measures of plaque burden. Conclusion Positive associations between RANTES and carotid wall thickness and lipid-core volume (in univariate analysis) suggest that higher RANTES levels may be associated with extent of carotid atherosclerosis and high-risk plaques. Associations between fibrous cap thickness and RANTES likely reflect the lower reliability estimate for fibrous cap measurements compared with wall volume or lipid-core volume measurements. Statin use may modify the association between RANTES and carotid atherosclerosis. Furthermore, RANTES levels vary by race. PMID:20943669

Virani, Salim S.; Nambi, Vijay; Hoogeveen, Ron; Wasserman, Bruce A.; Coresh, Josef; Gonzalez, Franklyn; Chambless, Lloyd E.; Mosley, Thomas H.; Boerwinkle, Eric; Ballantyne, Christie M.

2011-01-01

328

ABNORMAL REGULATORY AND EFFECTOR T CELL FUNCTION PREDISPOSE TO AUTOIMMUNITY FOLLOWING XENOGENEIC THYMIC TRANSPLANTATION1  

PubMed Central

Porcine thymus grafts support robust murine and human thymopoiesis, generating a diverse T cell repertoire that is deleted of donor and host-reactive cells, achieving specific xenograft tolerance. Positive selection is mediated exclusively by the xenogeneic thymic MHC. While thymectomized, T cell-depleted normal mice usually remain healthy following xenogeneic thymic transplantation, thymus-grafted congenitally athymic mice frequently develop multiorgan autoimmunity. We investigated the etiology of this syndrome by adoptively transferring lymphocyte populations from fetal pig (FP) thymus (THY)-grafted (FPG) BALB/c nude mice to secondary BALB/c nude recipients. FPG nude mice generated normal numbers of CD25+Foxp3+CD4 T cells, but these cells lacked the capacity to block autoimmunity. Moreover, thymocytes and peripheral CD4+CD25? cells from FPG nude mice, but not those from normal mice, induced autoimmunity in nude recipients. Injection of thymic epithelial cells from normal BALB/c mice into FP THY grafts reduced autoimmunity and enhanced regulatory function of splenocytes. Our data implicate abnormalities in post-thymic maturation, expansion and/or survival of T cells positively selected by a xenogeneic MHC, as well as incomplete intrathymic deletion of thymocytes recognizing host tissue-specific antigens, in autoimmune pathogenesis. Regulatory cell function is enhanced and negative selection of host-specific thymocytes may potentially also be improved by co-implantation of recipient thymicepithelial cells in the thymus xenograft. PMID:19017953

Fudaba, Yasuhiro; Onoe, Takashi; Chittenden, Meredith; Shimizu, Akira; Shaffer, Juanita M.; Bronson, Roderick; Sykes, Megan

2009-01-01

329

T-cell metabolism in autoimmune disease.  

PubMed

Cancer cells have long been known to fuel their pathogenic growth habits by sustaining a high glycolytic flux, first described almost 90 years ago as the so-called Warburg effect. Immune cells utilize a similar strategy to generate the energy carriers and metabolic intermediates they need to produce biomass and inflammatory mediators. Resting lymphocytes generate energy through oxidative phosphorylation and breakdown of fatty acids, and upon activation rapidly switch to aerobic glycolysis and low tricarboxylic acid flux. T cells in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have a disease-specific metabolic signature that may explain, at least in part, why they are dysfunctional. RA T cells are characterized by low adenosine triphosphate and lactate levels and increased availability of the cellular reductant NADPH. This anti-Warburg effect results from insufficient activity of the glycolytic enzyme phosphofructokinase and differentiates the metabolic status in RA T cells from those in cancer cells. Excess production of reactive oxygen species and a defect in lipid metabolism characterizes metabolic conditions in SLE T cells. Owing to increased production of the glycosphingolipids lactosylceramide, globotriaosylceramide and monosialotetrahexosylganglioside, SLE T cells change membrane raft formation and fail to phosphorylate pERK, yet hyperproliferate. Borrowing from cancer metabolomics, the metabolic modifications occurring in autoimmune disease are probably heterogeneous and context dependent. Variations of glucose, amino acid and lipid metabolism in different disease states may provide opportunities to develop biomarkers and exploit metabolic pathways as therapeutic targets. PMID:25776624

Yang, Zhen; Matteson, Eric L; Goronzy, Jörg J; Weyand, Cornelia M

2015-12-01

330

Nod2 Activates NF-kB in CD4+ T Cells but Its Expression Is Dispensable for T Cell-Induced Colitis  

PubMed Central

Although the etiology of Crohn's disease (CD) remains elusive this disease is characterized by T cell activation that leads to chronic inflammation and mucosal damage. A potential role for maladaptation between the intestinal microbiota and the mucosal immune response is suggested by the fact that mutations in the pattern recognition receptor Nod2 are associated with higher risks for developing CD. Although Nod2 deletion in CD4+ T cells has been shown to impair the induction of colitis in the murine T cell transfer model, the analysis of T cell intrinsic Nod2 function in T cell differentiation and T cell-mediated immunity is inconsistent between several studies. In addition, the role of T cell intrinsic Nod2 in regulatory T cell (Treg) development and function during colitis remain to be analyzed. In this study, we show that Nod2 expression is higher in activated/memory CD4+ T cells and its expression was inducible after T cell receptor (TCR) ligation. Nod2 stimulation with muramyl dipeptide (MDP) led to a nuclear accumulation of c-Rel NF-kB subunit. Although functionally active in CD4+ T cells, the deletion of Nod2 did not impair the induction and the prevention of colitis in the T cell transfer model. Moreover, Nod2 deletion did not affect the development of Foxp3+ Treg cells in the spleen of recipient mice and Nod2 deficient CD4 T cells expressing the OVA specific transgenic TCR were able to differentiate in Foxp3+ Treg cells after OVA feeding. In vitro, CD25+ Nod2 deficient T cells suppressed T cell proliferation as well as wild type counter parts and T cell stimulation with MDP did not affect the proliferation and the cytokine secretion of T cells. In conclusion, our data indicate that Nod2 is functional in murine CD4+ T cells but its expression is dispensable for the T cell regulation of colitis. PMID:24324812

Zanello, Galliano; Goethel, Ashleigh; Forster, Katharina; Geddes, Kaoru; Philpott, Dana J.; Croitoru, Kenneth

2013-01-01

331

Development of ultra-super sensitive immunohistochemistry and its application to the etiological study of adult T-cell leukemia/lymphoma.  

PubMed

Antigen retrieval (AR) and ultra-super sensitive immunohistochemistry (ultra-IHC) have been established for application to archival human pathology specimens. The original ultra-IHC was the ImmunoMax method or the catalyzed signal amplification system (ImmunoMax/CSA method), comprising the streptavidin-biotin complex (sABC) method and catalyzed reporter deposition (CARD) reaction with visualization of its deposition. By introducing procedures to diminish non-specific staining in the original ultra-IHC method, we developed the modified ImmunoMax/CSA method with AR heating sections in an AR solution (heating-AR). The heating-AR and modified ImmunoMax/CSA method visualized expression of the predominantly simple present form of HTLV-1 proviral DNA pX region p40Tax protein (Tax) in adult T-cell leukemia/lymphoma (ATLL) cells in archival pathology specimens in approximately 75% of cases. The simple present form of Tax detected exhibited a close relation with ATLL cell proliferation. We also established a new simplified CSA (nsCSA) system by replacing the sABC method with the secondary antibody- and horse radish peroxidase-labeled polymer reagent method, introducing the pretreatments blocking non-specific binding of secondary antibody reagent, and diminishing the diffusion of deposition in the CARD reaction. Combined with AR treating sections with proteinase K solution (enzymatic-AR), the nsCSA system visualized granular immunostaining of the complex present form of Tax in a small number of ATLL cells in most cases, presenting the possibility of etiological pathological diagnosis of ATLL and suggesting that the complex present form of Tax-positive ATLL cells were young cells derived from ATLL stem cells. The heating-AR and ultra-IHC detected physiological expression of the p53 protein and its probable phosphorylation by Tax in peripheral blood mononuclear cells of peripheral blood tissue specimens from HTLV-1 carriers, as well as physiological and pathological expression of the molecules involved with G1 phase progression and G1-S phase transition (E2F-1, E2F-4, DP-1, and cyclin E) in ATLL and peripheral T-cell lymphoma cells. The ultra-IHC with AR is useful for etiological pathological diagnosis of ATLL since HTLV-1 pathogenicity depends on that of Tax, and can be a useful tool for studies translating advanced molecular biology and pathology to human pathology. PMID:22685351

Hasui, Kazuhisa; Wang, Jia; Tanaka, Yuetsu; Izumo, Shuji; Eizuru, Yoshito; Matsuyama, Takami

2012-04-26

332

Autoreactive T-cell clones from the nonobese diabetic mouse.  

PubMed

The availability of cloned lines of T cells reactive with islet antigens has provided investigators with new tools to study how T cells contribute to autoimmune disease. T-cell clones isolated from the diabetes-prone nonobese diabetic (NOD) mouse are proving to be particularly valuable for analyzing pathogenesis and hold great promise for determining which T-cell subsets are involved in beta-cell destruction versus immunoregulation of the inflammatory process. Diabetogenic T-cell clones have been mostly of the CD4+, Th1 phenotype, but CD8+ T cell clones are also capable of transferring disease. In some cases, T-cell lines and clones (CD4+ and CD8+) have been found to have protective properties. In general T-cell antigen specificities have not been defined, as islet cells or lysates were used as the selecting antigen. However, there is an increasing number of reports of T cells specific for defined islet proteins, such as insulin and GAD, and some of these lines can induce disease. The variety of T-cell clones that have been produced indicate that there may a variety of conditions that lead to or protect against beta-cell destruction and provide further evidence that autoantigens are generated during development of disease. PMID:9012359

Bergman, B; Haskins, K

1997-01-01

333

Human T-cell memory consists mainly of unexpanded clones  

Microsoft Academic Search

The immune system is able to respond to millions of antigens using adaptive receptors, including the ??-T-cell receptor (TCR). Upon antigen encounter a T-cell may proliferate to produce a clone of TCR-identical cells, which develop a memory phenotype. Previous studies suggested that most memory clones are clearly expanded. In accordance, the ?-chain repertoire of T-cell memory subsets was reported to

Paul L. Klarenbeek; Paul P. Tak; Barbera D. C. van Schaik; Aeilko H. Zwinderman; Marja E. Jakobs; Zhuoli Zhang; Antoine H. C. van Kampen; René A. W. van Lier; Frank Baas; Niek de Vries

2010-01-01

334

NOTCH1-induced T-cell leukemia in transgenic zebrafish  

Microsoft Academic Search

Activating mutations in the NOTCH1 gene have been found in about 60% of patients with T-cell acute lymphoblastic leukemia (T-ALL). In order to study the molecular mechanisms by which altered Notch signaling induces leukemia, a zebrafish model of human NOTCH1-induced T-cell leukemia was generated. Seven of sixteen mosaic fish developed a T-cell lymphoproliferative disease at about 5 months. These neoplastic

J Chen; C Jette; J P Kanki; J C Aster; A T Look; J D Griffin

2007-01-01

335

Discrete dynamic modeling of T cell survival signaling networks  

NASA Astrophysics Data System (ADS)

Biochemistry-based frameworks are often not applicable for the modeling of heterogeneous regulatory systems that are sparsely documented in terms of quantitative information. As an alternative, qualitative models assuming a small set of discrete states are gaining acceptance. This talk will present a discrete dynamic model of the signaling network responsible for the survival and long-term competence of cytotoxic T cells in the blood cancer T-LGL leukemia. We integrated the signaling pathways involved in normal T cell activation and the known deregulations of survival signaling in leukemic T-LGL, and formulated the regulation of each network element as a Boolean (logic) rule. Our model suggests that the persistence of two signals is sufficient to reproduce all known deregulations in leukemic T-LGL. It also indicates the nodes whose inactivity is necessary and sufficient for the reversal of the T-LGL state. We have experimentally validated several model predictions, including: (i) Inhibiting PDGF signaling induces apoptosis in leukemic T-LGL. (ii) Sphingosine kinase 1 and NF?B are essential for the long-term survival of T cells in T-LGL leukemia. (iii) T box expressed in T cells (T-bet) is constitutively activated in the T-LGL state. The model has identified potential therapeutic targets for T-LGL leukemia and can be used for generating long-term competent CTL necessary for tumor and cancer vaccine development. The success of this model, and of other discrete dynamic models, suggests that the organization of signaling networks has an determining role in their dynamics. Reference: R. Zhang, M. V. Shah, J. Yang, S. B. Nyland, X. Liu, J. K. Yun, R. Albert, T. P. Loughran, Jr., Network Model of Survival Signaling in LGL Leukemia, PNAS 105, 16308-16313 (2008).

Zhang, Ranran

2009-03-01

336

Retargeting T Cells to GD2 Pentasaccharide on Human Tumors Using Bispecific Humanized Antibody.  

PubMed

Anti-disialoganglioside GD2 IgG antibodies have shown clinical efficacy in solid tumors that lack human leukocyte antigens (e.g., neuroblastoma) by relying on Fc-dependent cytotoxicity. However, there are pain side effects secondary to complement activation. T-cell retargeting bispecific antibodies (BsAb) also have clinical potential, but it is thus far only effective against liquid tumors. In this study, a fully humanized hu3F8-BsAb was developed, in which the anti-CD3 huOKT3 single-chain Fv fragment (ScFv) was linked to the carboxyl end of the anti-GD2 hu3F8 IgG1 light chain, and was aglycosylated at N297 of Fc to prevent complement activation and cytokine storm. In vitro, hu3F8-BsAb activated T cells through classic immunologic synapses, inducing GD2-specific tumor cytotoxicity at femtomolar EC50 with >10(5)-fold selectivity over normal tissues, releasing Th1 cytokines (TNF?, IFN?, and IL2) when GD2(+) tumors were present. In separate murine neuroblastoma and melanoma xenograft models, intravenous hu3F8-BsAb activated T cells in situ and recruited intravenous T cells for tumor ablation, significantly prolonging survival from local recurrence or from metastatic disease. Hu3F8-BsAb, but not control BsAb, drove T cells and monocytes to infiltrate tumor stroma. These monocytes were necessary for sustained T-cell proliferation and/or survival and contributed significantly to the antitumor effect. The in vitro and in vivo antitumor properties of hu3F8-BsAb and its safety profile support its further clinical development as a cancer therapeutic, and provide the rationale for exploring aglycosylated IgG-scFv as a structural platform for retargeting human T cells. Cancer Immunol Res; 3(3); 266-77. ©2014 AACR. PMID:25542634

Xu, Hong; Cheng, Ming; Guo, Hongfen; Chen, Yuedan; Huse, Morgan; Cheung, Nai-Kong V

2015-03-01

337

T cell-specific inhibition of multiple apoptotic pathways blocks negative selection and causes autoimmunity  

PubMed Central

T cell self-tolerance is thought to involve peripheral tolerance and negative selection, involving apoptosis of autoreactive thymocytes. However, evidence supporting an essential role for negative selection is limited. Loss of Bim, a Bcl-2 BH3-only protein essential for thymocyte apoptosis, rarely results in autoimmunity on the C57BL/6 background. Mice with T cell-specific over-expression of Bcl-2, that blocks multiple BH3-only proteins, are also largely normal. The nuclear receptor Nur77, also implicated in negative selection, might function redundantly to promote apoptosis by associating with Bcl-2 and exposing its potentially pro-apoptotic BH3 domain. Here, we report that T cell-specific expression of a Bcl2 BH3 mutant transgene results in enhanced rescue of thymocytes from negative selection. Concomitantly, Treg development is increased. However, aged BH3 mutant mice progressively accumulate activated, autoreactive T cells, culminating in development of multi-organ autoimmunity and lethality. These data provide strong evidence that negative selection is crucial for establishing T cell tolerance. DOI: http://dx.doi.org/10.7554/eLife.03468.001 PMID:25182415

Burger, Megan L; Leung, Kenneth K; Bennett, Margaux J; Winoto, Astar

2014-01-01

338

New insights of T cells in the pathogenesis of psoriasis  

PubMed Central

Psoriasis is one of the most common immune-mediated chronic, inflammatory skin diseases characterized by hyperproliferative keratinocytes and infiltration of T cells, dendritic cells, macrophages and neutrophils. Although the pathogenesis of psoriasis is not fully understood, there is ample evidence suggesting that the dysregulation of immune cells in the skin, particularly T cells, plays a critical role in psoriasis development. In this review, we mainly focus on the pathogenic T cells and discuss how these T cells are activated and involved in the disease pathogenesis. Newly identified ‘professional' IL-17-producing dermal ?? T cells and their potential role in psoriasis will also be included. Finally, we will briefly summarize the recent progress on the T cell and its related cytokine-targeted therapy for psoriasis treatment. PMID:22705915

Cai, Yihua; Fleming, Chris; Yan, Jun

2012-01-01

339

Intestinal ?? T-cell lymphomas are most frequently of type II enteropathy-associated T-cell type  

PubMed Central

Summary Enteropathy-associated T-cell lymphoma includes type I cases and distinctive type II cases that, according to 2008 and 2010 World Health Organization descriptions, are T-cell receptor ?+. Although T-cell receptor ?? enteropathy-associated T-cell lymphomas are reported, it is unknown if they have distinctive features and if they should be categorized as enteropathy-associated T-cell lymphoma or as a mucocutaneous ?? T-cell lymphoma. To address these questions, the clinicopathologic, immunophenotypic, molecular, and cytogenetic features of 5 ??-enteropathy-associated T-cell lymphomas were investigated. Only 1 patient had celiac disease and had type I enteropathy-associated T-cell lymphoma, and the others fulfilled the histopathologic criteria for type II enteropathy-associated T-cell lymphoma. All lacked cutaneous involvement. A celiac disease–associated HLA type was found in the patient with CD and one of four others. All were T-cell receptor ?+, T-cell receptor ?+, ?F1?, CD3+, CD7+, CD5?, CD4?, and TIA-1+ with variable staining for CD2 (3/5), CD8 (2/5), Granzyme B (1/5), and CD56 (4/5). Fluorescence in situ hybridization demonstrated 9q34 gains in 4 cases, with 9q33-34 gains by single nucleotide polymorphism in 3 of these. Single nucleotide polymorphism analysis also demonstrated gains in 5q34-q35.1/5q35.1 (4/5), 8q24 (3/5), and in 32 other regions in 3 of 5 cases. V?1 rearrangements were identified in 4 of 4 cases with documented clonality showing the same clone in normal-appearing distant mucosa (3/3 tested cases). Thus, ??-enteropathy-associated T-cell lymphomas share many features with other enteropathy-associated T-cell lymphoma and are mostly of type II. Their usual nonactivated cytotoxic phenotype and V?1 usage are features unlike many other mucocutaneous ?? T-cell lymphomas but shared with hepatosplenic T-cell lymphoma. These findings support the conclusion that a ?? T-cell origin at extracutaneous sites does not define a specific entity. PMID:23332928

Wilson, Amanda L.; Swerdlow, Steven H.; Przybylski, Grzegorz K.; Surti, Urvashi; Choi, John K.; Campo, Elias; Trucco, Massimo M.; Van Oss, S. Branden; Felgar, Raymond E.

2013-01-01

340

Human T cell development in the liver of humanized NOD/SCID/IL-2R?(null)(NSG) mice generated by intrahepatic injection of CD34(+) human (h) cord blood (CB) cells.  

PubMed

In this study, we explore the possibility of human T cell development in the liver of humanized mice generated by intrahepatic injection of CD34(+) hCB cells into conditioned NOD/SCID/IL-2R?(null)(NSG) newborn mice. The intrahepatic injection of CD34(+) hCB cells led to effective reconstitution of human myeloid and lymphoid lineage cells. In contrast to the previously reported Rag2(-/-)?(c)(-/-) humanized mice, interestingly, the thymus function of humanized NSG mice was markedly reduced in terms of its size and cell contents, whereas the livers of humanized NSG mice profoundly contained double-positive (DP), hCD4 and hCD8 single positive (SP), hCD34(+)hCD38(lo)hCD1a(-) (TSP), hCD34(+)hCD38(hi)hCD1a(-) (ETP), and hCD34(+)hCD38(+)hCD1a(+) (pre-T cells) cells. Furthermore, immunostaining of the liver revealed that human T cells were co-localized with hDCs. Taken together, our results demonstrate that the intrahepatic injection of hCD34(+) hCB cells can facilitate human T cell development in the livers of humanized NSG mice. PMID:21429805

Choi, Bongkum; Chun, Eunyoung; Kim, Miyoung; Kim, So Yong; Kim, Seong-Tae; Yoon, Keejung; Lee, Ki-Young; Kim, Sung Joo

2011-06-01

341

Tissue-resident memory T cells  

PubMed Central

Summary Tissues such as the genital tract, skin, and lung act as barriers against invading pathogens. To protect the host, incoming microbes must be quickly and efficiently controlled by the immune system at the portal of entry. Memory is a hallmark of the adaptive immune system, which confers long-term protection and is the basis for efficacious vaccines. While the majority of existing vaccines rely on circulating antibody for protection, struggles to develop antibody-based vaccines against infections such as herpes simplex virus (HSV) and human immunodeficiency virus (HIV) have underscored the need to generate memory T cells for robust antiviral control. The circulating memory T-cell population is generally divided into two subsets: effector memory (TEM) and central memory (TCM). These two subsets can be distinguished by their localization, as TCM home to secondary lymphoid organs and TEM circulate through non-lymphoid tissues. More recently, studies have identified a third subset, called tissue-resident memory (TRM) cells, based on its migratory properties. This subset is found in peripheral tissues that require expression of specific chemoattractants and homing receptors for T-cell recruitment and retention, including barrier sites such as the skin and genital tract. In this review, we categorize different tissues in the body based on patterns of memory T-cell migration and tissue residency. This review also describes the rules for TRM generation and the properties that distinguish them from circulating TEM and TCM cells. Finally, based on the failure of recent T-cell-based vaccines to provide optimal protection, we also discuss the potential role of TRM cells in vaccine design against microbes that invade through the peripheral tissues and highlight new vaccination strategies that take advantage of this newly described memory T-cell subset. PMID:23947354

Shin, Haina; Iwasaki, Akiko

2013-01-01

342

T Cells in Vascular Inflammatory Diseases  

PubMed Central

Inflammation of the human vasculature is a manifestation of many different diseases ranging from systemic autoimmune diseases to chronic inflammatory diseases, in which multiple types of immune cells are involved. For both autoimmune diseases and chronic inflammatory diseases several observations support a key role for T lymphocytes in these disease pathologies, but the underlying mechanisms are poorly understood. Previous studies in several autoimmune diseases have demonstrated a significant role for a specific subset of CD4+ T cells termed effector memory T (TEM) cells. This expanded population of TEM cells may contribute to tissue injury and disease progression. These cells exert multiple pro-inflammatory functions through the release of effector cytokines. Many of these cytokines have been detected in the inflammatory lesions and participate in the vasculitic reaction, contributing to recruitment of macrophages, neutrophils, dendritic cells, natural killer cells, B cells, and T cells. In addition, functional impairment of regulatory T cells paralyzes anti-inflammatory effects in vasculitic disorders. Interestingly, activation of TEM cells is uniquely dependent on the voltage-gated potassium Kv1.3 channel providing an anchor for specific drug targeting. In this review, we focus on the CD4+ T cells in the context of vascular inflammation and describe the evidence supporting the role of different T cell subsets in vascular inflammation. Selective targeting of pathogenic TEM cells might enable a more tailored therapeutic approach that avoids unwanted adverse side effects of generalized immunosuppression by modulating the effector functions of T cell responses to inhibit the development of vascular inflammation. PMID:25352848

Lintermans, Lucas L.; Stegeman, Coen A.; Heeringa, Peter; Abdulahad, Wayel H.

2014-01-01

343

The generation and use of human T cell clones.  

PubMed

In this review a number of uses of human T cell clones have been discussed. Before considering T cell cloning, however, it is worth bearing in mind that there are certain disadvantages to this approach to T cell immunity, not the least of which is that these cells, adapted as they are for in vitro growth, may be unrepresentative of the normal T cell, in terms of both specificity, and function. In addition, cloning is sufficiently difficult for it to be undertaken only where monoclonal populations are essential to the desired aim. Nevertheless, the range of uses discussed, and the fact that many have had a fundamental impact on our understanding of immune mechanisms, not only as mediated by T cells, but also of the intracellular mechanisms of antigen-presentation, the nature and mode of action of the cytokines, as well as the cell surface molecules and cascade of signals that orchestrate T cell activation, indicate the importance of T cell cloning. In the future, it is probable that the use of T cell clones with defined receptor usage will improve our understanding of the mechanisms underlying disease pathogenesis, and thus aid both the prevention and treatment of disease. In addition, the T cell receptor structure will, no doubt, be elucidated, leading to a further quantum leap in our understanding of T cell immune mechanisms, as well as suggesting other avenues for exploration. In all these areas there is no doubt that the methodology of T cell cloning will continue to make a fundamental contribution. PMID:2087232

Rees, A D

1990-12-01

344

Biomarkers in T cell therapy clinical trials  

PubMed Central

T cell therapy represents an emerging and promising modality for the treatment of both infectious disease and cancer. Data from recent clinical trials have highlighted the potential for this therapeutic modality to effect potent anti-tumor activity. Biomarkers, operationally defined as biological parameters measured from patients that provide information about treatment impact, play a central role in the development of novel therapeutic agents. In the absence of information about primary clinical endpoints, biomarkers can provide critical insights that allow investigators to guide the clinical development of the candidate product. In the context of cell therapy trials, the definition of biomarkers can be extended to include a description of parameters of the cell product that are important for product bioactivity. This review will focus on biomarker studies as they relate to T cell therapy trials, and more specifically: i. An overview and description of categories and classes of biomarkers that are specifically relevant to T cell therapy trials, and ii. Insights into future directions and challenges for the appropriate development of biomarkers to evaluate both product bioactivity and treatment efficacy of T cell therapy trials. PMID:21851646

2011-01-01

345

Utilizing Regulatory T Cells Against Rheumatoid Arthritis  

PubMed Central

Regulatory T (Treg) cells are essential for normal immune surveillance systems, and their dysfunction leads to development of diseases, such as autoimmune disorders. CD4+CD25+ Treg cells are well-known suppressive cells, which express the transcription factor Foxp3, are indispensable for the maintenance of immune self-tolerance and homeostasis by suppressing aberrant or excessive immune response. Other Foxp3? Treg cells include Tr1, Th3, CD8+CD28?/?, and Qa1-restricted T cells; however, the contribution of these Treg cells to self-tolerance, immune homeostasis as well as preventing autoimmunity is not well defined. Here, we discuss the phenotypes and function of Foxp3+ Treg cells and the potential use of such Treg cells against rheumatoid arthritis (RA). Of note, even though most expanded populations of Foxp3+ Treg cells exhibit suppressive activity, tissue-associated or antigen-specific Treg cells appear superior in suppressing local autoimmune disorders such as RA. In addition, utilizing tissue-associated Foxp3+ Treg cells from stem cells may stable Foxp3 expression and avoid induction of a potentially detrimental systemic immunosuppression. PMID:25152867

Haque, Mohammad; Fino, Kristin; Lei, Fengyang; Xiong, Xiaofang; Song, Jianxun

2014-01-01

346

Host T Cells Affect Donor T Cell Engraftment and Graft-versus-Host Disease after Reduced-Intensity Hematopoietic Stem Cell Transplantation  

PubMed Central

Mixed chimerism in the T cell compartment (MCT) after reduced-intensity stem cell transplantation (RIST) may influence immune repopulation with alloreactive donor T cells. We examined effects of host T cell numbers on donor T cell engraftment and recovery and on acute graft-versus-host disease (GVHD) in a relatively homogeneous patient population with respect to residual host T cells through quantified immune depletion prior to RIST and to donor T cells by setting the allograft T cell dose of 1×105 CD3+ cells/kg. In this setting, two patterns of early donor T cell engraftment could be distinguished by Day +42: (1) early and complete donor chimerism in the T cell compartment (FDCT) and (2) persistent MCT. FDCT was associated with lower residual host CD8+ T cell counts prior to transplant and acute GVHD. With persistent MCT, subsequent development of acute GVHD could be predicted by the direction of change in T cell donor chimerism after donor lymphocyte infusion, and no acute GVHD occurred until FDCT was established. MCT did not affect recovery of donor T cell counts. These observations suggest that the relative number and alloreactivity of donor and host T cells are more important than the absolute allograft T cell dose in determining donor engraftment and acute GVHD after RIST. PMID:17697964

Hardy, Nancy M.; Hakim, Frances; Steinberg, Seth M.; Krumlauf, Michael; Cvitkovic, Romana; Babb, Rebecca; Odom, Jeanne; Fowler, Daniel H.; Gress, Ronald E.; Bishop, Michael R.

2009-01-01

347

Helicobacter pylori induces transendothelial migration of activated memory T cells.  

PubMed

Helicobacter pylori infection is associated with pronounced infiltration of granulocytes and lymphocytes into the gastric mucosa, resulting in active chronic gastritis that may develop into duodenal ulcer disease or gastric adenocarcinoma. Infiltrating T cells play a major role in the pathology of these diseases, but the signals involved in recruitment of T cells from blood to H. pylori-infected tissues are not well understood. We therefore examined H. pylori-induced T-cell transendothelial migration (TEM). The Transwell system, employing a monolayer of human umbilical vein endothelial cells, was used as a model to study TEM. H. pylori induced a significant T-cell migration, compared to spontaneous migration. CD4+ and CD8+ T cells migrated to the same extent in response to H. pylori, whereas there was significantly larger transmigration of memory T cells compared to naive T cells. Both H. pylori culture filtrate and urease induced migration, and the presence of the H. pylori cag pathogenicity island increased TEM. T-cell TEM was mediated by LFA-1-ICAM-1 interactions in accordance with an increased ICAM-1 expression on the endothelial cells after contact with H. pylori. Migrating T cells had increased expression of activation marker CD69 and chemokine receptors CXCR3, CCR4, and CCR9. Furthermore, T cells migrating in response to H. pylori secreted Th1 but not Th2 cytokines upon stimulation. In conclusion, our data indicate that live H. pylori and its secreted products contribute to T-cell recruitment to the gastric mucosa and that the responding T cells have an activated memory Th1 phenotype. PMID:15664914

Enarsson, Karin; Brisslert, Mikael; Backert, Steffen; Quiding-Järbrink, Marianne

2005-02-01

348

Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice  

PubMed Central

Mutations in the tumor-suppressor gene phosphatase and tensin homolog deleted on chromosome 10 (Pten) are associated with multiple cancers in humans, including T cell malignancies. Targeted deletion of Pten in T cells induces both a disseminated “mature phenotype” lymphoma and a lymphoproliferative autoimmune syndrome in mice. Here, we have shown that these two diseases are separable and mediated by T lineage cells of distinct developmental stages. Loss of PTEN was found to be a powerful driver of lymphomagenesis within the thymus characterized by overexpression of the c-myc oncogene. In an otherwise normal thymic environment, PTEN-deficient T cell lymphomas invariably harbored RAG-dependent reciprocal t(14:15) chromosomal translocations involving the T cell receptor alpha/delta locus and c-myc, and their survival and growth was TCR dependent, but Notch independent. However, lymphomas occurred even if TCR recombination was prevented, although these lymphomas were less mature, arose later in life, and, importantly, were dependent upon Notch pathways to upregulate c-myc expression. In contrast, using the complementary methods of early thymectomy and adoptive transfers, we found that PTEN-deficient mature T cells were unable to undergo malignant transformation but were sufficient for the development of autoimmunity. These data suggest multiple and distinct regulatory roles for PTEN in the molecular pathogenesis of lymphoma and autoimmunity. PMID:20516645

Liu, Xiaohe; Karnell, Jodi L.; Yin, Bu; Zhang, Ruan; Zhang, Jidong; Li, Peiying; Choi, Yongwon; Maltzman, Jonathan S.; Pear, Warren S.; Bassing, Craig H.; Turka, Laurence A.

2010-01-01

349

Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice.  

PubMed

Mutations in the tumor-suppressor gene phosphatase and tensin homolog deleted on chromosome 10 (Pten) are associated with multiple cancers in humans, including T cell malignancies. Targeted deletion of Pten in T cells induces both a disseminated "mature phenotype" lymphoma and a lymphoproliferative autoimmune syndrome in mice. Here, we have shown that these two diseases are separable and mediated by T lineage cells of distinct developmental stages. Loss of PTEN was found to be a powerful driver of lymphomagenesis within the thymus characterized by overexpression of the c-myc oncogene. In an otherwise normal thymic environment, PTEN-deficient T cell lymphomas invariably harbored RAG-dependent reciprocal t(14:15) chromosomal translocations involving the T cell receptor alpha/delta locus and c-myc, and their survival and growth was TCR dependent, but Notch independent. However, lymphomas occurred even if TCR recombination was prevented, although these lymphomas were less mature, arose later in life, and, importantly, were dependent upon Notch pathways to upregulate c-myc expression. In contrast, using the complementary methods of early thymectomy and adoptive transfers, we found that PTEN-deficient mature T cells were unable to undergo malignant transformation but were sufficient for the development of autoimmunity. These data suggest multiple and distinct regulatory roles for PTEN in the molecular pathogenesis of lymphoma and autoimmunity. PMID:20516645

Liu, Xiaohe; Karnell, Jodi L; Yin, Bu; Zhang, Ruan; Zhang, Jidong; Li, Peiying; Choi, Yongwon; Maltzman, Jonathan S; Pear, Warren S; Bassing, Craig H; Turka, Laurence A

2010-07-01

350

Response of Murine and Normal Human Skin to Injection of Allogeneic Blood-Derived Psoriatic Immunocytes Detection of T Cells Expressing Receptors Typically Present on Natural Killer Cells, Including CD94, CD158, and CD161  

Microsoft Academic Search

Background: The genetic and immunological basis for psoriasis is unknown. Through the use of a severe com- bined immunodeficient mouse-human skin model, T cells have been shown to induce psoriasis, which points to a pathological role for such immunocompetent cells. Dur- ing ongoing studies using this model, a previously over- looked subset of immunocytes expressing receptors typi- cally present on

Brian J. Nickoloff; Tamara Wrone-Smith; Brian Bonish; Steven A. Porcelli

351

Rictor/mammalian target of rapamycin 2 regulates the development of Notch1 induced murine T-cell acute lymphoblastic leukemia via forkhead box O3.  

PubMed

Mammalian target of rapamycin (mTOR) is composed of two distinct biochemical complexes, mTORC1 and mTORC2. In response to nutrients and growth factors, mTORC1 is known to control cellular growth by regulating the translational regulators S6 kinase 1 and 4E binding protein 1, whereas mTORC2 mediates cell proliferation and survival by activating Akt through phosphorylation at Ser473. Studies have shown that the deregulation of mTORC2 leads to the development of myeloproliferative disorder and leukemia in the phosphatase and tensin homolog deleted on chromosome ten (PTEN)-deleted mouse model. However, the mechanism by which mTORC2 specifically affects leukemogenesis is still not fully understood. Here, we investigated the role of mTORC2 in NOTCH1-driven T-cell acute lymphoblastic leukemia (T-ALL) in a Rictor-deficient mouse model. We found that, by deleting Rictor, an essential component of mTORC2, leukemia progression was significantly suppressed by arresting a greater proportion of Rictor(?/?) leukemic cells at the G0 phase of the cell cycle. Furthermore, the absence of Rictor led to the overexpression of chemotaxis-related genes, such as CCR2, CCR4 and CXCR4, which contributed to the homing and migration of Rictor-deficient T-ALL cells to the spleen but not the bone marrow. In addition, we demonstrated that inactivation of mTORC2 caused the overexpression of forkhead box O3 and its downstream effectors and eased the progression of leukemia in T-ALL mice. Our study thus indicates that forkhead box O3 could be a potential drug target for the treatment of T-ALL leukemia. PMID:25201756

Hua, Chunlan; Guo, Huidong; Bu, Jiachen; Zhou, Mi; Cheng, Hui; He, Fuhong; Wang, Jinhong; Wang, Xiaomin; Zhang, Yinchi; Wang, Qianfei; Zhou, Jianfeng; Cheng, Tao; Xu, Mingjiang; Yuan, Weiping

2014-12-01

352

T-cell exhaustion in allograft rejection and tolerance  

PubMed Central

Purpose of review The role of T-cell exhaustion in the failure of clearance of viral infections and tumors is well established. There are several ongoing trials to reverse T-cell exhaustion for treatment of chronic viral infections and tumors. The mechanisms leading to T-cell exhaustion and its role in transplantation, however, are only beginning to be appreciated and are the focus of the present review. Recent findings Exhausted T cells exhibit a distinct molecular profile reflecting combinatorial mechanisms involving the interaction of multiple transcription factors important in control of cell metabolism, acquisition of effector function and memory capacity. Change of microenvironmental cues and limiting leukocyte recruitment can modulate T-cell exhaustion. Impaired leukocyte recruitment induces T-cell exhaustion and prevents allograft rejection. Summary Preventing or reversing T-cell exhaustion may lead to prevention of transplant tolerance or triggering of rejection; therefore, caution should be exercised in the use of agents blocking inhibitory receptors for the treatment of chronic viral infections or tumors in transplant recipients. Further definition of the role of T-cell exhaustion in clinical transplantation and an understanding of the mechanisms of induction of T-cell exhaustion are needed to develop strategies for preventing allograft rejection and induction of tolerance. PMID:25563990

Thorp, Edward B.; Stehlik, Christian; Ansari, M. Javeed

2015-01-01

353

Reduced IL-7 responsiveness defined by signal transducer and activator of transcription 5 phosphorylation in T cells may be a marker for increased risk of developing cytomegalovirus disease in patients after hematopoietic stem cell transplantation.  

PubMed

Cytomegalovirus (CMV) reactivation may lead to CMV disease associated with high morbidity and mortality in patients after hematopoietic stem cell transplantation (HSCT); the identification of clinically relevant markers may aid in the identification of patients at increased risk for developing CMV-associated complications. We evaluated the phosphorylation of signal transducer and activator of transcription 5 (STAT5) in CD4(+) T cells, CD8(+) T cells, and TCR?? T cells in response to stimulation with IL-7 or IL-2 after HSCT by analyzing blood samples taken monthly 1 to 6 months after HSCT. Patients were monitored weekly with a quantitative PCR from the time of engraftment for CMV viral load in whole blood until at least day 100 after HSCT. We identified a correlation between clinical outcome regarding CMV replication and the ability to respond to IL-7 and IL-2 defined by STAT5 phosphorylation (pSTAT5). Patients with recurrent or prolonged CMV replications had significantly lower pSTAT5 upon stimulation of T cells with either IL-7 or IL-2 at time points 1 through 3 than those without CMV replication (P < .05). This was also found after stimulation of CD8(+) T cells at time point 2 (P < .05). We conclude that reduced responses to IL-7, reflected by pSTAT5, may represent a clinically relevant functional biomarker for individuals at increased risk for CMV reactivation; our data may also aid in designing better strategies to improve anti-CMV immune responses without increasing the risk of developing graft-versus-host disease. PMID:24140122

Pérez-Bercoff, Lena; Vudattu, Nalini K; Byrareddy, Siddappa N; Mattsson, Jonas; Maeurer, Markus; Ljungman, Per

2014-01-01

354

B and T cell screen  

MedlinePLUS

Direct immunofluorescence; E-rosetting; T and B lymphocyte assays; B and T lymphocyte assays ... identifiers are added to distinguish between T and B cells. The E-rosetting test identifies T cells ...

355

Signaling microdomains in T cells.  

PubMed

Sub-micron scale signaling domains induced in the plasma membrane of cells are thought to play important roles in signal transduction. In T cells, agonist MHC-peptide complexes induce small diffraction-limited domains enriched in T cell receptor (TCR) and signaling molecules. These microclusters serve as transient platforms for signal initiation and are required for sustained signaling in T cells, although each microcluster functions for only a couple of minutes. How they are formed, and what mechanisms promote and regulate signaling within TCR microclusters is largely unknown, although it is clear that TCR engagement and dynamic reorganization of cortical actin are involved. Here, we review current understanding of signaling within microclusters in T cells, and speculate on how these structures may form, initiate biochemical signals, and serve as sites of both signal integration and amplification, while also facilitating appropriate termination of TCR and related signaling. PMID:20965175

Choudhuri, Kaushik; Dustin, Michael L

2010-12-15

356

Self-determination in the T cell repertoire.  

PubMed

The number of T cells specific for various antigens can vary dramatically. In this issue of Immunity, Nelson et al. (2015) report that these differences might be, at least in part, set by the number of cross-reactive self peptides encountered by T cells during development. PMID:25607452

Birnbaum, Michael E; Garcia, K Christopher

2015-01-20

357

Shaping and reshaping CD8+ T-cell memory  

Microsoft Academic Search

The ability to develop and sustain populations of memory T cells after infection or immunization is a hallmark of the adaptive immune response and a basis for protective vaccination against infectious disease. Technical advances that allow direct ex vivo identification and characterization of antigen-specific CD8+ T cells at various stages of the response to infection or vaccination in mouse models

Vladimir P. Badovinac; John T. Harty

2008-01-01

358

Regulatory T Cells in Psoriasis  

Microsoft Academic Search

Psoriasis is a chronic autoimmune disease in which T lymphocytes are thought to be central in the pathogenesis. Recently,\\u000a a T cell subset population was identified, whose role is to suppress inflammatory responses triggered by T effector cells.\\u000a T cells in this new population are referred to as T regulatory cells. We studied their number and activity in psoriatic lesions

M. H. Kagen; T. S. McCormick; K. D. Cooper

359

MicroRNA-128-3p is a novel oncomiR targeting PHF6 in T-cell acute lymphoblastic leukemia  

PubMed Central

T-cell acute lymphoblastic leukemia arises from the leukemic transformation of developing thymocytes and results from cooperative genetic lesions. Inactivation of the PHF6 gene is frequently observed in T-cell acute lymphoblastic leukemia, suggesting an important tumor suppressive role for PHF6 in the pathobiology of this leukemia. Although the precise function of PHF6 is still unknown, this gene is most likely involved in chromatin regulation, a strongly emerging theme in T-cell acute lymphoblastic leukemia. In this context, our previous description of a cooperative microRNA regulatory network controlling several well-known T-cell acute lymphoblastic leukemia tumor suppressor genes, including PHF6, is of great importance. Given the high frequency of PHF6 lesions in T-cell acute lymphoblastic leukemia and the integration of PHF6 in this microRNA regulatory network, we aimed to identify novel oncogenic microRNAs in T-cell acute lymphoblastic leukemia which suppress PHF6. To this end, we performed an unbiased PHF6 3?UTR-microRNA library screen and combined the results with microRNA profiling data of samples from patients with T-cell acute lymphoblastic leukemia and normal thymocyte subsets. We selected miR-128-3p as a candidate PHF6-targeting, oncogenic microRNA and demonstrated regulation of PHF6 expression upon modulation of this microRNA in T-cell acute lymphoblastic leukemia cell lines. In vivo evidence of an oncogenic role of this microRNA in T-cell acute lymphoblastic leukemia was obtained through accelerated leukemia onset in a NOTCH1-induced T-cell acute lymphoblastic leukemia mouse model upon miR-128-3p over-expression. We conclude that miR-128-3p is a strong novel candidate oncogenic microRNA in T-cell acute lymphoblastic leukemia which targets the PHF6 tumor suppressor gene. PMID:24895337

Mets, Evelien; Van Peer, Gert; Van der Meulen, Joni; Boice, Michael; Taghon, Tom; Goossens, Steven; Mestdagh, Pieter; Benoit, Yves; De Moerloose, Barbara; Van Roy, Nadine; Poppe, Bruce; Vandesompele, Jo; Wendel, Hans-Guido; Van Vlierberghe, Pieter; Speleman, Frank; Rondou, Pieter

2014-01-01

360

ZFAT plays critical roles in peripheral T cell homeostasis and its T cell receptor-mediated response  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer We generated Cd4-Cre-mediated T cell-specific Zfat-deficient mice. Black-Right-Pointing-Pointer Zfat-deficiency leads to reduction in the number of the peripheral T cells. Black-Right-Pointing-Pointer Impaired T cell receptor-mediated response in Zfat-deficient peripheral T cells. Black-Right-Pointing-Pointer Decreased expression of IL-7R{alpha}, IL-2R{alpha} and IL-2 in Zfat-deficient peripheral T cells. Black-Right-Pointing-Pointer Zfat plays critical roles in peripheral T cell homeostasis. -- Abstract: ZFAT, originally identified as a candidate susceptibility gene for autoimmune thyroid disease, has been reported to be involved in apoptosis, development and primitive hematopoiesis. Zfat is highly expressed in T- and B-cells in the lymphoid tissues, however, its physiological function in the immune system remains totally unknown. Here, we generated the T cell-specific Zfat-deficient mice and demonstrated that Zfat-deficiency leads to a remarkable reduction in the number of the peripheral T cells. Intriguingly, a reduced expression of IL-7R{alpha} and the impaired responsiveness to IL-7 for the survival were observed in the Zfat-deficient T cells. Furthermore, a severe defect in proliferation and increased apoptosis in the Zfat-deficient T cells following T cell receptor (TCR) stimulation was observed with a reduced IL-2R{alpha} expression as well as a reduced IL-2 production. Thus, our findings reveal that Zfat is a critical regulator in peripheral T cell homeostasis and its TCR-mediated response.

Doi, Keiko [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan) [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute of Life Sciences for the Next Generation of Women Scientists, Fukuoka University, Fukuoka (Japan); Fujimoto, Takahiro [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan) [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Okamura, Tadashi [Division of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo (Japan)] [Division of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo (Japan); Ogawa, Masahiro [Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan)] [Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Tanaka, Yoko [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan)] [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Mototani, Yasumasa; Goto, Motohito [Division of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo (Japan)] [Division of Animal Models, Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, Tokyo (Japan); Ota, Takeharu; Matsuzaki, Hiroshi [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan)] [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Kuroki, Masahide [Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan)] [Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Tsunoda, Toshiyuki [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan) [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan); Sasazuki, Takehiko [Institute for Advanced Study, Kyushu University, Fukuoka (Japan)] [Institute for Advanced Study, Kyushu University, Fukuoka (Japan); Shirasawa, Senji, E-mail: sshirasa@fukuoka-u.ac.jp [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan) [Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka (Japan); Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka (Japan)

2012-08-17

361

Attenuation of Peripheral Regulatory T-Cell Suppression of Skin-Homing CD8+T Cells in Atopic Dermatitis  

PubMed Central

Purpose Cutaneous lymphocyte-associated antigen (CLA)-expressing CD8+T cells have been known to play an important role in the pathogenesis of atopic dermatitis (AD). However, the mechanisms underlying the loss of self-tolerance remain unclear. Regulatory T cells (Tregs) play a key role in the development of homeostasis in the immune system. We, therefore, hypothesized that a reduced ability of Tregs to inhibit autologous CD8+CLA+T cells might be underlying mechanism in AD. Materials and Methods CD8+CLA+T cells and Tregs were obtained from the peripheral blood of AD patients and control volunteers. The frequencies of CD8+CLA+T cells were evaluated. The proliferative responses of CD8+CLA+T cells were assessed by flow cytometry, and the levels of transforming growth factor-?1 (TGF-?1) and interleukin-10 (IL-10) in culture supernatants were detected by enzyme-linked immunosorbent assay. Results Our results revealed higher frequency and increased expression of perforin and granzyme-B in peripheral CD8+CLA+T cells in AD, and lower inhibitory ability of Tregs on proliferation of CD8+CLA+T cells in AD. Meanwhile, the levels of TGF-?1 produced by Tregs were significantly lower in AD, and anti-TGF-?1 abolished such suppression. Conclusion The attenuated inhibitory ability of Tregs on hyper-activated autologous CD8+CLA+T cells, mediated by TGF-?1, plays an important role in the pathogenesis of AD. PMID:25510765

Zhang, Bao-Xiang; Lyu, Jun-Cheng; Liu, Hai-Bo; Feng, Dian-Qin; Zhang, Dian-Cai; Bi, Xing-Jie; Duan, Zhi-Wu

2015-01-01

362

The ontogeny of naïve and regulatory CD4+ T-cell subsets during the first postnatal year: a cohort study  

PubMed Central

As there is limited knowledge regarding the longitudinal development and early ontogeny of naïve and regulatory CD4+ T-cell subsets during the first postnatal year, we sought to evaluate the changes in proportion of naïve (thymic and central) and regulatory (resting and activated) CD4+ T-cell populations during the first postnatal year. Blood samples were collected and analyzed at birth, 6 and 12 months of age from a population-derived sample of 130 infants. The proportion of naïve and regulatory CD4+ T-cell populations was determined by flow cytometry, and the thymic and central naïve populations were sorted and their phenotype confirmed by relative expression of T cell-receptor excision circle DNA (TREC). At birth, the majority (94%) of CD4+ T cells were naïve (CD45RA+), and of these, ~80% had a thymic naïve phenotype (CD31+ and high TREC), with the remainder already central naïve cells (CD31? and low TREC). During the first year of life, the naïve CD4+ T cells retained an overall thymic phenotype but decreased steadily. From birth to 6 months of age, the proportion of both resting naïve T regulatory cells (rTreg; CD4+CD45RA+FoxP3+) and activated Treg (aTreg, CD4+CD45RA?FoxP3high) increased markedly. The ratio of thymic to central naïve CD4+ T cells was lower in males throughout the first postnatal year indicating early sexual dimorphism in immune development. This longitudinal study defines proportions of CD4+ T-cell populations during the first year of postnatal life that provide a better understanding of normal immune development.

Collier, Fiona M; Tang, Mimi L K; Martino, David; Saffery, Richard; Carlin, John; Jachno, Kim; Ranganathan, Sarath; Burgner, David; Allen, Katrina J; Vuillermin, Peter; Ponsonby, Anne-Louise

2015-01-01

363

Interleukin-27 in T Cell Immunity  

PubMed Central

Interleukin (IL)-27, a member of IL-12/IL-23 heterodimeric family of cytokines, has pleiotropic properties that can enhance or limit immune responses. IL-27 acts on various cell types, including T cells, B cells, macrophages, dendritic cells, natural killer (NK) cells and non-hematopoietic cells. Intensive studies have been conducted especially on T cells, revealing that various subsets of T cells respond uniquely to IL-27. IL-27 induces expansion of Th1 cells by activating signal transducer and activator of transcription (STAT) 1-mediated T-bet signaling pathway. On the other hand, IL-27 suppresses immune responses through inhibition of the development of T helper (Th) 17 cells and induction of IL-10 production in a STAT1- and STAT3-dependent manner. IL-27 is a potentially promising cytokine for therapeutic approaches on various human diseases. Here, we provide an overview of the biology of IL-27 related to T cell subsets, its structure, and production mechanism. PMID:25633106

Iwasaki, Yukiko; Fujio, Keishi; Okamura, Tomohisa; Yamamoto, Kazuhiko

2015-01-01

364

Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein  

Microsoft Academic Search

Structural similarity between viral T cell epitopes and self-peptides could lead to the induction of an autoaggressive T cell response. Based on the structural requirements for both MHC class 11 binding and TCR recognition of an immunodominant myelin basic protein (MBP) peptide, criteria for a data base search were developed in which the degeneracy of amino acid side chains required

Kai W Wucherpfennig; Jack L Strominger

1995-01-01

365

Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid leukemia undergoing WT1 peptide vaccination following chemotherapy  

PubMed Central

PR1, an HLA-A*0201 epitope shared by proteinase-3 (PR3) and elastase (ELA2) proteins, is expressed in normal neutrophils and overexpressed in myeloid leukemias. PR1-specific T cells have been linked to graft-versus-leukemia (GVL) effect. We hypothesized that lymphopenia induced by chemo-radiotherapy can enhance weak autoimmune responses to self-antigens such as PR1. We measured PR1-specific responses in 27 patients 30–120 days following allogeneic stem cell transplant (SCT) and correlated these with ELA2 and PR3 expression and minimal residual disease (MRD). Post-SCT 10/13 CML, 6/9 ALL, and 4/5 solid tumor patients had PR1 responses correlating with PR3 and ELA2 expression. At day 180 post-SCT, 8/8 CML patients with PR1 responses were BCR-ABL-negative compared with 2/5 BCR-ABL-positive patients (P = 0.025). In contrast, PR1 responses were detected in 2/4 MRD-negative compared with 4/5 MRD-positive ALL patients (P = 0.76). To assess whether the lymphopenic milieu also exaggerates weak T-cell responses in the autologous setting, we measured spontaneous induction of PR1 responses in 3 AML patients vaccinated with WT1-126 peptide following lymphodepletion. In addition to WT1-specific T cells, we detected PR1-specific T cells in 2 patients during hematopoietic recovery. Our findings suggest that lymphopenia induced by chemo-radiotherapy enhances weak autoimmune responses to self-antigens, which may result in GVL if the leukemia expresses the relevant self-antigen. PMID:22198310

Rezvani, Katayoun; Yong, Agnes S. M.; Mielke, Stephan; Savani, Bipin N.; Jafarpour, Behnam; Eniafe, Rhoda; Le, Robert Quan; Musse, Laura; Boss, Carole; Childs, Richard; Barrett, A. John

2014-01-01

366

PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine.  

PubMed

We have developed a cancer vaccine in which autologous tumor is fused with dendritic cells (DCs) resulting in the presentation of tumor antigens in the context of DC-mediated costimulation. In clinical trials, immunologic responses have been observed, however responses may be muted by inhibitory pathways. The PD1/PDL1 pathway is an important element contributing to tumor-mediated immune suppression. In this study, we demonstrate that myeloma cells and DC/tumor fusions strongly express PD-L1. Compared with a control population of normal volunteers, increased PD-1 expression was observed on T cells isolated from patients with myeloma. It is interesting to note that after autologous transplantation, T-cell expression of PD-1 returned to levels seen in normal controls. We examined the effect of PD-1 blockade on T-cell response to DC/tumor fusions ex vivo. Presence of CT-011, an anti-PD1 antibody, promoted the vaccine-induced T-cell polarization towards an activated phenotype expressing Th1 compared with Th2 cytokines. A concomitant decrease in regulatory T cells and enhanced killing in a cytotoxicity assay was observed. In summary, we demonstrate that PD-1 expression is increased in T cells of patients with active myeloma, and that CT-011 enhances activated T-cell responses after DC/tumor fusion stimulation. PMID:21577144

Rosenblatt, Jacalyn; Glotzbecker, Brett; Mills, Heidi; Vasir, Baldev; Tzachanis, Dimitrios; Levine, James D; Joyce, Robin M; Wellenstein, Kerry; Keefe, Whitney; Schickler, Michael; Rotem-Yehudar, Rinat; Kufe, Donald; Avigan, David

2011-06-01

367