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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

T Cells Develop Normally in the Absence of both Deltex1 and Deltex2  

Microsoft Academic Search

The cells of the mammalian immune system are continu- ously generated throughout life. Among these cells, T and B lymphocytes form the adaptive immune system (for general reviews, see references 1 and 68). T and B lymphocytes express antigen receptors that are generated by random rearrange- ment of the genes encoding the B-cell receptor (or immuno- globulin) or T-cell receptor

Sophie M. Lehar; Michael J. Bevan

2006-01-01

3

Role of gammadelta T cells in protecting normal airway function  

PubMed Central

Since their discovery 15 years ago, the role of ?? T cells has remained somewhat elusive. Responses of ?? T cells have been found in numerous infectious and non-infectious diseases. New evidence points to ?? T cells' functioning in the airways to maintain normal airway responsiveness or tone. In the lung, distinct subsets of ?? T cell subsets seem to have specific roles, one subset promoting allergic inflammation, the other serving a protective role. PMID:11667979

Born, Willi K; Lahn, Michael; Takeda, Katsuyuki; Kanehiro, Arihiko; O'Brien, Rebecca L; Gelfand, Erwin W

2000-01-01

4

Receptor editing in developing T cells  

Microsoft Academic Search

A central tenet of T cell development postulates that if a developing thymocyte encounters self-antigen, it is induced to die via apoptosis, thereby protecting the organism from autoreactive T cells. We created transgenic mice that expressed a peptide antigen in the cortical epithelial cells of the thymus. This did not, however, result in deletion of specific T cells. Instead, antigen

Maureen A. McGargill; Jens M. Derbinski; Kristin A. Hogquist

2000-01-01

5

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

6

Molecular Mechanisms of Regulatory T Cell Development  

Microsoft Academic Search

Background  CD4+CD25+ natural regulatory T (nTR) lymphocytes represent a distinct thymus-derived T cell lineage that serves to establish immunological tolerance in the periphery.\\u000a The discovery of Foxp3 as a transcription factor essential to the differentiation of CD4+CD25+ TR cells enabled detailed studies into the molecular mechanisms of TR cell development, peripheral homeostasis, and effector functions.\\u000a \\u000a \\u000a \\u000a Discussion  Comparative analysis of Foxp3+ nTR cells

Talal Chatila

2008-01-01

7

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

8

T cell immunosurveillance controls B lymphoma development  

PubMed Central

We recently showed a critical role for T cells in the immunosurveillance of nascent B cell lymphomas arising from mutations impacting plasma cell differentiation. Our data suggest that CD8+ T cells continuously eliminate mutated B cells that fail to downregulate their co-stimulatory machinery and the Fas death receptor, thus constraining B lymphoma pathogenesis. PMID:25050223

Kallies, Axel

2014-01-01

9

Harnessing CD4? T cell responses in HIV vaccine development.  

PubMed

CD4(+) T cells can perform a panoply of tasks to shape an effective response against a pathogen. Limited attention has been paid to the potential importance of functional CD4(+) T cell responses in the context of the development of next-generation vaccines, including HIV vaccines. Many CD4(+) T cell functions are newly appreciated and only partially understood. A workshop was held as a forum to bring together a small group of experts to exchange ideas on the role of CD4(+) T cells in developing durable functional antibody responses, via follicular helper T cells, as well as on the roles of CD4(+) T cells in other aspects of protective immunity. Here we discuss whether CD4(+) T cell responses may represent a beneficial component of an efficacious HIV vaccine. PMID:23389614

Streeck, Hendrik; D'Souza, M Patricia; Littman, Dan R; Crotty, Shane

2013-02-01

10

Harnessing CD4+ T cell responses in HIV vaccine development  

PubMed Central

CD4+ T cells can perform a panoply of tasks to shape an effective response against a pathogen. Limited attention has been paid to the potential importance of functional CD4+ T cell responses in the context of the development of next-generation vaccines, including HIV vaccines. Many CD4+ T cell functions are newly appreciated and only partially understood. A workshop was held as a forum to bring together a small group of experts to exchange ideas on the role of CD4+ T cells in developing durable functional antibody responses, via follicular helper T cells, as well as on the roles of CD4+ T cells in other aspects of protective immunity. Here we discuss whether CD4+ T cell responses may represent a beneficial component of an efficacious HIV vaccine. PMID:23389614

Streeck, Hendrik; D’Souza, M Patricia; Littman, Dan R; Crotty, Shane

2013-01-01

11

Early TCR Expression and Aberrant T Cell Development in Mice with Endogenous Prerearranged T Cell Receptor Genes1  

Microsoft Academic Search

The factors that regulate the rate of production of T cells by the thymus remain incompletely defined. To test whether generation of functional T cell receptors limits the rate of thymic T cell export, we made use of a line of mice, LN3, that have endogenously prerearranged TCR genes. The prerearranged TCR genes were expressed abnormally early in hemopoietic development,

Thomas Serwold; Konrad Hochedlinger; Matthew A. Inlay; Rudolf Jaenisch; Irving L. Weissman

12

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

13

The Development and Function of Regulatory T Cells  

PubMed Central

Regulatory T cells [Tregs] are a critical subset of T cells that mediate peripheral tolerance. There are two types of Tregs: natural Tregs, which develop in the thymus, and induced Tregs, which are derived from naïve CD4+ T cells in the periphery. Tregs utilize a variety of mechanisms to suppress the immune response. While Tregs are critical for the peripheral maintenance of potential autoreactive T cells, they can also be detrimental by preventing effective anti-tumor responses and sterilizing immunity against pathogens. In this review, we will discuss the development of natural and induced Tregs as well as the role of Tregs in a variety of disease settings and the mechanisms they utilize for suppression. PMID:19390784

Workman, Creg J.; Szymczak-Workman, Andrea L.; Collison, Lauren W.; Pillai, Meenu R.; Vignali, Dario A.A.

2009-01-01

14

The role of programming in memory T-cell development  

Microsoft Academic Search

Recent studies suggest that memory T-cell differentiation continues for weeks or months following antigen clearance, although commitment to the memory lineage occurs during the effector stage of development. Several variables associated with priming, such as the duration of antigenic stimulation, degree of co-stimulation, cytokine environment, and CD4+ T-cell help, may program epigenetic qualitative differences into the ensuing effector and memory

David Masopust; Susan M Kaech; E John Wherry; Rafi Ahmed

2004-01-01

15

Inhibition of T cell activation by normal human biliary epithelial cells  

Microsoft Academic Search

Background\\/Aims: Human intrahepatic biliary epithelial cells can express immune recognition elements and are targets for immune attack in several liver pathologies. The aim of this study was to investigate the ability of biliary epithelial cells to act as accessory cells for T cell activation in normal and inflammatory conditions.Methods: Normal biliary epithelial cells were cocultured with allogeneic unstimulated and mitogen-

Sheena M Cruickshank; Jennifer Southgate; Peter J Selby; Ludwik K Trejdosiewicz

1999-01-01

16

Normal T cell homeostasis: the conversion of na?ve cells into memory-phenotype cells  

PubMed Central

Covert TCR signals from contact with self-ligands synergize with IL-7-induced anti-apoptotic signals to promote survival of naïve T cells in a resting state. The level of background TCR signaling in naïve T cells is set by post-thymic TCR tuning and operates at an intensity just below that required to induce entry into cell-cycle. Co-stimulation from raised levels of IL-7 and other ?c cytokines can induce T cells to undergo “homeostatic” proliferation and conversion into cells with the phenotype of memory cells; many of these memory-phenotype (MP) cells may be the progeny of cells responding to self-antigens. The molecular mechanisms that control TCR/?c cytokine-driven conversion of naïve resting T cells into MP cells in normal animals are beginning to be understood. PMID:21739670

Sprent, Jonathan; Surh, Charles D

2012-01-01

17

Jurkat T cells and development of the T-cell receptor signalling paradigm  

Microsoft Academic Search

Twenty years of investigation have yielded a detailed view of the signalling machinery engaged by T-cell receptors (TCRs). Many of the fundamental insights into TCR signalling came from studies carried out with transformed T-cell lines. Perhaps the best known of these model systems is the Jurkat leukaemic T-cell line, and here we review some of the key advances in the

Arthur Weiss; Robert T. Abraham

2004-01-01

18

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

19

?? T cells restrain extrathymic development of Foxp3+-inducible regulatory T cells via IFN-?.  

PubMed

Inducible Treg (iTreg) cells generated from Ag-stimulated naïve CD4(+) T cells in the periphery play an important role in regulating immune responses. TGF-? is a key cytokine that promotes this conversion process; however, how this process is regulated in vivo remains unclear. Here, we report that ?? T cells play a crucial role in controlling iTreg generation and suppressor function. Ag-induced iTreg generation was significantly enhanced in C57BL/6 mice in the absence of ?? T cells. Inhibition of iTreg conversion was mediated by IFN-? produced by activated ?? T cells but not by activated CD4(+) T cells. BM chimera experiments further confirmed ??-derived IFN-?-dependent mechanism in regulating iTreg generation in vivo. Lastly, human peripheral blood ?? T cells also interfere with iTreg conversion via IFN-?. Our results suggest a novel function of ?? T cells in limiting the generation of iTreg cells, potentially balancing immunity and tolerance. PMID:24799116

Visperas, Anabelle; Shen, Bo; Min, Booki

2014-08-01

20

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

21

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

22

??T cells regulate chronic airway inflammation and development of airway remodelling  

PubMed Central

Background ??T cells play a crucial immunoregulatory role in the lung, maintaining normal airway tone and preventing hyperresponsiveness to innocuous allergen. During acute inflammatory episodes, ??T cells promote resolution of acute inflammation. However, their contribution to inflammation-associated airway remodelling remains unexplored. Here we investigate the effects of ??T cell blockade on established allergic airway inflammation and development of remodelling. Methods Sensitised mice were exposed to prolonged ovalbumin challenge or continuous house-dust mite exposure to induce chronic inflammation and remodelling. Functional blocking anti-TCR? antibody was administered therapeutically, and parameters of airway inflammation and remodelling were examined. Results Therapeutic blockade of ??T cells prevented the typical resolution of acute airway inflammation characterised by elevated eosinophil and Th2 cell numbers. Moreover, the lung displayed exacerbated airway remodelling, typified by excess peribronchiolar collagen deposition. Conclusions These results demonstrate a unique role for ??T cells in constraining allergen-induced airway remodelling. Manipulating the ??T cell compartment may therefore contribute to strategies to prevent and treat remodelling. PMID:25146585

Murdoch, J R; Gregory, L G; Lloyd, C M

2014-01-01

23

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

24

Mechanism of IL10Induced T Cell Inactivation in Allergic Inflammation and Normal Response to Allergens  

Microsoft Academic Search

Background: Induction of specific unresponsiveness (tolerance\\/anergy) in peripheral T cells and recovery by cytokines from the tissue microenvironment represent two key steps in specific immunotherapy (SIT) with whole allergen or antigenic T cell peptides. Methods: Antigen-specific T cell responses and molecular mechanisms of T cell inactivation were investigated during conventional SIT, T cell epitope peptide immunotherapy and natural exposure to

Cezmi A. Akdis; Andrea Joss; Mübeccel Akdis; Kurt Blaser

2001-01-01

25

The microRNA Biogenesis Machinery Modulates Lineage Commitment during ?? T Cell Development.  

PubMed

Differentiation of CD4(+) helper and CD8(+) cytotoxic ?? T cells from CD4(+)CD8(+) thymocytes involves upregulation of lineage-specifying transcription factors and transcriptional silencing of CD8 or CD4 coreceptors, respectively, in MHC class II or I (MHCII or I)-restricted thymocytes. In this study, we demonstrate that inactivation of the Dicer RNA endonuclease in murine thymocytes impairs initiation of Cd4 and Cd8 silencing, leading to development of positively selected MHCI- and MHCII-restricted mature CD4(+)CD8(+) thymocytes. Expression of the antiapoptotic BCL2 protein or inactivation of the p53 proapoptotic protein rescues these thymocytes from apoptosis, increasing their frequency and permitting accumulation of CD4(+)CD8(+) ?? T cells in the periphery. Dicer-deficient MHCI-restricted ?? T cells fail to normally silence Cd4 and display impaired induction of the CD8 lineage-specifying transcription factor Runx3, whereas Dicer-deficient MHCII-restricted ?? T cells show impaired Cd8 silencing and impaired induction of the CD4 lineage-specifying transcription factor Thpok. Finally, we show that the Drosha RNA endonuclease, which functions upstream of Dicer in microRNA biogenesis, also regulates Cd4 and Cd8 silencing. Our data demonstrate a previously dismissed function for the microRNA biogenesis machinery in regulating expression of lineage-specifying transcription factors and silencing of Cd4 and Cd8 during ?? T cell differentiation. PMID:25217159

Rupp, Levi J; Brady, Brenna L; Carpenter, Andrea C; De Obaldia, Maria Elena; Bhandoola, Avinash; Bosselut, Remy; Muljo, Stefan A; Bassing, Craig H

2014-10-15

26

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

27

Restoration of T Cell Development in RAG2Deficient Mice by Functional TCR Transgenes  

Microsoft Academic Search

Introduction of TCRalpha transgene, TCRbeta transgene, or both into RAG-2-\\/- mice differentially rescues T cell development. RAG-2-\\/- mice have small numbers of TCR^-CD4^-CD8^- (double negative, DN) thymocytes that express CD3gammadelta? and zeta proteins intracellularly. Introduction of a TCRbeta transgene, but not a TCRalpha transgene, into the RAG-2-\\/- background restored normal numbers of thymocytes. These cells were CD4^+CD8^+ (double positive, DP)

Yoichi Shinkai; Shigeo Koyasu; Kei-Ichi Nakayama; Kenneth M. Murphy; Dennis Y. Loh; Ellis L. Reinherz; Frederick W. Alt

1993-01-01

28

An epigenetic profile of early T-cell development from multipotent progenitors to committed T-cell descendants.  

PubMed

Cellular differentiation of the T-cell branch of the immune system begins with the HSC, which undergoes a series of stages characterized by progressive restriction in multipotency and acquisition of specific lineage identity At the molecular level, the restriction of cell potential, commitment, and differentiation to a specific lineage is achieved through the coordinated control of gene expression and epigenetic mechanisms. Here, we analyzed and compared the gene expression profiles and the genome-wide histone modification marks H3K4me3 (H3 lysine 4 trimethylation) and H3K27me3 (H3 lysine 27 trimethylation) in (i) in vitro propagated HSCs, (ii) in vitro generated and propagated pro-T cells derived from these stem cells, and (iii) double-positive thymocytes derived from these pro-T cells after injection into Rag-deficient mice. The combined analyses of the different datasets in this unique experimental system highlighted the importance of both transcriptional and epigenetic repression in shaping the early phases of T-cell development. PMID:24374622

Vigano, Maria Alessandra; Ivanek, Robert; Balwierz, Piotr; Berninger, Philipp; van Nimwegen, Erik; Karjalainen, Klaus; Rolink, Antonius

2014-04-01

29

The Development, Activation, Function and Mechanisms of Immunosuppressive Double Negative (DN) T Cells  

Microsoft Academic Search

Double negative (DN) T cells are a subset of T cells, present in the peripheral lymphatic organs and blood in very low numbers\\u000a (1–2% of lymphocytes) in mice and humans. DN T cells have been shown to inhibit transplant rejection, lymphoma development\\u000a and graft versus host disease. Furthermore, recent studies have suggested that DN T cells may play a role

Megan S. Ford; Li Zhang

30

Critical Roles of Lysosomal Acid Lipase in T Cell Development and Function  

PubMed Central

Lysosomal acid lipase (LAL) cleaves cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in lysosomes. In LAL gene-knockout (lal?/?) mice, blockage of cholesteryl ester and triglyceride metabolism led to abnormal organization of the thymus and spleen, as well as neutral lipid accumulation in these organs. LAL deficiency impaired T cell development in the thymus. Peripheral T cells were reduced dramatically in lal?/? mice, due largely to increased apoptosis and decreased proliferation of lal?/? T cells in the thymus and peripheral compartments. These lal?/? T cells lost the ability to respond to T cell receptor stimulation, including reduced expression of cell surface receptor CD69, abolishment of T cell proliferation, and decreased expression of T lymphokines after stimulation by either anti-CD3 plus anti-CD28 or phorbol-12-myristate-13-acetate and ionomycin. Differentiation of Th1 and Th2 CD4+ effector lymphocytes by T cell receptor stimulation was blocked in lal?/? mice. The ratio of CD4+CD25+FoxP3+ Tregs to CD4+ T cells was increased in lal?/? spleens. Bone marrow chimeras demonstrated retardation of T cell development and maturation in lal?/? mice due to defects in T cell precursors. Therefore, LAL, its downstream genes, and lipid mediators all play essential roles in development, homeostasis, and function of T cells. The altered development and function of lal?/? T cells contributes to disease formation in various organs during LAL deficiency. PMID:19179613

Qu, Peng; Du, Hong; Wilkes, David S.; Yan, Cong

2009-01-01

31

Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusions compared to normal pleural fluid  

PubMed Central

Background Malignant pleural effusions (MPE) are a common and fatal complication in cancers including lung or breast cancers, or malignant pleural mesothelioma (MPM). MPE animal models and immunotherapy trials in MPM patients previously suggested defects of the cellular immunity in MPE. However only few observational studies of the immune response were done in MPM patients, using questionable control groups (transudate…). Methods We compared T cell populations evaluated by flow cytometry from blood and pleural effusion of untreated patients with MPM (n?=?58), pleural metastasis of adenocarcinoma (n?=?30) or with benign pleural lesions associated with asbestos exposure (n?=?23). Blood and pleural fluid were also obtained from healthy subjects, providing normal values for T cell populations. Results Blood CD4+ or CD8+ T cells percentages were similar in all groups of patients or healthy subjects. Whereas pleural fluid from healthy controls contained mainly CD8+ T cells, benign or malignant pleural effusions included mainly CD4+ T cells. Effector memory T cells were the main T cell subpopulation in pleural fluid from healthy subjects. In contrast, there was a striking and selective recruitment of central memory CD4+ T cells in MPE, but not of effector cells CD8+ T cells or NK cells in the pleural fluid as one would expect in order to obtain an efficient immune response. Conclusions Comparing for the first time MPE to pleural fluid from healthy subjects, we found a local defect in recruiting effector CD8+ T cells, which may be involved in the escape of tumor cells from immune response. Further studies are needed to characterize which subtypes of effector CD8+ T cells are involved, opening prospects for cell therapy in MPE and MPM. PMID:23816056

2013-01-01

32

Type 1 Diabetes Development Requires Both CD4+ and CD8+ T cells and Can Be Reversed by Non-Depleting Antibodies Targeting Both T Cell Populations  

PubMed Central

Type 1 diabetes development in NOD mice appears to require both CD4+ and CD8+ T cells. However, there are some situations where it has been suggested that either CD4+ or CD8+ T cells are able to mediate diabetes in the absence of the other population. In the case of transgenic mice, this may reflect the numbers of antigen-specific T cells able to access the pancreas and recruit other cell types such as macrophages leading to a release of high concentrations of damaging cytokines. Previous studies examining the requirement for CD8+ T cells have used antibodies specific for CD8?. It is known that CD8? is expressed not only on ?? T cells, but also on other cell types, including a DC population that may be critical for presenting islet antigen in the pancreatic draining lymph nodes. Therefore, we have re-examined the need for both CD4+ and CD8+ T cell populations in diabetes development in NOD mice using an antibody to CD8?. Our studies indicate that by using highly purified populations of T cells and antibodies specific for CD8+ T cells, there is indeed a need for both cell types. In accordance with some other reports, we found that CD4+ T cells appeared to be able to access the pancreas more readily than CD8+ T cells. Despite the ability of CD4+ T cells to recruit CD11b class II positive cells, diabetes did not develop in the absence of CD8+ T cells. These studies support the observation that CD8+ T cells may be final effector cells. As both T cell populations are clearly implicated in diabetes development, we have used a combination of non-depleting antibodies to target both CD4-positive and CD8-positive cells and found that this antibody combination was able to reverse diabetes onset in NOD mice as effectively as anti-CD3 antibodies. PMID:19806239

Phillips, Jenny M.; Parish, Nicole M.; Raine, Tim; Bland, Chris; Sawyer, Yvonne; De La Pena, Hugo; Cooke, Anne

2009-01-01

33

Osteopetrotic ( op\\/ op) Mice Deficient in Macrophages Have the Ability to Mount a Normal T-Cell-Dependent Immune Response  

Microsoft Academic Search

The osteopetrotic (op\\/op) mouse possesses an inactivating mutation in the CSF-1 gene that is associated with a lack of certain mononuclear phagocyte populations. To examine the effects of these deficiencies on T-cell-dependent immune functions, the responses of op\\/ op and normal mice to a T-cell-dependent antigen, ovalbumin, and to a foreign histocompatibility antigen were compared. The ability of op\\/op mice

Ming-Der Y. Chang; E. Richard Stanley; Houman Khalili; Orin Chisholm; Jeffrey W. Pollard

1995-01-01

34

The role of LAT-PLC?1 interaction in ?? T cell development and homeostasis.  

PubMed

LAT is a transmembrane adaptor protein that is vital for integrating TCR-mediated signals to modulate T cell development, activation, and proliferation. Upon T cell activation, LAT is phosphorylated and associates with Grb2, Gads, and PLC?1 through its four distal tyrosine residues. Mutation of one of these tyrosines, Y136, abolishes LAT binding to PLC?1. This results in impaired TCR-mediated calcium mobilization and Erk activation. CD4 ?? T cells in LATY136F knock-in mice undergo uncontrolled expansion, resulting in a severe autoimmune syndrome. In this study, we investigated the importance of the LAT-PLC?1 interaction in ?? T cells by crossing LATY136F mice with TCR?(-/-) mice. Our data showed that the LATY136F mutation had no major effect on homeostasis of epithelial ?? T cells, which could be found in the skin and small intestine. Interestingly, a population of CD4(+) ?? T cells in the spleen and lymph nodes underwent continuous expansion and produced elevated amounts of IL-4, resulting in an autoimmune syndrome similar to that caused by ?? T cells in LATY136F mice. Development of these hyperproliferative ?? T cells was not dependent on MHC class II expression or CD4, and their proliferation could be suppressed, in part, by regulatory T cells. Our data indicated that a unique subset of CD4 ?? T cells can hyperproliferate in LATY136F mice and suggested that LAT-PLC?1 signaling may function differently in various subsets of ?? T cells. PMID:24523509

Sullivan, Sarah A; Zhu, Minghua; Bao, Steven; Lewis, Catherine A; Ou-Yang, Chih-wen; Zhang, Weiguo

2014-03-15

35

Thyrotrophin receptor-specific memory T cell responses require normal B cells in a murine model of Graves' disease.  

PubMed

The role of B cells as antigen-presenting cells is being recognized increasingly in immune responses to infections and autoimmunity. We compared T cell responses in wild-type and B cell-deficient mice immunized with the thyrotrophin receptor (TSHR), the major autoantigen in Graves' disease. Three B cell-deficient mouse strains were studied: JHD (no B cells), mIgM (membrane-bound monoclonal IgM+ B cells) and (m + s)IgM (membrane-bound and secreted monoclonal IgM). Wild-type and B cell-deficient mice (BALB/c background) were studied 8 weeks after three injections of TSHR or control adenovirus. Only wild-type mice developed IgG class TSHR antibodies and hyperthyroidism. After challenge with TSHR antigen, splenocyte cultures were tested for cytokine production. Splenocytes from TSHR adenovirus injected wild-type and mIgM-mice, but not from JHD- or (m + s)IgM- mice, produced interferon (IFN)-gamma in response to TSHR protein. Concanavalin A and pokeweed mitogen induced comparable IFN-gamma secretion in all groups of mice except in the JHD strain in which responses were reduced. The absence in (m + s)IgM mice and presence in mIgM mice of an anamnestic response to TSHR antigen was unrelated to lymphoid cell types. Surprisingly, although TSHR-specific antibodies were undetectable, low levels of serum IgG were present in mIgM- but not (m + s)IgM mice. Moreover, IFN-gamma production by antigen-stimulated splenocytes correlated with IgG levels. In conclusion, T cell responses to TSHR antigen developed only in mice with IgG-secreting B cells. Consequently, in the TSHR-adenovirus model of Graves' disease, some normal B cells appear to be required for the development of memory T cells. PMID:14632743

Pichurin, P; Aliesky, H; Chen, C-R; Nagayama, Y; Rapoport, B; McLachlan, S M

2003-12-01

36

Thyrotrophin receptor-specific memory T cell responses require normal B cells in a murine model of Graves's disease  

PubMed Central

The role of B cells as antigen-presenting cells is being recognized increasingly in immune responses to infections and autoimmunity. We compared T cell responses in wild-type and B cell-deficient mice immunized with the thyrotrophin receptor (TSHR), the major autoantigen in Graves' disease. Three B cell-deficient mouse strains were studied: JHD (no B cells), mIgM (membrane-bound monoclonal IgM+ B cells) and (m + s)IgM (membrane-bound and secreted monoclonal IgM). Wild-type and B cell-deficient mice (BALB/c background) were studied 8 weeks after three injections of TSHR or control adenovirus. Only wild-type mice developed IgG class TSHR antibodies and hyperthyroidism. After challenge with TSHR antigen, splenocyte cultures were tested for cytokine production. Splenocytes from TSHR adenovirus injected wild-type and mIgM-mice, but not from JHD- or (m + s)IgM- mice, produced interferon (IFN)-? in response to TSHR protein. Concanavalin A and pokeweed mitogen induced comparable IFN-? secretion in all groups of mice except in the JHD strain in which responses were reduced. The absence in (m + s)IgM mice and presence in mIgM mice of an anamnestic response to TSHR antigen was unrelated to lymphoid cell types. Surprisingly, although TSHR-specific antibodies were undetectable, low levels of serum IgG were present in mIgM- but not (m + s)IgM mice. Moreover, IFN-? production by antigen-stimulated splenocytes correlated with IgG levels. In conclusion, T cell responses to TSHR antigen developed only in mice with IgG-secreting B cells. Consequently, in the TSHR–adenovirus model of Graves' disease, some normal B cells appear to be required for the development of memory T cells. PMID:14632743

PICHURIN, P; ALIESKY, H; CHEN, C-R; NAGAYAMA, Y; RAPOPORT, B; MCLACHLAN, S M

2003-01-01

37

Effect of reduced EPHB4 expression in thymic epithelial cells on thymocyte development and peripheral T cell function.  

PubMed

The Eph kinase (EPH) and ephrin (EFN) families are involved in a broad range of developmental processes. Increasing evidence is demonstrating the important roles of EPHBs and EphrinBs in the immune system. In this study on epithelial cell-specific Ephb4 knockout (KO) mice, we investigated T-cell development and function after EPHB4 deletion. KO mice presented normal thymic weight and cellularity. Their thymocyte subpopulation percentages were in the normal range. KO mice had normal T-cell numbers and percentages in the spleen, and T cells were activated and proliferated normally upon TCR ligation. Furthermore, naïve spleen CD4 cells from KO and wild type mice were capable of differentiating, in a comparable manner, into Th1, Th17 and Treg cells. In vivo, KO mice mounted effective delayed type hypersensitivity responses, indicating that thymocytes develop normally in the absence of TEC EPHB4, and T cells derived from EPHB4-deleted thymic epithelian cells (TEC) have normal function. Our data suggest that heavy redundancy and promiscuous interaction between EPHs and EFNs compensate for the missing EPHB4 in TECs, and TEC EPHB4's role in T cell development might only be revealed if multiple EPHs are ablated simultaneously. We cannot exclude the possibility that (1) some immunological parameters not examined in this study are affected by the deletion; (2) the deletion is not complete due to the leaky Cre-LoxP system, and the remaining EPHB4 in TEC is sufficient for thymocyte development; or (3) EPHB4 expression in TEC is not required for T cell development and function. PMID:24246266

Jin, Wei; Luo, Hongyu; Wu, Jiangping

2014-03-01

38

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.

39

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...

40

Evidence for a stepwise program of extrathymic T cell development within the human tonsil.  

PubMed

The development of a broad repertoire of T cells, which is essential for effective immune function, occurs in the thymus. Although some data suggest that T cell development can occur extrathymically, many researchers remain skeptical that extrathymic T cell development has an important role in generating the T cell repertoire in healthy individuals. However, it may be important in the setting of poor thymic function or congenital deficit and in the context of autoimmunity, cancer, or regenerative medicine. Here, we report evidence that a stepwise program of T cell development occurs within the human tonsil. We identified 5 tonsillar T cell developmental intermediates: (a) CD34?CD38dimLin? cells, which resemble multipotent progenitors in the bone marrow and thymus; (b) more mature CD34?CD38brightLin? cells; (c) CD34?CD1a?CD11c? cells, which resemble committed T cell lineage precursors in the thymus; (d) CD34?CD1a?CD3?CD11c? cells, which resemble CD4?CD8? double-positive T cells in the thymus; and (e) CD34?CD1a?CD3?CD11c? cells. The phenotype of each subset closely resembled that of its thymic counterpart. The last 4 populations expressed RAG1 and PTCRA, genes required for TCR rearrangement, and all 5 subsets were capable of ex vivo T cell differentiation. TdT? cells found within the tonsillar fibrous scaffold expressed CD34 and/or CD1a, indicating that this distinct anatomic region contributes to pre-T cell development, as does the subcapsular region of the thymus. Thus, we provide evidence of a role for the human tonsil in a comprehensive program of extrathymic T cell development. PMID:22378041

McClory, Susan; Hughes, Tiffany; Freud, Aharon G; Briercheck, Edward L; Martin, Chelsea; Trimboli, Anthony J; Yu, Jianhua; Zhang, Xiaoli; Leone, Gustavo; Nuovo, Gerard; Caligiuri, Michael A

2012-04-01

41

Evidence for a stepwise program of extrathymic T cell development within the human tonsil  

PubMed Central

The development of a broad repertoire of T cells, which is essential for effective immune function, occurs in the thymus. Although some data suggest that T cell development can occur extrathymically, many researchers remain skeptical that extrathymic T cell development has an important role in generating the T cell repertoire in healthy individuals. However, it may be important in the setting of poor thymic function or congenital deficit and in the context of autoimmunity, cancer, or regenerative medicine. Here, we report evidence that a stepwise program of T cell development occurs within the human tonsil. We identified 5 tonsillar T cell developmental intermediates: (a) CD34+CD38dimLin– cells, which resemble multipotent progenitors in the bone marrow and thymus; (b) more mature CD34+CD38brightLin– cells; (c) CD34+CD1a+CD11c– cells, which resemble committed T cell lineage precursors in the thymus; (d) CD34–CD1a+CD3–CD11c– cells, which resemble CD4+CD8+ double-positive T cells in the thymus; and (e) CD34–CD1a+CD3+CD11c– cells. The phenotype of each subset closely resembled that of its thymic counterpart. The last 4 populations expressed RAG1 and PTCRA, genes required for TCR rearrangement, and all 5 subsets were capable of ex vivo T cell differentiation. TdT+ cells found within the tonsillar fibrous scaffold expressed CD34 and/or CD1a, indicating that this distinct anatomic region contributes to pre–T cell development, as does the subcapsular region of the thymus. Thus, we provide evidence of a role for the human tonsil in a comprehensive program of extrathymic T cell development. PMID:22378041

McClory, Susan; Hughes, Tiffany; Freud, Aharon G.; Briercheck, Edward L.; Martin, Chelsea; Trimboli, Anthony J.; Yu, Jianhua; Zhang, Xiaoli; Leone, Gustavo; Nuovo, Gerard; Caligiuri, Michael A.

2012-01-01

42

Influence of time and number of antigen encounters on memory CD8 T cell development.  

PubMed

CD8 T cells are an important part of the adaptive immune system providing protection against intracellular bacteria, viruses, and protozoa. After infection and/or vaccination, increased numbers of antigen-specific CD8 T cells remain as a memory population that is capable of responding and providing enhanced protection during reinfection. Experimental studies indicate that while memory CD8 T cells can be maintained for great lengths of time, their properties change with time after infection and/or vaccination. However, the full scope of these changes and what effects they have on memory CD8 T cell function remain unknown. In addition, memory CD8 T cells can encounter antigen multiple times through either reinfection or prime-boost vaccine strategies designed to increase numbers of protective memory CD8 T cells. Importantly, recent studies suggest that memory CD8 T cell development following infection and/or vaccination is influenced by the number of times they have encountered cognate antigen. Since protection offered by memory CD8 T cells in response to infection depends on both the numbers and quality (functional characteristics) at the time of pathogen re-encounter, a thorough understanding of how time and antigen stimulation history impacts memory CD8 T cell properties is critical for the design of vaccines aimed at establishing populations of long-lived, protective memory CD8 T cells. PMID:24825776

Martin, Matthew D; Badovinac, Vladimir P

2014-08-01

43

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

44

MUC1 (CD227) interacts with lck tyrosine kinase in Jurkat lymphoma cells and normal T cells.  

PubMed

MUC1 (CD227) is a large transmembrane epithelial mucin glycoprotein, which is aberrantly overexpressed in most adenocarcinomas and is a target for immune therapy for epithelial tumors. Recently, MUC1 has been detected in a variety of hematopoietic cell malignancies including T and B cell lymphomas and myelomas; however, its function in these cells is not clearly defined. Using the Jurkat T cell lymphoma cell line and normal human T cells, we demonstrate that MUC1 is not only expressed in these cells but is also phosphorylated upon T cell receptor (TCR) ligation and associates with the Src-related T cell tyrosine kinase, p56lck. Upon TCR-mediated activation of Jurkat cells, MUC1 is found in the low-density membrane fractions, where linker of T cell activation is contained. Abrogation of MUC1 expression in Jurkat cells by MUC1-specific small interfering RNA resulted in defects in TCR-mediated downstream signaling events associated with T cell activation. These include reduction in Ca2+ influx and extracellular signal-regulated kinase 1/2 phosphorylation, leading to a decrease in CD69 expression, proliferation, and interleukin-2 production. These results suggest a regulatory role of MUC1 in modulating proximal signal transduction events through its interaction with proteins of the activation complex. PMID:15513966

Mukherjee, P; Tinder, T L; Basu, G D; Gendler, S J

2005-01-01

45

TRAF3 enforces the requirement for T cell cross-talk in thymic medullary epithelial development.  

PubMed

Induction of self-tolerance in developing T cells depends on medullary thymic epithelial cells (mTECs), whose development, in turn, requires signals from single-positive (SP) thymocytes. Thus, the absence of SP thymocytes in Tcra(-/-) mice results in a profound deficiency in mTECs. Here, we have probed the mechanism that underlies this requirement for cross-talk with thymocytes in medullary development. Previous studies have implicated nonclassical NF-?B as a pathway important in the development of mTECs, because mice lacking RelB, NIK, or IKK?, critical components of this pathway, have an almost complete absence of mTECs, with resulting autoimmune pathology. We therefore assessed the effect of selective deletion in TEC of TNF receptor-associated factor 3 (TRAF3), an inhibitor of nonclassical NF-?B signaling. Deletion of TRAF3 in thymic epithelial cells allowed RelB-dependent development of normal numbers of AIRE-expressing mTECs in the complete absence of SP thymocytes. Thus, mTEC development can occur in the absence of cross-talk with SP thymocytes, and signals provided by SP T cells are needed to overcome TRAF3-imposed arrest in mTEC development mediated by inhibition of nonclassical NF-?B. We further observed that TRAF3 deletion is also capable of overcoming all requirements for LT?R and CD40, which are otherwise necessary for mTEC development, but is not sufficient to overcome the requirement for RANKL, indicating a role for RANKL that is distinct from the signals provided by SP thymocytes. We conclude that TRAF3 plays a central role in regulation of mTEC development by imposing requirements for SP T cells and costimulation-mediated cross-talk in generation of the medullary compartment. PMID:24324158

Jenkinson, S Rhiannon; Williams, Joy A; Jeon, Hyein; Zhang, Jingjing; Nitta, Takeshi; Ohigashi, Izumi; Kruhlak, Michael; Zuklys, Saulius; Sharrow, Susan; Adams, Anthony; Granger, Larry; Choi, Yongwon; Siebenlist, Ulrich; Bishop, Gail A; Hollander, Georg A; Takahama, Yousuke; Hodes, Richard J

2013-12-24

46

New Perspective on Dextran Sodium Sulfate Colitis: Antigen-Specific T Cell Development during Intestinal Inflammation  

PubMed Central

CD4+ T cell responses against oral antigens can develop in inflammatory bowel disease (IBD) patients, which may modulate disease. Dextran sodium sulfate (DSS) colitis is commonly used to study IBD, however, it is not considered the best model in which to study T cell involvement in intestinal disease. Our aim was to determine if antigen-specific T cells could be induced during DSS colitis and if they could be detected after disease resolution. To induce antigen-specific T cells, the tracking antigen, ovalbumin (OVA), was administered orally during colitis initiation. Disease severity was monitored, and the antigen-reactivity of CD4+ T cells examined using CD69 expression. While OVA-directed, CD4+ Foxp3+ regulatory T cells could be detected in the spleens of both OVA-treated control and DSS mice, OVA-reactive, CD4+ Foxp3-T cells were only found in the OVA and DSS-treated mice. These results indicate that during DSS colitis T cells develop that are specific against oral antigens, and they are found systemically after colitis resolution. This gives added depth and utility to the DSS model as well as a way to track T cells that are primed against luminal antigens. PMID:23936123

Morgan, Mary E.; Zheng, Bin; Koelink, Pim J.; van de Kant, Hendrick J. G.; Haazen, Lizette C. J. M.; van Roest, Manon; Garssen, Johan; Folkerts, Gert; Kraneveld, Aletta D.

2013-01-01

47

Role of the multichain IL-2 receptor complex in the control of normal and malignant T-cell proliferation  

SciTech Connect

Antigen-induced activation of resting T-cells induces the synthesis of interleukin-2 (IL-2), as well as the expression of specific cell surface receptors for this lymphokine. There are at least two forms of the cellular receptors for IL-2, one with a very high affinity and the other with a lower affinity. The authors have identified two IL-2 binding peptides, a 55-kd peptide reactive with the anti-Tac monoclonal antibody, and a novel 75-kd non-Tac IL-2 binding peptide. Cell lines bearing either the p55, Tac, or the p75 peptide along manifested low-affinity IL-2 binding, whereas cell lines bearing both peptides manifested both high- and low-affinity receptors. Fusion of cell membranes from low-affinity IL-2 binding cells bearing the Tac peptide alone with membranes from a cell line bearing the p75 peptide alone generates hybrid membranes bearing high-affinity receptors. They propose a multichain model for the high-affinity IL-2 receptor in which both the Tac and the p75 IL-2 binding peptides are associated in a receptor complex. In contrast to resting T-cells, human T-cell lymphotropic virus I-associated adult T-cell leukemia cells constitutively express large numbers of IL-2 receptors. Because IL-2 receptors are present on the malignant T-cells but not on normal resting cells, clinical trials have been initiated in which patients with adult T-cell leukemia are being treated with either unmodified or toxin-conjugated forms of anti-Tac monoclonal antibody directed toward this growth factor receptor. Cross-linking studies were done using (/sup 125/I) IL-2.

Waldmann, T.A.

1987-11-01

48

Jak3 Selectively Regulates Bax and Bcl-2 Expression To Promote T-Cell Development  

PubMed Central

Jak3-deficient mice display vastly reduced numbers of lymphoid cells. Thymocytes and peripheral T cells from Jak3-deficient mice have a high apoptotic index, suggesting that Jak3 provides survival signals. Here we report that Jak3 regulates T lymphopoiesis at least in part through its selective regulation of Bax and Bcl-2. Jak3-deficient thymocytes express elevated levels of Bax and reduced levels of Bcl-2 relative to those in wild-type littermates. Notably, up-regulation of Bax in Jak3-deficient T cells is physiologically relevant, as Jak3 Bax double-null mice have marked increases in thymocyte and peripheral T-cell numbers. Rescue of T lymphopoiesis by Bax loss was selective, as mice deficient in Jak3 plus p53 or in Jak3 plus Fas remained lymphopenic. However, Bax loss failed to restore proper ratios of peripheral CD4/CD8 T cells, which are abnormally high in Jak3-null mice. Transplantation into Jak3-deficient mice of Jak3-null bone marrow transduced with a Bcl-2-expressing retrovirus also improved peripheral T-cell numbers and restored the ratio of peripheral CD4/CD8 T cells to wild-type levels. The data support the concepts that Jak kinases regulate cell survival through their selective and cell context-dependent regulation of pro- and antiapoptotic Bcl-2 family proteins and that Bax and Bcl-2 play distinct roles in T-cell development. PMID:11134353

Wen, Renren; Wang, Demin; McKay, Catriona; Bunting, Kevin D.; Marine, Jean-Christophe; Vanin, Elio F.; Zambetti, Gerard P.; Korsmeyer, Stanley J.; Ihle, James N.; Cleveland, John L.

2001-01-01

49

The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation  

PubMed Central

Transcription factors of the STAT (signal transducer and activator of transcription) family are critical in the cytokine-mediated functional differentiation of CD4+ helper T cells. Members of the SOCS (suppressor of cytokine signaling) family negatively regulate the activation of STAT proteins; however, their roles in the differentiation and function of helper T cells are not well understood. Here we found that the SOCS protein CIS, which was substantially induced by interleukin 4 (IL-4), negatively regulated the activation of STAT3, STAT5 and STAT6 in T cells. CIS-deficient mice spontaneously developed airway inflammation, and CIS deficiency in T cells led to greater susceptibility to experimental allergic asthma. CIS-deficient T cells showed enhanced differentiation into the TH2 and TH9 subsets of helper T cells. STAT5 and STAT6 regulated IL-9 expression by direct binding to its gene. Our data thus demonstrate a critical role for CIS in controlling proallergic generation of helper T cells. PMID:23727894

Yang, Xuexian O; Zhang, Huiyuan; Kim, Byung-Seok; Niu, Xiaoyin; Peng, Juan; Chen, Yuhong; Kerketta, Romica; Lee, Young-Hee; Chang, Seon Hee; Corry, David B; Wang, Demin; Watowich, Stephanie S; Dong, Chen

2014-01-01

50

T cell alloreactivity induced by normal G-CSF-mobilized CD34+ blood cells  

Microsoft Academic Search

In this study, the hypothesis that a subset of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ blood cells may actively induce an allogeneic T cell response in vitro was tested. Circulating CD34+ cells were purified to ?98% by high gradient magnetic separation and then analyzed for the coexpression of HLA-DR, the common ?-chain of the leukointegrin family CD18 and costimulatory molecules CD80

D Rondelli; C Anasetti; A Fortuna; M Ratta; M Arpinati; G Bandini; RM Lemoli; S Tura

1998-01-01

51

CD28 in thymocyte development and peripheral T cell activation in mice exposed to suspended particulate matter  

SciTech Connect

The CD28:B7 signaling pathway is very important for the activity of mature peripheral T lymphocytes and thymocyte development. The proper development of thymocytes into mature single positive CD4{sup +}and CD8{sup +} T cells is crucial for almost all immune functions. In naturally occurring conditions, T cells maturation in the thymus is influenced by environmental agents. The expression of CD28 and the distribution of CD28{sup low/high} thymocytes have been examined at various stages of thymocyte development in BALB/c mice exposed to air-suspended particulate matter (ASM). Acute exposure to ASM resulted in the decrease of CD28 expression in the total thymocyte population. The increase of the percentage of CD28{sup low} and the decrease of CD28{sup high} thymocytes were observed, which may account for the acceleration of thymocyte development under the conditions of elevated risk resulting from the exposure of animals to environmental xenobiotics. ASM exposure resulted in the increase of the level of proliferation of lymph node T cells induced by anti-CD3 and anti-CD28 monoclonal antibodies activation despite normal expression of CD28 molecule. In contrast, the level of proliferation of spleen T cells was lowered or normal dependently of the concentration of stimuli used for activation. Results of these studies demonstrate that acute exposure of mice to ASM can result in the progression of two contrasting processes in the immune system: upregulation of thymocyte development, which contributes to the maintenance of peripheral T cell pool, and over-activation of lymph node lymphocytes, which may lead to uncontrolled immunostimulation.

Drela, Nadzieja [Department of Immunology, Faculty of Biology, Warsaw University, Miecznikowa 1, 02-096 Warsaw (Poland)]. E-mail: ndrela@biol.uw.edu.pl; Zesko, Izabela [Department of Immunology, Faculty of Biology, Warsaw University, Miecznikowa 1, 02-096 Warsaw (Poland); Jakubowska, Martyna [Department of Immunology, Faculty of Biology, Warsaw University, Miecznikowa 1, 02-096 Warsaw (Poland); Biernacka, Marzena [Department of Immunology, Faculty of Biology, Warsaw University, Miecznikowa 1, 02-096 Warsaw (Poland)

2006-09-01

52

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

53

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

54

T cell alloreactivity induced by normal G-CSF-mobilized CD34+ blood cells.  

PubMed

In this study, the hypothesis that a subset of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ blood cells may actively induce an allogeneic T cell response in vitro was tested. Circulating CD34+ cells were purified to > or =98% by high gradient magnetic separation and then analyzed for the coexpression of HLA-DR, the common beta-chain of the leukointegrin family CD18 and costimulatory molecules CD80 (B7-1) and CD86 (B7-2). These antigens were expressed on average on: 94.9 +/- 2.5%, 64.4 +/- 15.4%, 0% and 1.9 +/- 1.2% CD34+ blood cells, respectively. Irradiated CD34+ cells induced a high proliferative response of allogeneic, but not autologous, purified CD4+ and CD8+ T cells in primary mixed leukocyte culture (MLC). An average three-fold lower CD4+ and CD8+ T cell response was induced by mononuclear cells from G-CSF-treated donors. A lower frequency of allostimulating cells among mononuclear cells rather than among CD34+ cells in the apheresis was documented by limiting dilution assay (LDA). As previously observed with marrow, sorted CD34+/CD18+ cells induced the proliferation of allogeneic T cells in MLC, while CD34+/CD18- cells, which were >94% HLA-DR+ and contained both committed (CFU-C) and early (LTC-IC) hematopoietic progenitors, stimulated allogeneic T cells poorly. Three-color staining cytofluorimetry indicated that expression of CD80 and CD86 were upregulated in 6.9 +/- 4.9 and 10.7 +/- 2.6% CD34+ blood cells respectively, after 24-30 h of culture with autologous or allogeneic mononuclear cells, or with CD4+, or CD8+ T cells, but not with medium alone. Moreover, the upregulation of CD86 was observed on CD34+/CD18+ rather than on CD34+/CD18- cells after 30 h in MLC. Blocking experiments demonstrated that preincubation of stimulator and responder cells with anti-CD80 plus anti-CD86 monoclonal antibodies induced a 84 +/- 8% inhibition of CD34+ cell allostimulating activity after 6 days in primary MLC. These results suggest that G-CSF-mobilized CD34+ hematopoietic progenitors with alloantigen presenting function express CD18 and may upregulate CD80 and CD86 upon interaction with T cells. Since activation of B7 costimulatory molecules represents an active costimulatory pathway on G-CSF-mobilized CD34+ cells, the blockade of these molecules or, alternatively, the use of selected non-immunogenic CD34+/CD18- blood stem cells may represent a new strategy for reducing graft rejection and overcoming HLA barriers in allogeneic stem cell transplantation. PMID:9674849

Rondelli, D; Anasetti, C; Fortuna, A; Ratta, M; Arpinati, M; Bandini, G; Lemoli, R M; Tura, S

1998-06-01

55

Regulation of an extrathymic T-cell development pathway by oncostatin M.  

PubMed

Most of the T lymphocytes that populate the immune system develop in the thymus before its involution during late adolescence. Therefore, subsequent losses in T cells caused by HIV infection, chemotherapy or age-related factors can greatly diminish immune responses to new antigenic challenge. Here we report the discovery of a thymus-independent pathway of T-cell development that may provide help for T-cell immunodeficiency. We show that expression of an oncostatin M transgene in the early T lineage stimulates a dramatic accumulation of immature and mature T cells in lymph nodes. A functional thymus is not required for this effect as reconstitution of nu/nu mice with transgenic bone marrow stimulated a 500-fold increase in Thy-1+ lymph node cells and restored immune responsiveness to allogeneic mouse melanoma cells. This lymphopoietic pathway is not unique to transgenic mice because administration of oncostatin M protein produced a similar response in non-transgenic mice. These results identify a new pathway of T-cell development and a potential treatment for T-cell immunodeficiency with oncostatin M. PMID:8918875

Clegg, C H; Rulffes, J T; Wallace, P M; Haugen, H S

1996-11-21

56

Themis sets the signal threshold for positive and negative selection in T-cell development.  

PubMed

Development of a self-tolerant T-cell receptor (TCR) repertoire with the potential to recognize the universe of infectious agents depends on proper regulation of TCR signalling. The repertoire is whittled down during T-cell development in the thymus by the ability of quasi-randomly generated TCRs to interact with self-peptides presented by major histocompatibility complex (MHC) proteins. Low-affinity TCR interactions with self-MHC proteins generate weak signals that initiate 'positive selection', causing maturation of CD4- or CD8??-expressing 'single-positive' thymocytes from CD4(+)CD8??(+) 'double-positive' precursors. These develop into mature naive T cells of the secondary lymphoid organs. TCR interaction with high-affinity agonist self-ligands results in 'negative selection' by activation-induced apoptosis or 'agonist selection' of functionally differentiated self-antigen-experienced T cells. Here we show that positive selection is enabled by the ability of the T-cell-specific protein Themis to specifically attenuate TCR signal strength via SHP1 recruitment and activation in response to low- but not high-affinity TCR engagement. Themis acts as an analog-to-digital converter translating graded TCR affinity into clear-cut selection outcome. By dampening mild TCR signals Themis increases the affinity threshold for activation, enabling positive selection of T cells with a naive phenotype in response to low-affinity self-antigens. PMID:24226767

Fu, Guo; Casas, Javier; Rigaud, Stephanie; Rybakin, Vasily; Lambolez, Florence; Brzostek, Joanna; Hoerter, John A H; Paster, Wolfgang; Acuto, Oreste; Cheroutre, Hilde; Sauer, Karsten; Gascoigne, Nicholas R J

2013-12-19

57

A new approach to understanding T cell development: the isolation and characterization of immature CD4-, CD8-, CD3- T cell cDNAs by subtraction cloning.  

PubMed Central

During T cell development in the mammalian thymus, immature T cells are observed that lack the cell surface markers CD4, CD8, and CD3. A subtracted cDNA library was constructed to isolate cDNAs that are specific for these immature T cells. Tissue-specific expression of 97 individual cDNAs were examined using different cell types by Northern blot analysis, and six cDNAs were analyzed by reverse transcriptase (RT) polymerase chain reaction (PCR) detection of RNA. Approximately 50% of the clones could not be detected on Northern blots, and 40% of the clones were expressed by at least one other cell-type including monocytes, mature T cells, and B cells. Eight cDNA clones appear to be specific for the CD4-, CD8-, CD3- T cell line, used to construct the library, as determined by Northern blot analysis. In addition, 330 cDNA clones were subjected to partial automated DNA sequence determination. Database searches, with both nucleotide and protein translations, revealed cDNAs that exhibit interesting similarities to human cell-cycle gene 1, platelet-derived growth factor receptor, c-fms oncogene (CSF-1) receptor, and members of the immunoglobulin gene superfamily. This approach of employing subtraction coupled with large scale partial cDNA sequence determination can be useful to identify genes that may be involved in early T cell growth, cellular recognition or differentiation. Images PMID:1387565

Orr, S L; Gese, E; Hood, L

1992-01-01

58

Nippostrongylus brasiliensis can induce B7-independent antigen-specific development of IL-4-producing T cells from naive CD4 T cells in vivo.  

PubMed

Th2 immune responses to a number of infectious pathogens are dependent on B7-1/B7-2 costimulatory molecule interactions. We have now examined the Th2 immune response to Nippostrongylus brasiliensis (Nb) in B7-1/B7-2(-/-) mice and show that Th2 effector cells develop that can mediate worm expulsion and produce substantial Th2 cytokines comparable with wild-type infected mice; however, in marked contrast, B cell Ag-specific Ab production is abrogated after B7 blockade. To examine the mechanism of T cell activation, OVA-specific DO11.10 T cells were transferred to recipient mice, which were then immunized with a combination of Nb plus OVA or either alone. Only the combination of Nb plus OVA triggered T cell differentiation to OVA-specific Th2 cells, suggesting that Nb acts as an adjuvant to stimulate Ag-specific naive T cells to differentiate to effector Th2 cells. Furthermore, using the DO11.10 TCR-transgenic T cell adoptive transfer model, we show that blocking B7-1/B7-2 interactions does not impair nonparasite Ag-specific DO11.10 Th2 cell differentiation; however, DO11.10 T cell cycle progression and migration to the B cell zone are inhibited. PMID:12471130

Liu, Zhugong; Liu, Qian; Pesce, John; Whitmire, Jeannette; Ekkens, Melinda J; Foster, Anthony; VanNoy, Jansie; Sharpe, Arlene H; Urban, Joseph F; Gause, William C

2002-12-15

59

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

60

Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development  

PubMed Central

Proper thymocyte development is required to establish T-cell central tolerance and to generate naive T cells, both of which are essential for T-cell homeostasis and a functional immune system. Here we demonstrate that the loss of transcription factor Foxp1 results in the abnormal development of T cells. Instead of generating naive T cells, Foxp1-deficient single-positive thymocytes acquire an activated phenotype prematurely in the thymus and lead to the generation of peripheral CD4+ T and CD8+ T cells that exhibit an activated phenotype and increased apoptosis and readily produce cytokines upon T-cell receptor engagement. These results identify Foxp1 as an essential transcriptional regulator for thymocyte development and the generation of quiescent naive T cells. PMID:19965654

Feng, Xiaoming; Ippolito, Gregory C.; Tian, Lifeng; Wiehagen, Karla; Oh, Soyoung; Sambandam, Arivazhagan; Willen, Jessica; Bunte, Ralph M.; Maika, Shanna D.; Harriss, June V.; Caton, Andrew J.; Bhandoola, Avinash

2010-01-01

61

T cells modulate glycans on CD43 and CD45 during development and activation, signal regulation, and survival  

PubMed Central

Glycosylation affects many essential T cell processes and is intrinsically controlled throughout the lifetime of a T cell. CD43 and CD45 are the two most abundant glycoproteins on the T cell surface and are decorated with O- and N-glycans. Global T cell glycosylation and specific glycosylation of CD43 and CD45 are modulated during thymocyte development and T cell activation; T cells control the type and abundance of glycans decorating CD43 and CD45 by regulating expression of glycosyltransferases and glycosidases. Additionally, T cells regulate glycosylation of CD45 by expressing alternatively spliced isoforms of CD45 that have different glycan attachment sites. The glycophenotype of CD43 and CD45 on T cells influences how T cells interact with the extracellular environment, including how T cells interact with endogenous lectins. This review focuses on changes in glycosylation of CD43 and CD45 occurring throughout T cell development and activation and the role that glycosylation plays in regulating T cell processes, such as migration, T cell receptor signaling, and apoptosis. PMID:22288421

Clark, Mary C.; Baum, Linda G.

2013-01-01

62

Activation requirements for normal T cells: accessory cell-dependent and -independent stimulation by anti-receptor antibodies.  

PubMed

We have examined the requirements for the activation of normal T cells by two anti-T cell receptor antibody preparations, including a rabbit antiserum, R3497, which binds to all normal T cells, and a rat monoclonal antibody, KJ16-133, which binds to about 20% of T cells. The requirements for stimulation of T cells by both antibodies were similar. Soluble antibodies in the absence of accessory cells (AC) failed to induce either proliferation or the expression of IL 2 receptors, and the addition of either IL 2 or PMA failed to synergize with these soluble antibodies for an AC-independent proliferative response. Activation could only be achieved in the presence of Fc receptor-positive AC, although Fc receptor expression alone appeared not to be sufficient for AC activity because some Fc receptor-positive cells did not function in this capacity. Activation with anti-receptor antibody conjugated to Sepharose 4B beads could be demonstrated in the presence of some exogenous cofactors, such as IL 2 and PMA, but not in the presence of recombinant IL 1. When activation by soluble antibody plus AC was compared to activation by bead-conjugated antibody + recombinant IL 2, it was found that the former favored the stimulation of Lyt-2+ cells. The effects of the addition of anti-L3T4 monoclonal antibody was also examined in this system. Anti-L3T4 inhibited the response of L3T4+ cells when used in the presence of Ia+ as well as Ia- AC, and it also inhibited activation in a system in which KJ16-133 conjugated to Sepharose was used in the absence of AC. Because anti-L3T4 had an inhibitory effect in the presence of Ia- AC as well as in the absence of any AC, it is concluded that L3T4 does not necessarily function by interacting with Ia on the surface of AC, and may directly transmit down-regulatory signals when bound by anti-L3T4. PMID:3489033

Bekoff, M; Kubo, R; Grey, H M

1986-09-01

63

SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors.  

PubMed

Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) plays an essential role in the immune system mediating the function of several members of the SLAM family (SLAMF) of receptors, whose expression is essential for T, NK, and B-cell responses. Additionally, the expression of SAP in double-positive thymocytes is mandatory for natural killer T (NKT) cells and, in mouse, for innate CD8(+) T cell development. To date, only two members of the SLAMF of receptors, Slamf1 and Slamf6, have been shown to positively cooperate during NKT cell differentiation in mouse. However, it is less clear whether other members of this family may also participate in the development of these innate T cells. Here, we show that Slamf[1?+?6](-/-) and Slamf[1?+?5?+?6](-/-) B6 mice have ~70% reduction of NKT cells compared to wild-type B6 mice. Unexpectedly, the proportion of innate CD8(+) T cells slightly increased in the Slamf[1?+?5?+?6](-/-) , but not in the Slamf[1?+?6](-/-) strain, suggesting that Slamf5 may function as a negative regulator of innate CD8(+) T cell development. Accordingly, Slamf5(-/-) B6 mice showed an exclusive expansion of innate CD8(+) T cells, but not NKT cells. Interestingly, the SAP-independent Slamf7(-/-) strain showed an expansion of both splenic innate CD8(+) T cells and thymic NKT cells. On the other hand, and similar to what was recently shown in Slamf3(-/-) BALB/c mice, the proportions of thymic promyelocytic leukemia zinc finger (PLZF(hi)) NKT cells and innate CD8(+) T cells significantly increased in the SAP-independent Slamf8(-/-) BALB/c strain. In summary, these results show that NKT and innate CD8(+) T cell development can be regulated in a SAP-dependent and -independent fashion by SLAMF receptors, in which Slamf1, Slamf6, and Slamf8 affect development of NKT cells, and that Slamf5, Slamf7, and Slamf8 affect the development of innate CD8(+) T cells. PMID:24795728

De Calisto, Jaime; Wang, Ninghai; Wang, Guoxing; Yigit, Burcu; Engel, Pablo; Terhorst, Cox

2014-01-01

64

Notch1 and IL-7 receptor signalling in early T-cell development and leukaemia.  

PubMed

Notch receptors are master regulators of many aspects of development and tissue renewal in metazoans. Notch1 activation is essential for T-cell specification of bone marrow-derived multipotent progenitors that seed the thymus, and for proliferation and further progression of early thymocytes along the T-cell lineage. Deregulated activation of Notch1 significantly contributes to the generation of T-cell acute lymphoblastic leukaemia (T-ALL). In addition to Notch1 signals, survival and proliferation signals provided by the IL-7 receptor (IL-7R) are also required during thymopoiesis. Our understanding of the molecular mechanisms controlling stage-specific survival and proliferation signals provided by Notch1 and IL-7R has recently been improved by the discovery that the IL-7R is a transcriptional target of Notch1. Thus, Notch1 controls T-cell development, in part by regulating the stage- and lineage-specific expression of IL-7R. The finding that induction of IL-7R expression downstream of Notch1 also occurs in T-ALL highlights the important contribution that deregulated IL-7R expression and function may have in this pathology. Confirming this notion, oncogenic IL7R gain-of-function mutations have recently been identified in childhood T-ALL. Here we discuss the fundamental role of Notch1 and IL-7R signalling pathways in physiological and pathological T-cell development in mice and men, highlighting their close molecular underpinnings. PMID:22695916

González-García, Sara; García-Peydró, Marina; Alcain, Juan; Toribio, María L

2012-01-01

65

Dynamic microRNA gene transcription and processing during T cell development  

PubMed Central

By disrupting microRNA (miRNA) biogenesis, we previously showed that this pathway is critical for the differentiation and function of T cells. While various cloning studies have shown that many miRNAs are expressed during T cell development, and in a dynamic manner, it was unclear how comprehensive these earlier analyses were. We therefore decided to profile miRNA expression by means of Next Generation Sequencing. Furthermore, we profiled miRNA expression starting from the hematopoietic stem cell. This analysis revealed that miRNA expression during T cell development is extremely dynamic, with 645 miRNAs sequenced, and the expression of some varying by as much as 3 orders of magnitude. Furthermore, changes in precursor processing led to altered mature miRNA sequences. We also analyzed the structures of the primary miRNA transcripts expressed in T cells, and found that many were extremely long. The longest was pri-mir-29b-1/29a at ~168kb. All the long pri-miRNAs also displayed extensive splicing. Our findings indicate that miRNA expression during T cell development is both a highly dynamic and a highly regulated process. PMID:22379031

Kirigin, Francis F.; Lindstedt, Kenneth; Sellars, Maclean; Ciofani, Maria; Low, Siao Li; Jones, Lachlan; Bell, Fiona; Pauli, Florencia; Bonneau, Richard; Myers, Richard M.; Littman, Dan R.; Chong, Mark M.W.

2014-01-01

66

Dynamic microRNA gene transcription and processing during T cell development.  

PubMed

By disrupting microRNA (miRNA) biogenesis, we previously showed that this pathway is critical for the differentiation and function of T cells. Although various cloning studies have shown that many miRNAs are expressed during T cell development, and in a dynamic manner, it was unclear how comprehensive these earlier analyses were. We therefore decided to profile miRNA expression by next generation sequencing. Furthermore, we profiled miRNA expression starting from the hematopoietic stem cell. This analysis revealed that miRNA expression during T cell development is extremely dynamic, with 645 miRNAs sequenced, and the expression of some varying by as much as 3 orders of magnitude. Furthermore, changes in precursor processing led to altered mature miRNA sequences. We also analyzed the structures of the primary miRNA transcripts expressed in T cells and found that many were extremely long. The longest was pri-mir-29b-1/29a at ?168 kb. All the long pri-miRNAs also displayed extensive splicing. Our findings indicate that miRNA expression during T cell development is both a highly dynamic and a highly regulated process. PMID:22379031

Kirigin, Francis F; Lindstedt, Kenneth; Sellars, Maclean; Ciofani, Maria; Low, Siao Li; Jones, Lachlan; Bell, Fiona; Pauli, Florencia; Bonneau, Richard; Myers, Richard M; Littman, Dan R; Chong, Mark M W

2012-04-01

67

Molecular insights into the development of T cell-based immunotherapy for prostate cancer.  

PubMed

Using a patient's own immune system to fight cancer is a highly active area of cancer research. Four years ago, sipuleucel-T became the first approved cancer vaccine, which was developed to enhance T-cell immunity against metastatic castration-resistant prostate cancer. Other prostate cancer vaccines, including a viral-based vaccine PROSTVAC-VF and a cellular vaccine GVAX, are in development. Moreover, several clinical trials are investigating the role of immune checkpoint blockade in the treatment of prostate cancer. Ipilimumab and nivolumab are potent T cell checkpoint inhibitors that reverse immunologic tolerance in multiple types of cancers. Here we discuss the mechanisms underlying antitumor T cell responses as well as the development of immunotherapies for prostate cancer. PMID:25259804

Dong, Baijun; Minze, Laurie J; Xue, Wei; Chen, Wenhao

2014-11-01

68

Engineered regulatory T cells coexpressing MHC class II:peptide complexes are efficient inhibitors of autoimmune T cell function and prevent the development of autoimmune arthritis.  

PubMed

Regulatory T cells (Tregs) are critical homeostatic components in preventing the development of autoimmunity, and are a major focus for their therapeutic potential for autoimmune diseases. To enhance the efficacy of Tregs in adoptive therapy, we developed a strategy for generating engineered Tregs that have the capacity to target autoimmune T cells in an Ag-specific manner. Using a retroviral expression system encoding Foxp3 and HLA-DR1 covalently linked to the immunodominant peptide of the autoantigen type II collagen (DR1-CII), naive T cells were engineered to become Tregs that express DR1-CII complexes on their surface. When these cells were tested for their ability to prevent the development of collagen induced arthritis, both the engineered DR1-CII-Foxp3 and Foxp3 only Tregs significantly reduced the severity and incidence of disease. However, the mechanism by which these two populations of Tregs inhibited disease differed significantly. Disease inhibition by the DR1-CII-Foxp3 Tregs was accompanied by significantly lower numbers of autoimmune CII-specific T cells in vivo and lower levels of autoantibodies in comparison with engineered Tregs expressing Foxp3 alone. In addition, the numbers of IFN-?- and IL-17-expressing T cells in mice treated with DR1-CII-Foxp3 Tregs were also significantly reduced in comparison with mice treated with Foxp3 engineered Tregs or vector control cells. These data indicate that the coexpression of class II autoantigen-peptide complexes on Tregs provides these cells with a distinct capacity to regulate autoimmune T cell responses that differs from that used by conventional Tregs. PMID:23630354

Qian, Zhaohui; Latham, Kary A; Whittington, Karen B; Miller, David C; Brand, David D; Rosloniec, Edward F

2013-06-01

69

TAK1 is indispensable for development of T cells and prevention of colitis by the generation of regulatory T cells  

Microsoft Academic Search

Transforming growth factor (TGF)-b-activating kinase 1 (TAK1) is critical for Toll-like receptor- and tumor necrosis factor-mediated cellular responses. In B cells, TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs), but not nuclear factor-jB (NF-jB), in antigen receptor signaling. In this study, we generate T cell-specific TAK1-deficient (LckCre\\/1Tak1flox\\/flox) mice and show that TAK1 is indispensable for the maintenance

Shintaro Sato; Hideki Sanjo; Tohru Tsujimura; Jun Ninomiya-Tsuji; Masahiro Yamamoto; Taro Kawai; Osamu Takeuchi; Shizuo Akira

2006-01-01

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

Differential G-protein expression during B- and T-cell development.  

PubMed Central

The molecular mechanisms underlying B- and T-cell development are, as yet, poorly understood. However, as G proteins regulate a diverse range of biological responses including growth, proliferation and differentiation, we have investigated differential expression of G proteins during B- and T-cell development with the aim of identifying key signals involved in lymphocyte maturation. Differential expression of beta 1/2 and alpha-subunits of the Gs-, i- and q-families was found throughout lymphoid development. Most strikingly, G alpha i1 and G alpha i1 were very weakly, or not expressed in pre-, immature and mature B cells, thymocytes or mature T cells, but strongly induced in mature B-lymphoblastoid cell lines, some of which have been used as models of germinal centre B cells, suggesting that expression of these G proteins may correlate with the later stages of B-cell development. In contrast, G alpha 16 expression was highest in T cells and pre-B cells and progressively declined with B-cell maturation. These findings suggest that G proteins, and the signals they regulate, such as ion channels and/or adenylate cyclase (G alpha s/i) and phospholipase C (G beta gamma and G alpha 11/16) are differentially regulated in lymphoid cells in a maturation-and lineage-dependent manner. Images Figure 1 PMID:9176110

Grant, K R; Harnett, W; Milligan, G; Harnett, M M

1997-01-01

72

Differential requirement of PKC-? in the development and function of Natural Regulatory T cells  

PubMed Central

CD4+CD25+ natural Treg cells, which are developed in the thymus, migrate to the periphery to actively maintain self-tolerance. Similar to conventional T cells, TCR signals are critical for the development and activation of Treg cell inhibitory function. While PKC-?-mediated TCR signals are required for the activation of peripheral naïve T cells, they are dispensable for their thymic development. Here, we show that mice deficient in PKC-? had a greatly reduced number of CD4+Foxp3+ Treg cells, which was independent of PKC-?-regulated survival, as transgenic Bcl-xL could not restore the Treg cell population in PKC-??/? mice. Active and WT PKC-? markedly stimulated, whereas inactive PKC-? and dominant negative NFAT inhibited Foxp3 promoter activity. In addition, mice-deficient in calcineurin A? had a decreased Treg cell population, similar to that observed in PKC-? deficient mice. It is likely that PKC-? promoted the development of Treg cells by enhancing Foxp3 expression via activation of the calcineurin/NFAT pathway. Finally, Treg cells deficient in PKC-? were as potent as WT Treg cells in inhibiting T cell activation, indicating that PKC-? was not required for Treg cell-mediated inhibitory function. Our data highlight the contrasting roles PKC-? plays in conventional T cell and natural Treg cell function. PMID:18842300

Gupta, Sonal; Manicassamy, Santhakumar; Vasu, Chenthamarakshan; Kumar, Anvita; Shang, Weirong; Sun, Zuoming

2008-01-01

73

VaccinesEffector and memory T-cell differentiation: implications for vaccine development  

Microsoft Academic Search

Recent work shows that after stimulation with antigen, CD4+ and CD8+ T cells embark on a programme of proliferation that is closely linked with the acquisition of effector functions and leads ultimately to memory-cell formation. Here, we discuss the signals required for commitment to this programme of development and the factors that might influence its progression. Models of the pathways

Susan M. Kaech; E. John Wherry; Rafi Ahmed

2002-01-01

74

The TCF-1 and LEF-1 transcription factors have cooperative and opposing roles in T-cell development and malignancy  

PubMed Central

SUMMARY The TCF-1 and LEF-1 transcription factors are known to play critical roles in normal thymocyte development. Unexpectedly, we found that TCF-1-deficient (Tcf7?/?) mice developed aggressive T-cell malignancy, resembling human T-cell acute lymphoblastic leukemia (T-ALL). Surprisingly, LEF-1 was aberrantly upregulated in pre-malignant Tcf7?/? early thymocytes and lymphoma cells. We further demonstrated that TCF-1 directly repressed LEF-1 expression in early thymocytes and that conditional inactivation of Lef1 greatly delayed or prevented T-cell malignancy in Tcf7?/? mice. In human T-ALLs, an early thymic progenitor (ETP) subtype was associated with diminished TCF7 expression, and two of the ETP-ALL cases harbored TCF7 gene deletions. We also showed that TCF-1 and LEF-1 were dispensable for T-lineage commitment but instead were required for early thymocytes to mature beyond the CD4?CD8? stage. TCF-1 thus has dual roles, i.e., acting cooperatively with LEF-1 to promote thymocyte maturation while restraining LEF-1 expression to prevent malignant transformation of developing thymocytes. PMID:23103132

Yu, Shuyang; Zhou, Xinyuan; Steinke, Farrah C.; Liu, Chengyu; Chen, Shann-Ching; Zagorodna, Oksana; Jing, Xuefang; Yokota, Yoshifumi; Meyerholz, David K.; Mullighan, Charles G.; Knudson, C. Michael; Zhao, Dong-Mei; Xue, Hai-Hui

2012-01-01

75

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

76

Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations.  

PubMed

Mice deficient in the DNA damage sensor P53 display normal T cell development but eventually succumb to thymic lymphomas. Here, we show that inactivation of the TCR beta gene enhancer (E beta) results in a block of T cell development at stages where recombination-activating genes (RAG) are expressed. Introduction of the E beta mutation into p53-/- mice dramatically accelerates the onset of lethal thymic lymphomas that harbor RAG-dependent aberrant rearrangements, chromosome 14 and 12 translocations, and amplification of the chromosomal region 9A1-A5.3. Phenotypic and genetic analyses suggest that lymphomas emerge through a normal thymocyte development pathway. These findings provide genetic evidence that block of lymphocyte development at stages with RAG endonuclease activity can provoke lymphomagenesis on a background with deficient DNA damage responses. PMID:16473278

Haines, Brian B; Ryu, Chun Jeih; Chang, Sandy; Protopopov, Alexei; Luch, Andreas; Kang, Yun Hee; Draganov, Dobrin D; Fragoso, Maria F; Paik, Sang Gi; Hong, Hyo Jeong; DePinho, Ronald A; Chen, Jianzhu

2006-02-01

77

Ikaros Represses the Transcriptional Response to Notch Signaling in T-Cell Development ? †  

PubMed Central

Notch activity is essential for early T-cell differentiation, but aberrant activity induces T-cell transformation. Thus, Notch target genes must be efficiently silenced in cells where Notch activity is no longer required. How these genes are repressed remains poorly understood. We report here that the Ikaros transcription factor plays a crucial role in repressing the transcriptional response to Notch signaling in T-cell development. Using the Notch target gene Hes-1 as a model, we show that Ikaros and RBP-J?, the transcriptional mediator of Notch signaling, compete for binding to two elements in the Hes-1 promoter in immature thymocytes. This antagonistic interaction likely occurs at the CD4? CD8? CD3? double-negative 4 (DN4) stage, where Ikaros levels and binding to the Hes-1 promoter increase sharply and wild-type thymocytes lose their capacity to transcribe Hes-1 upon Notch stimulation. Nonresponsiveness to Notch signaling requires Ikaros, as Ikaros-deficient DN4 and CD4+ CD8+ double-positive (DP) cells remain competent to express Hes-1 after Notch activation. Further, Hes-1 promoter sequences from Ikaros-deficient DP cells show reduced trimethylated H3K27, a modification associated with silent chromatin. These results indicate that Ikaros functions as a transcriptional checkpoint to repress Notch target gene expression in T cells. PMID:18852286

Kleinmann, Eva; Geimer Le Lay, Anne-Solen; Sellars, MacLean; Kastner, Philippe; Chan, Susan

2008-01-01

78

Dietary Zinc Deficiency in Rodents: Effects on T-Cell Development, Maturation and Phenotypes  

PubMed Central

Zinc deficiency is one of the leading risk factors for developing disease and yet we do not have a clear understanding of the mechanisms behind the increased susceptibility to infection. This review will examine the interrelationships among the hypothalamus-pituitary-adrenal stress axis, p56lck, and T-cell maturation in both zinc deficiency and responses during zinc repletion. We will highlight differences between the adult mouse model (wasting malnutrition) and growing rat model (stunting malnutrition) of dietary zinc deficiency and discuss the use of various controls to separate out the effects of zinc deficiency from the associated malnutrition. Elevated serum corticosterone in both zinc deficient and pair-fed rats does not support the hypothesis that zinc deficiency per se leads to corticosterone-induced apoptosis and lymphopenia. In fact, the zinc deficient rat does not have lymphopenia. Thymocytes from zinc deficient mice and rats have elevated levels of p56lck, a signalling protein with a zinc clasp structure, but this does not appear to affect thymocyte maturation. However, post-thymic T-cell maturation appears to be altered based on the lower proportion of splenic late thymic emigrants in zinc deficient rats. Fewer new T-cells in the periphery could adversely affect the T-cell repertoire and contribute to immunodeficiency in zinc deficiency. PMID:22822446

Blewett, Heather J.; Taylor, Carla G.

2012-01-01

79

CD8+ T Cell-Mediated Immunity during Trypanosoma cruzi Infection: A Path for Vaccine Development?  

PubMed Central

MHC-restricted CD8+ T cells are important during infection with the intracellular protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. Experimental studies performed in the past 25 years have elucidated a number of features related to the immune response mediated by these T cells, which are important for establishing the parasite/host equilibrium leading to chronic infection. CD8+ T cells are specific for highly immunodominant antigens expressed by members of the trans-sialidase family. After infection, their activation is delayed, and the cells display a high proliferative activity associated with high apoptotic rates. Although they participate in parasite control and elimination, they are unable to clear the infection due to their low fitness, allowing the parasite to establish the chronic phase when these cells then play an active role in the induction of heart immunopathology. Vaccination with a number of subunit recombinant vaccines aimed at eliciting specific CD8+ T cells can reverse this path, thereby generating a productive immune response that will lead to the control of infection, reduction of symptoms, and reduction of disease transmission. Due to these attributes, activation of CD8+ T lymphocytes may constitute a path for the development of a veterinarian or human vaccine. PMID:25104879

dos Santos Virgilio, Fernando; Pontes, Camila; Dominguez, Mariana Ribeiro; Ersching, Jonatan; Rodrigues, Mauricio Martins; Vasconcelos, Jose Ronnie

2014-01-01

80

Normal Tissue Depresses While Tumor Tissue Enhances Human T Cell Responses In Vivo to a Novel Self/Tumor Melanoma Antigen, OA1  

PubMed Central

Antitumor T cells often recognize targets that are nonmutated “self” tissue differentiation Ags, but the relative impact of Ag expression by normal and transformed tissue for a human self/tumor Ag has not been studied. To examine the influence of self-tolerance mechanisms on the function of self/tumor-specific T cell responses in humans, we sought to identify an Ag that was expressed, processed, and presented in an MHC-restricted fashion by tumor cells, but for which there was the human equivalent of a “knockout.” In this study, we report the first immunological characterization of a melanoma/melanocyte differentiation Ag, called OA1, which meets these criteria. This Ag, an X chromosome-encoded melanoma/melanocyte differentiation Ag, was completely deleted in a male patient. Using a newly identified HLA-A*2402-restricted epitope (LYSACFWWL) to study T cell tolerance, we found that OA1-specific T cell reactivity was more than five SD higher in the knockout patient that in normal controls. These data provide compelling evidence for T cell tolerance to OA1 in humans. Most surprisingly, we found elevated levels of OA1-specific T cells in patients with metastatic malignant melanoma, indicating that the tumor-bearing state partially reversed tolerance observed in normal (non-“knockout”) individuals. Taken together, these findings indicated that tolerance can exist for self/tumor Ags in humans, and that this tolerance could be partially abrogated by the growth of the tumor, increasing the reactivity of tumor Ag-specific T cells. Thus, the tumor-bearing state reverses, in part, the tolerance of T cells that results from the normal expression of tissue differentiation Ags. PMID:12538723

Touloukian, Christopher E.; Leitner, Wolfgang W.; Schnur, Rhonda E.; Robbins, Paul F.; Li, Yong; Southwood, Scott; Sette, Alessandro; Rosenberg, Steven A.; Restifo, Nicholas P.

2008-01-01

81

Development of innate CD4+ and CD8+ T cells in Itk-deficient mice is regulated by distinct pathways.  

PubMed

T cell development in the thymus produces multiple lineages of cells, including innate T cells such as ?? TCR(+) cells, invariant NKT cells, mucosal-associated invariant T cells, and H2-M3-specific cells. Although innate cells are generally a minor subset of thymocytes, in several strains of mice harboring mutations in T cell signaling proteins or transcriptional regulators, conventional CD8(+) T cells develop as innate cells with characteristics of memory T cells. Thus, in Itk-deficient mice, mature CD4(-)CD8(+) (CD8 single-positive [SP]) thymocytes express high levels of the transcription factor eomesodermin (Eomes) and are dependent on IL-4 being produced in the thymic environment by a poorly characterized subset of CD4(+) thymocytes expressing the transcriptional regulator promyelocytic leukemia zinc finger. In this study, we show that a sizeable proportion of mature CD4(+)CD8(-) (CD4SP) thymocytes in itk(-/-) mice also develop as innate Eomes-expressing T cells. These cells are dependent on MHC class II and IL-4 signaling for their development, indicating that they are conventional CD4(+) T cells that have been converted to an innate phenotype. Surprisingly, neither CD4SP nor CD8SP innate Eomes(+) thymocytes in itk(-/-) or SLP-76(Y145F) mice are dependent on ?? T cells for their development. Instead, we find that the predominant population of Eomes(+) innate itk(-/-) CD4SP thymocytes is largely absent in mice lacking CD1d-specific invariant NKT cells, with no effect on innate itk(-/-) CD8SP thymocytes. In contrast, both subsets of innate Eomes(+)itk(-/-) T cells require the presence of a novel promyelocytic leukemia zinc finger-expressing, SLAM family receptor adapter protein-dependent thymocyte population that is essential for the conversion of conventional CD4(+) and CD8(+) T cells into innate T cells with a memory phenotype. PMID:24943215

Prince, Amanda L; Kraus, Zachary; Carty, Shannon A; Ng, Caleb; Yin, Catherine C; Jordan, Martha S; Schwartzberg, Pamela L; Berg, Leslie J

2014-07-15

82

Evidence that CD8+ Dendritic Cells Enable the Development of ?? T Cells that Modulate Airway Hyperresponsiveness2  

PubMed Central

Airway hyperresponsiveness (AHR), a hallmark of asthma and several other diseases, can be modulated by ?? T cells. In mice sensitized and challenged with ovalbumin, AHR depends on allergen-specific ?? T cells, but V??1+ ?? T cells spontaneously enhance AHR, whereas V?4+ ?? T cells after being induced by airway challenge suppress AHR. The activity of these ?? T cell modulators is allergen-nonspecific, and how they develop is unclear. We now show that CD8 is essential for the development of both the AHR-suppressor and enhancer ?? T cells although neither type needs to express CD8 itself. Both cell types encounter CD8-expressing non-T cells in the spleen, and their functional development in an otherwise CD8-negative environment can be restored with transferred spleen cell preparations containing CD8+ DC, but not CD8+ T cells or CD8? DC. Our findings suggest that CD8+ DC in the lymphoid tissues enable an early step in the development of ?? T cells, through direct cell-contact. DC-expressed CD8 might take part in this interaction. PMID:18566396

Cook, Laura; Miyahara, Nobuaki; Jin, Niyun; Wands, JM; Taube, Christian; Roark, Christina L.; Potter, Terry A.; Gelfand, Erwin W.; O'Brien, Rebecca L.; Born, Willi K.

2008-01-01

83

Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms  

PubMed Central

Background A nef gene is present in all primate lentiviral genomes and is important for high viral loads and progression to AIDS in human or experimental macaque hosts of HIV or SIV, respectively. In these hosts, infection of the thymus results in a decreased output of naive T cells that may contribute to the development of immunodeficiency. We have previously shown that HIV-1 subtype B Nef proteins can block human T-cell development. However, the underlying mechanism(s) and the conservation of this Nef function between different groups of HIV and SIV remained to be determined. Results We investigated whether reduction of thymic output is a conserved function of highly divergent lentiviral Nef proteins including those from both types of human immunodeficiency viruses (HIV-1 and HIV-2), their direct simian counterparts (SIVcpz, SIVgor and SIVsmm, respectively), and some additional SIV strains. We found that expression of most of these nef alleles in thymocyte progenitors impaired T-cell development and reduced thymic output. For HIV-1 Nef, binding to active p21 protein (Cdc42/Rac)-activated kinase (PAK2) was a major determinant of this function. In contrast, selective disruption of PAK2 binding did not eliminate the effect on T-cell development of SIVmac239 Nef, as was shown by expressing mutants in a newly discovered PAK2 activating structural motif (PASM) constituted by residues I117, H121, T218 and Y221, as well as previously described mutants. Rather, down-modulation of cell surface CD3 was sufficient for reduced thymic output by SIVmac Nef, while other functions of SIV Nefs contributed. Conclusions Our results indicate that primate lentiviral Nef proteins impair development of thymocyte precursors into T cells in multiple ways. The interaction of HIV-1 Nef with active PAK2 by HIV-1 seem to be most detrimental, and downregulation of CD3 by HIV-2 and most SIV Nef proteins sufficient for reduced thymic output. Since the reduction of thymic output by Nef is a conserved property of divergent lentiviruses, it is likely to be relevant for peripheral T-cell depletion in poorly adapted primate lentiviral infections. PMID:24237970

2013-01-01

84

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

85

How specificity for self-peptides shapes the development and function of regulatory T cells  

PubMed Central

The cataclysmic disease that develops in mice and humans lacking CD4+ T cells expressing the transcription factor Foxp3 has provided abundant evidence that Foxp3+CD4+ Tregs are required to suppress a latent autoreactivity of the immune system. There is also evidence for the existence of tissue-specific Tregs that can act to suppress regional autoimmune responses, suggesting that Tregs exert their effects, in part, through responding to self-peptides. However, how the immune system generates a repertoire of Tregs that is designed to recognize and direct regulatory function to self-peptides is incompletely understood. This review describes studies aimed at determining how T cell recognition of self-peptide(s) directs Treg formation in the thymus, including discussion of a modified “avidity” model of thymocyte development. Studies aimed at determining how TCR specificity contributes to the ability of Tregs to suppress autoimmune diseases are also discussed. PMID:20495071

Simons, Donald M.; Picca, Cristina Cozzo; Oh, Soyoung; Perng, Olivia A.; Aitken, Malinda; Erikson, Jan; Caton, Andrew J.

2010-01-01

86

T cell- but not tumor cell-produced TGF-?1 promotes the development of spontaneous mammary cancer  

PubMed Central

During their development, tumors acquire multiple capabilities that enable them to proliferate, disseminate and evade immunosurveillance. A putative mechanism is through the production of the cytokine TGF-?1. We showed in our recent studies that T cell-produced TGF-?1 inhibits antitumor T cell responses to foster tumor growth raising the question of the precise function of TGF-?1 produced by tumor cells in tumor development. Here, using a transgenic model of mammary cancer, we report that deletion of TGF-?1 from tumor cells did not protect mice from tumor development. However, ablation of TGF-?1 from T cells significantly inhibited mammary tumor growth. Additionally, absence of TGF-?1 in T cells prevented tumors from advancing to higher pathological grades and further suppressed secondary tumor development in the lungs. These findings reveal T cells but not tumor cells as a critical source of TGF-?1 that promotes tumor development. PMID:22248703

Sarkar, Abira; Donkor, Moses K.; Li, Ming O.

2011-01-01

87

Fetal Regulatory T Cells and Peripheral Immune Tolerance in utero: Implications for Development and Disease  

PubMed Central

The developing fetus must actively learn to tolerate benign antigens, or suffer the consequences of broken tolerance. Tolerance of self-antigens prevents development of autoimmune diseases, and is achieved by both deletion of autoreactive T cell clones in the thymus (central tolerance) and by the suppressive influence of CD4+CD25+FoxP3+ regulatory T cells (Tregs) in the periphery. Fetal CD4+ T cells have a strong predisposition to differentiate into tolerogenic Tregs that actively promote self-tolerance, as well as tolerance to non-inherited antigens on chimeric maternal cells that reside in most fetal tissues. As the fetus nears birth, a crucial transition must occur between the tolerogenic fetal immune system and a more defensive adult-type immune system that is able to combat pathogens. This paper will review the unique tolerogenic nature of the human fetal immune system and will examine evidence for a novel model of fetal immune development: the layered immune system hypothesis. PMID:23432802

Burt, Trevor D.

2014-01-01

88

Depletion of CD4 T cells enhances immunotherapy for neuroblastoma after syngeneic HSCT but compromises development of antitumor immune memory.  

PubMed

High-risk neuroblastoma remains a clinically challenging disease. Here, we report that a multifaceted immunotherapeutic approach including syngeneic hematopoietic stem cell transplantation (HSCT), adoptive transfer of sensitized T cells (from syngeneic donors vaccinated to tumor antigens), and early posttransplantation tumor vaccination can effectively treat mice with established neuroblastoma. Vaccination was an important component of this immunotherapy, as it resulted in enhanced and prolonged tumor-specific CD8 T-cell activity and improved antitumor efficacy. Surprisingly, CD4 cell depletion of mice given sensitized T cells resulted in better tumor-free survival, which was associated with an early increased expansion of CD8 T cells with an effector phenotype, increased numbers of tumor-reactive CD8 T cells, and increased tumor infiltration by CD8 T cells. However, in the absence of CD4 T cells, development of long-term tumor immunity (memory) was severely compromised as reflected by diminished CD8 T-cell recall responses and an inability to resist tumor rechallenge in vivo. Based on these results, a major challenge with this immunotherapeutic approach is how to obtain the ideal initial antitumor response but still preserve antitumor immune memory. These data suggest that identification and selective depletion of immune inhibitory CD4 T cells may be a strategy to enhance early antitumor immunity and induce a long-lasting tumor response after HSCT. PMID:19182203

Jing, Weiqing; Gershan, Jill A; Johnson, Bryon D

2009-04-30

89

Epidermal T Cells and Wound Healing  

PubMed Central

The murine epidermis contains resident T cells that express a canonical ?? TCR. These cells arise from fetal thymic precursors and use a TCR that is restricted to the skin in adult animals. These cells assume a dendritic morphology in normal skin and constitutively produce low levels of cytokines that contribute to epidermal homeostasis. When skin is wounded, an unknown antigen is expressed on damaged keratinocytes. Neighboring ?? T cells then round up and contribute to wound healing by local production of epithelial growth factors and inflammatory cytokines. In the absence of skin ?? T cells, wound healing is impaired. Similarly, epidermal T cells from patients with healing wounds are activated and secreting growth factors. Patients with non-healing wounds have a defective epidermal T cell response. Information gained on the role of epidermal-resident T cells in the mouse may provide information for development of new therapeutic approaches to wound healing. PMID:20483798

Havran, Wendy L.; Jameson, Julie M.

2010-01-01

90

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

91

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

92

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

Federal Register 2010, 2011, 2012, 2013

...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

93

Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota.  

PubMed

To maintain intestinal health, the immune system must faithfully respond to antigens from pathogenic microbes while limiting reactions to self-molecules. The gastrointestinal tract represents a unique challenge to the immune system, as it is permanently colonized by a diverse amalgam of bacterial phylotypes producing multitudes of foreign microbial products. Evidence from human and animal studies indicates that inflammatory bowel disease results from uncontrolled inflammation to the intestinal microbiota. However, molecular mechanisms that actively promote mucosal tolerance to the microbiota remain unknown. We report herein that a prominent human commensal, Bacteroides fragilis, directs the development of Foxp3(+) regulatory T cells (Tregs) with a unique "inducible" genetic signature. Monocolonization of germ-free animals with B. fragilis increases the suppressive capacity of Tregs and induces anti-inflammatory cytokine production exclusively from Foxp3(+) T cells in the gut. We show that the immunomodulatory molecule, polysaccharide A (PSA), of B. fragilis mediates the conversion of CD4(+) T cells into Foxp3(+) Treg cells that produce IL-10 during commensal colonization. Functional Foxp3(+) Treg cells are also produced by PSA during intestinal inflammation, and Toll-like receptor 2 signaling is required for both Treg induction and IL-10 expression. Most significantly, we show that PSA is not only able to prevent, but also cure experimental colitis in animals. Our results therefore demonstrate that B. fragilis co-opts the Treg lineage differentiation pathway in the gut to actively induce mucosal tolerance. PMID:20566854

Round, June L; Mazmanian, Sarkis K

2010-07-01

94

High levels of heterodisperse RNAs accumulate in T cells infected with human immunodeficiency virus and in normal thymocytes.  

PubMed Central

Infection by human immunodeficiency virus (HIV-1) of a human T leukemia cell line (HUT 78) leads to a rapid accumulation at an elevated level (10- to 20-fold) of heterodisperse RNAs, revealed by their containing repetitive sequences. Sequence data indicate that the repetitive elements (e.g., Alu) are associated with transcripts with no apparent long open reading frame. In contrast, a large increase of such heterodisperse RNAs is not seen in T lymphocytes activated by phytohemagglutinin or in a variety of leukemic cell lines. Examination of several cellular messages showed that the levels of some of their "fully processed" transcripts are reduced late after infection of HUT 78 cells, indicating that the levels of some mRNAs may decrease. Surprisingly, similar heterodisperse transcripts are also seen in great abundance in normal fresh thymocytes. It is possible that in HIV-infected T lymphocytes, the accumulation of high levels of such aberrant RNAs may directly or indirectly contribute to the death of HIV-infected T cells. Images PMID:2454474

Koga, Y; Lindstrom, E; Fenyo, E M; Wigzell, H; Mak, T W

1988-01-01

95

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

96

Peripheral engraftment of fetal intestine into athymic mice sponsors T cell development: direct evidence for thymopoietic function of murine small intestine  

PubMed Central

Adult athymic, lethally irradiated, F1-->parent bone marrow- reconstituted (AT x BM) mice were engrafted bilaterally with day 16-18 fetal intestine or fetal thymus into the kidney capsule and were studied for evidence of peripheral T cell repopulation of 1-12 wk postengraftment. Throughout that time period, both types of grafts were macroscopically and histologically characteristic of differentiated thymus or intestine tissues, respectively. Beginning at week 2 postengraftment, clusters of lymphocytes were present within intestine grafts, particularly in subepithelial regions and in areas below villus crypts. As determined by immunofluorescence staining and flow cytometric analyses, lymphocytes from spleen and lymph nodes of sham- engrafted mice (AT x BM-SHAM) were essentially void of T cells, whereas in AT x BM thymus-engrafted (AT x BM-THG) mice, which served as a positive control for T cell repopulation, normal levels of T cells were present in spleen and lymph nodes by week 3 postengraftment, and at times thereafter. Most striking, however, was the finding that T cell repopulation of the spleen and lymph nodes occurred in AT x BM fetal intestine-engrafted (AT x BM-FIG) mice beginning 3 wk postengraftment. Based on H-2 expression, peripheral T cells in AT x BM-FIG mice were of donor bone marrow origin, and consisted of CD3+, T cell receptor (TCR)- alpha/beta+ T cells with both CD4+8- and CD4-8+ subsets. Peripheral T cells in AT x BM-FIG mice were functionally mature, as demonstrated by their capacity to proliferate after stimulation of CD3 epsilon. Moreover, alloreactive cytotoxic T lymphocytes were generated in primary in vitro cultures of spleen cells from AT x BM-FIG and AT x BM- THG mice, though not in spleen cell cultures from AT x BM-SHAM mice. Histologic studies of engrafted tissues 3-4 wk postengraftment demonstrated that thymus leukemia (Tl) antigens were expressed on epithelial surfaces of intestine grafts, and that both TCR-alpha/beta+ and TCR-gamma/delta+ lymphocytes were present in intestine grafts. Collectively, these findings indicate that the murine small intestine has the capacity to initiate and regulate T cell development from bone marrow precursors, thus providing a mechanism by which extrathymic development of intestine lymphocytes occur. PMID:1402681

1992-01-01

97

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

98

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 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.

Kosmrlj, Andrej; Chakraborty, Arup K

2012-01-01

99

Distinct cytokines balance the development of regulatory T cells and interleukin-10-producing regulatory B cells.  

PubMed

Regulatory T cells have been well described and the factors regulating their development and function have been identified. Recently, a growing body of evidence has documented the existence of interleukin-10 (IL-10) -producing B cells, which are called regulatory B10 cells. These cells attenuate autoimmune, inflammatory and transplantation reactions, and the main mechanism of their inhibitory action is the production of IL-10. We show that the production of IL-10 by lipopolysaccharide-stimulated B cells is significantly enhanced by IL-12 and interferon-? and negatively regulated by IL-21 and transforming growth factor-?. In addition, exogenous IL-10 also inhibits B-cell proliferation and the expression of the IL-10 gene in lipopolysaccharide-stimulated B cells. The negative autoregulation of IL-10 production is supported by the observation that the inclusion of anti-IL-10 receptor monoclonal antibody enhances IL-10 production and the proliferation of activated B cells. The effects of cytokines on IL-10 production by B10 cells did not correlate with their effects on B-cell proliferation or on IL-10 production by T cells or macrophages. The cytokine-induced changes in IL-10 production occurred on the level of IL-10 gene expression, as confirmed by increased or decreased IL-10 mRNA expression in the presence of a particular cytokine. The regulatory cytokines modulate the number of IL-10-producing cells rather than augmenting or decreasing the secretion of IL-10 on a single-cell level. Altogether these data show that the production of IL-10 by B cells is under the strict regulatory control of cytokines and that individual cytokines differentially regulate the development and activity of regulatory T cells and IL-10-producing regulatory B cells. PMID:24256319

Holan, Vladimir; Zajicova, Alena; Javorkova, Eliska; Trosan, Peter; Chudickova, Milada; Pavlikova, Michaela; Krulova, Magdalena

2014-04-01

100

Accelerated chemically induced tumor development mediated by CD4+CD25+ regulatory T cells in wild-type hosts.  

PubMed

We examined the role of CD4+CD25+ regulatory T cells in the development of 3-methylcholanthrene (MCA)-induced tumors. Immunization of wild-type BALB/c mice with a series of SEREX (serological identification of antigens by recombinant expression cloning)-defined broadly expressed self-antigens results in the development of highly active CD4+CD25+ regulatory T cells. Accelerated tumor development was observed in mice immunized with self-antigens and was abolished by antibody-mediated depletion of CD4+ T cells or CD25+ T cells. A similar acceleration of tumorigenesis was also observed in mice adoptively transferred 2 or 4 weeks after MCA injection with CD4+CD25+ T cells derived from mice immunized with DnaJ-like 2, one of these self-antigens. Experiments with Jalpha281-/- mice lacking invariant natural killer (iNK) T cells indicated that iNK T cells, known for their protective role in the development of MCA-induced tumors, were suppressed in immunized hosts. NK cells, also known to play a protective role in MCA induced-tumorigenesis, were also suppressed in mice immunized with serologically defined self-antigens in a CD4+CD25+ T cell-dependent manner. We propose that CD4+CD25+ regulatory T cells generated by immunization with these self-antigens enhance susceptibility to MCA induced-tumorigenesis by down-regulating iNK T and NK reactivity, and suggest that these observations provide direct evidence for the existence of cancer immunosurveillance in this system of chemical carcinogenesis. PMID:15961541

Nishikawa, Hiroyoshi; Kato, Takuma; Tawara, Isao; Takemitsu, Tetsushi; Saito, Kanako; Wang, Linan; Ikarashi, Yoshinori; Wakasugi, Hiro; Nakayama, Toshinori; Taniguchi, Masaru; Kuribayashi, Kagemasa; Old, Lloyd J; Shiku, Hiroshi

2005-06-28

101

p57 regulates T-cell development and prevents lymphomagenesis by balancing p53 activity and pre-TCR signaling.  

PubMed

T cells are key components of the immune system, playing a central role in cell-mediated immunity. The sequential differentiation of T cells is associated with strict regulation of the cell cycle at each developmental stage. A balance between p53 activity and pre-T cell receptor (TCR) signaling regulates proliferation and differentiation decisions made by these cells. The relation between maintenance of this balance and the function of cell cycle regulators has remained largely unknown, however. We now show that mice with T cell-specific deficiency of the cyclin-dependent kinase inhibitor p57 manifest a differentiation block at the early stage of T cell maturation. Further genetic analysis showed that this defect is attributable to an imbalance between p53 activity and pre-TCR signaling caused by hyperactivation of the E2F-p53 pathway. Moreover, ablation of both p57 and p53 in T cells led to the development of aggressive thymic lymphomas with a reduced latency compared with that apparent for p53-deficient mice, whereas ablation of p57 alone did not confer susceptibility to this hematologic malignancy. Our results thus show that the p57-E2F-p53 axis plays a pivotal role in the proper development of T cells as well as in the prevention of lymphomagenesis. PMID:24652995

Matsumoto, Akinobu; Takeishi, Shoichiro; Nakayama, Keiichi I

2014-05-29

102

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

103

Enforced expression of Lin28b leads to impaired T-cell development, release of inflammatory cytokines, and peripheral T-cell lymphoma  

PubMed Central

LIN28A and LIN28B, the mammalian homologs of lin-28, are implicated in malignant transformation in part because of their ability to promote degradation of the let-7 family of miRs. In the present study, we show that overexpression of Lin28b in vivo leads to an aggressive peripheral T-cell lymphoma (PTCL) characterized by widespread infiltration of parenchymal organs with malignant CD4+ cells. Similar to patients with PTCL, Lin28b-transgenic mice show signs of inflammation such as eosinophilia, increased C-reactive protein, release of inflammatory cytokines, and pleural effusion. The PTCLs that develop in Lin28b mice are derived from activated T cells and show decreased let-7 expression, increased Il6 expression, activation of NF-?B, and infiltration of B cells, all resulting in an inflammatory microenvironment. In addition, LIN28B is overexpressed 7.5-fold in PTCL patient samples compared with activated CD4+ cells. The results of the present study demonstrate for the first time that Lin28b can transform primary cells in vivo, identify a previously unsuspected link between Lin28b and PTCL, and provide a unique animal model for the study of PTCL biology and therapy. PMID:22723554

Beachy, Sarah H.; Onozawa, Masahiro; Chung, Yang Jo; Slape, Chris; Bilke, Sven; Francis, Princy; Pineda, Marbin; Walker, Robert L.; Meltzer, Paul

2012-01-01

104

Cellular and molecular determinants for the development of natural and induced regulatory T cells  

PubMed Central

Regulation of immune responses to self and foreign antigens is critically dependent on suppressive CD4+ T cells characterized by expression of Foxp3. The large majority of regulatory T (Treg) cells develop in the thymus as a stable suppressive lineage. However, under the proper physiological conditions, conventional peripheral CD4+ T lymphocytes also develop into Treg cells, particularly in the gut mucosa and inflammatory tissue sites. This review will focus on our current understanding of the immunological and molecular signals controlling the development of thymic derived natural (n)Treg and peripheral converted induced (i)Treg cells. Given the importance of Foxp3 in the development of these cells, particular attention is placed on how such signals are integrated to induce and maintain the expression of this signature transcriptional regulator of Treg cells. PMID:22659217

Yuan, Xiaomei; Malek, Thomas R.

2012-01-01

105

Generation of Dhx9 deficient clones in T cell development with a mitotic recombination technique  

PubMed Central

Mitotic recombination is an effective tool for generating mutant clones in somatic tissues. Due to difficulties associated with detecting and quantifying mutant clones in mice, this technique is limited to analysis of growth related phenotypes induced by loss function of tumor suppressor genes. Here, we used the polymorphic CD45.1/CD45.2 alleles on chromosome 1 as pan-hematopoietic markers to track mosaic clones generated through mitotic recombination in developing T cells. We show that lineage specific mitotic recombination can be induced and reliably detected as CD45.1 or CD45.2 homozygous clones from the CD45.1/CD45.2 heterozygous background. We have applied this system in the analysis of a lethal mutation in the Dhx9 gene. Mosaic analysis revealed a stage specific role for Dhx9 during T cell maturation. Thus, the experimental system described in this study offers a practical means for mosaic analysis of germline mutations in the hematopoietic system. PMID:22988576

Zhu, Yi; Liu, Shiwei; Yin, Qili; Xu, Tian; Wu, Xiaohui; Zhuang, Yuan

2012-01-01

106

A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia.  

PubMed

Efforts to identify and annotate cancer driver genetic lesions have been focused primarily on the analysis of protein-coding genes; however, most genetic abnormalities found in human cancer are located in intergenic regions. Here we identify a new long range-acting MYC enhancer controlled by NOTCH1 that is targeted by recurrent chromosomal duplications in human T cell acute lymphoblastic leukemia (T-ALL). This highly conserved regulatory element, hereby named N-Me for NOTCH MYC enhancer, is located within a broad super-enhancer region +1.47 Mb from the MYC transcription initiating site, interacts with the MYC proximal promoter and induces orientation-independent MYC expression in reporter assays. Moreover, analysis of N-Me knockout mice demonstrates a selective and essential role of this regulatory element during thymocyte development and in NOTCH1-induced T-ALL. Together these results identify N-Me as a long-range oncogenic enhancer implicated directly in the pathogenesis of human leukemia and highlight the importance of the NOTCH1-MYC regulatory axis in T cell transformation and as a therapeutic target in T-ALL. PMID:25194570

Herranz, Daniel; Ambesi-Impiombato, Alberto; Palomero, Teresa; Schnell, Stephanie A; Belver, Laura; Wendorff, Agnieszka A; Xu, Luyao; Castillo-Martin, Mireia; Llobet-Navás, David; Cordon-Cardo, Carlos; Clappier, Emmanuelle; Soulier, Jean; Ferrando, Adolfo A

2014-10-01

107

Aire-dependent thymic development of tumor-associated regulatory T cells*  

PubMed Central

Despite considerable interest in the modulation of tumor-associated Foxp3+ regulatory T cells (Tregs) for therapeutic benefit, little is known about the developmental origins of these cells and the nature of the antigens that they recognize. Here, we identified an endogenous population of antigen-specific Tregs (termed “MJ23” Tregs) found recurrently enriched in the tumors of mice with oncogene-driven prostate cancer. MJ23 Tregs were not reactive to a tumor-specific antigen, but instead recognized a prostate-associated antigen that was present in tumor-free mice. MJ23 Tregs underwent Aire-dependent thymic development in both male and female mice. Thus Aire-mediated expression of peripheral tissue antigens drives the thymic development of a subset of organ-specific Tregs, which are likely co-opted by tumors developing within the associated organ. PMID:23471412

Malchow, Sven; Leventhal, Daniel S.; Nishi, Saki; Fischer, Benjamin I.; Shen, Lynn; Paner, Gladell P.; Amit, Ayelet S.; Kang, Chulho; Geddes, Jenna E.; Allison, James P.; Socci, Nicholas D.; Savage, Peter A.

2013-01-01

108

A critical function for TGF-? signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells  

Microsoft Academic Search

The molecular mechanisms directing the development of 'natural' CD4+CD25+Foxp3+ regulatory T cells (Treg cells) in the thymus are not thoroughly understood. We show here that conditional deletion of transforming growth factor-? receptor I (T?RI) in T cells blocked the appearance of CD4+CD25+Foxp3+ thymocytes at postnatal days 3–5. Paradoxically, however, beginning 1 week after birth, the same T?RI-mutant mice showed accelerated

Yongzhong Liu; Pin Zhang; Jun Li; Ashok B Kulkarni; Sylvain Perruche; WanJun Chen

2008-01-01

109

Molecular mechanisms that control mouse and human TCR-?? and TCR-?? T cell development  

Microsoft Academic Search

Following specification of hematopoietic precursor cells into the T cell lineage, several developmental options remain available\\u000a to the immature thymocytes. The paradigm is that the outcome of the T cell receptor rearrangements and the corresponding T\\u000a cell receptor signaling events will be predominant to determine the first of these choices: the ?? versus ?? T cell pathways.\\u000a Here, we review

Tom Taghon; Ellen V. Rothenberg

2008-01-01

110

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

111

Mice expressing both B7-1 and viral glycoprotein on pancreatic beta cells along with glycoprotein-specific transgenic T cells develop diabetes due to a breakdown of T-lymphocyte unresponsiveness.  

PubMed Central

T lymphocytes have been implicated in the onset of many autoimmune diseases; however, the mechanisms underlying T-cell activation toward self antigens are poorly understood. To study whether T-lymphocyte costimulation can overcome the immunologic unresponsiveness observed in an in vivo model, we have created transgenic mice expressing the costimulatory mouse molecule B7-1, a ligand for the CD28 receptor, on pancreatic beta cells. We now report that triple-transgenic mice expressing both B7-1 and a viral glycoprotein on their beta cells, along with T cells expressing the viral-glycoprotein-specific transgenic T-cell receptor, all develop insulitis (lymphocytic infiltration of the pancreatic islets) and diabetes. In striking contrast, the T cells in double-transgenic mice expressing the same viral glycoprotein (but no B7) on their pancreatic beta cells and the transgenic T-cell receptor on their T cells, reported earlier, remain indifferent to the glycoprotein-expressing beta cells. In fact, all three transgenes are required to initiate immune-mediated destruction of the beta cells. Mice expressing any of the transgenes alone, or any two in combination, maintain normal islet architecture and never spontaneously develop insulitis or diabetes. Our results show that aberrant B7 expression on peripheral tissues may play an important role in the activation of self-reactive T cells and further suggest that abnormal expression of costimulatory receptors may be involved in various T-cell-mediated autoimmune diseases. Images PMID:7512724

Harlan, D M; Hengartner, H; Huang, M L; Kang, Y H; Abe, R; Moreadith, R W; Pircher, H; Gray, G S; Ohashi, P S; Freeman, G J

1994-01-01

112

TRIM28 mediates chromatin modifications at the TCR? enhancer and regulates the development of T and natural killer T cells  

PubMed Central

T-cell receptor–? (TCR?) rearrangement in CD4+CD8+ double-positive immature thymocytes is a prerequisite for production of ?? T cells and invariant natural killer T cells. This developmental event is regulated by the TCR? enhancer (E?), which induces chromatin modification and recruitment of the recombination-activating proteins Rag1 and Rag2. However, the molecular mechanism underlying the activation and long-range action of E? remains incompletely understood. We show here that the chromatin-modifying factor TRIM28 is highly expressed in double-positive thymocytes and persistently phosphorylated at serine 473. TRIM28 binds to E? and induces histone 3 lysine 4 trimethylation in the E? and distant regions of the TCR? locus, coupled with recruitment of Rag proteins. T-cell–conditional ablation of TRIM28 impaired TCR? gene rearrangement and compromised the development of ?? T cells and invariant natural killer T cells. These findings establish TRIM28 as a unique regulator of thymocyte development and highlight an epigenetic mechanism involving TRIM28-mediated active chromatin modification in the TCR? locus. PMID:23169648

Zhou, Xiao-Fei; Yu, Jiayi; Chang, Mikyoung; Zhang, Minying; Zhou, Dapeng; Cammas, Florence; Sun, Shao-Cong

2012-01-01

113

microRNA regulation of T lymphocyte immunity: modulation of molecular networks responsible for T cell activation, differentiation and development  

PubMed Central

MicroRNAs (miRNA) are a class of small non-coding RNAs that constitute an essential and evolutionarily conserved mechanism for post-transcriptional gene regulation. Multiple miRNAs have been described to play key roles in T lymphocyte development, differentiation and function. In this review we highlight the current literature regarding the differential expression of miRNAs in various models of mouse and human T cell biology and emphasize mechanistic understandings of miRNA regulation of thymocyte development, T cell activation, and differentiation into effector and memory subsets. We describe the participation of miRNAs in complex regulatory circuits shaping T cell proteomes in a context-dependent manner. It is striking that some miRNAs regulate multiple processes, while others only appear in limited functional contexts. It is also evident that the expression and function of specific miRNAs can differ between mouse and human systems. Ultimately, it is not always correct to simplify the complex events of T cell biology into a model driven by only one or two master regulator miRNAs. In reality, T cell activation and differentiation involves the expression of multiple miRNAs with many mRNA targets and thus, the true extent of miRNA regulation of T cell biology is likely far more vast than currently appreciated. PMID:24099302

Podshivalova, Katie; Salomon, Daniel R.

2014-01-01

114

From inception to output, Tcf1 and Lef1 safeguard development of T cells and innate immune cells.  

PubMed

Transcription factors have recurring roles during T cell development and activation. Tcf1 and Lef1 are known to be essential for early stages of thymocyte maturation. Recent research has revealed several novel aspects of their functionality. Tcf1 is induced at the very earliest step of specifying hematopoietic progenitors to the T cell lineage as a key target gene downstream of Notch activation. In addition to promoting maturation of T-lineage-committed thymocytes, Tcf1 functions as a tumor suppressor in developing thymocytes, and this is mediated, paradoxically, by restraining Lef1 expression. After positive selection, Tcf1 and Lef1 act together to direct CD4(+)CD8(+) double positive thymocytes to a CD4(+) T cell fate. Although not required for CD8(+) T cell differentiation, Tcf1 and Lef1 cooperate with Runx factors to achieve stable silencing of the Cd4 gene in CD8(+) T cells. Tcf1 is also found to have versatile roles in innate immune cells, which partly mirror its functions in mature T helper cells. Discrepancy in requirements of Tcf1/Lef1 and ?-catenin in T cells has been a long-standing enigma. We will review other protein factors interacting with Tcf1 and Lef1 and discuss their regulatory roles independent of ?-catenin. PMID:24847765

Steinke, Farrah C; Xue, Hai-Hui

2014-08-01

115

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

116

Diacylglycerol Kinases: Regulated Controllers of T Cell Activation, Function, and Development  

PubMed Central

Diacylglycerol kinases (DGKs) are a diverse family of enzymes that catalyze the conversion of diacylglycerol (DAG), a crucial second messenger of receptor-mediated signaling, to phosphatidic acid (PA). Both DAG and PA are bioactive molecules that regulate a wide set of intracellular signaling proteins involved in innate and adaptive immunity. Clear evidence points to a critical role for DGKs in modulating T cell activation, function, and development. More recently, studies have elucidated factors that control DGK function, suggesting an added complexity to how DGKs act during signaling. This review summarizes the available knowledge of the function and regulation of DGK isoforms in signal transduction with a particular focus on T lymphocytes. PMID:23531532

Joshi, Rohan P.; Koretzky, Gary A.

2013-01-01

117

In silico analysis of potential human T Cell antigens from Mycobacterium tuberculosis for the development of subunit vaccines against tuberculosis.  

PubMed

In silico analysis was used to predict MHC class I and class II promiscuous epitopes and potential antigens, from 24 novel T cell antigens of Mycobacterium tuberculosis. Majority of the antigens (16/24) had high affinity peptides to both MHC class I and class II alleles and higher population coverage compared to well-proven T cell antigens ESAT-6, CFP-10 and Ag85B. Among these, highest population coverage were calculated for three novel T cell antigens Rv0733 (97.24%), Rv0462 (96.9%) and Rv2251 (96.3%). The prediction results were experimentally tested by in vitro stimulation of these novel T cell antigens with blood drawn from QuantiFERON-TB Gold In-Tube (QFT-IT) positive healthy household contacts of tuberculosis patients and pulmonary TB patients. Significantly higher level interferon-? (IFN-?) was observed, with these novel T cell antigens, in healthy household contacts compared to pulmonary TB subjects (p?=?0.0001). In silico analysis also resulted in prediction of 36 promiscuous epitopes from the novel 24 T cell antigens. Population coverage for 4 out of the 36 promiscuous epitopes was >90% [67 VVLLWSPRS (Rv1324), 42 VVGVTTNPS (Rv1448c), 178 MRFLLSAKS (Rv0242c) and 842 IRLMALVEY (Rv3800c)]. Our results shows that these novel antigens and promiscuous epitopes identified from our analysis can further be investigated for their usefulness for subunit vaccine development. PMID:24467664

Devasundaram, Santhi; Deenadayalan, Anbarasu; Raja, Alamelu

2014-01-01

118

Differential Requirement for IL-2 and IL-15 during Bifurcated Development of Thymic Regulatory T Cells.  

PubMed

The developmental pathways of regulatory T cells (Treg) 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 Treg development. We find that Treg develop with distinctive kinetics, first appearing by day 4 among CD4 single-positive (SP) thymocytes. Accepted models of CD25(+)Foxp3(+) Treg 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 Treg 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

119

Dendritic cell-MHC class II and Itk regulate functional development of regulatory innate memory CD4+ T cells in bone marrow transplantation.  

PubMed

MHC class II (MHCII)-influenced CD4(+) T cell differentiation and function play critical roles in regulating the development of autoimmunity. The lack of hematopoietic MHCII causes autoimmune disease that leads to severe wasting in syngeneic recipients. Using murine models of bone marrow transplantation (BMT), we find that MHCII(-/-)?wild-type BMT developed disease, with defective development of innate memory phenotype (IMP, CD44(hi)/CD62L(lo)) CD4(+) T cells. Whereas conventional regulatory T cells are unable to suppress pathogenesis, IMP CD4(+) T cells, which include conventional regulatory T cells, can suppress pathogenesis in MHCII(-/-)?wild-type chimeras. The functional development of IMP CD4(+) T cells requires hematopoietic but not thymic MHCII. B cells and hematopoietic CD80/86 regulate the population size, whereas MHCII expression by dendritic cells is sufficient for IMP CD4(+) T cell functional development and prevention of pathogenesis. Furthermore, the absence of Tec kinase IL-2-inducible T cell kinase in MHCII(-/-) donors leads to preferential development of IMP CD4(+) T cells and partially prevents pathogenesis. We conclude that dendritic cells-MHCII and IL-2-inducible T cell kinase regulate the functional development of IMP CD4(+) T cells, which suppresses the development of autoimmune disorder in syngeneic BMTs. PMID:24610010

Huang, Weishan; Qi, Qian; Hu, Jianfang; Huang, Fei; Laufer, Terri M; August, Avery

2014-04-01

120

Instruction of naive CD4+ T-cell fate to T-bet expression and T helper 1 development: roles of T-cell receptor-mediated signals  

PubMed Central

Using T-cell receptor (TCR) transgenic mice, we demonstrate that TCR stimulation of naive CD4+ T cells induces transient T-bet expression, interleukin (IL)-12 receptor ?2 up-regulation, and GATA-3 down-regulation, which leads to T helper (Th)1 differentiation even when the cells are stimulated with peptide-loaded I-Ab-transfected Chinese hamster ovary cells in the absence of interferon-? (IFN-?) and IL-12. Sustained IFN-? and IL-12 stimulation augments naive T-cell differentiation into Th1 cells. Intriguingly, a significant Th1 response is observed even when T-bet–/– naive CD4+ T cells are stimulated through TCR in the absence of IFN-? or IL-12. Stimulation of naive CD4+ T cells in the absence of IFN-? or IL-12 with altered peptide ligand, whose avidity to the TCR is lower than that of original peptide, fails to up-regulate transient T-bet expression, sustains GATA-3 expression, and induces differentiation into Th2 cells. These results support the notion that direct interaction between TCR and peptide-loaded antigen-presenting cells, even in the absence of T-bet expression and costimulatory signals, primarily determine the fate of naive CD4+ T cells to Th1 cells. PMID:17490433

Ariga, Haruyuki; Shimohakamada, Yoko; Nakada, Makiyo; Tokunaga, Takeshi; Kikuchi, Takeshi; Kariyone, Ai; Tamura, Toshiki; Takatsu, Kiyoshi

2007-01-01

121

Bim dictates na?ve CD4 T cell lifespan and the development of age-associated functional defects1  

PubMed Central

With age peripheral naïve CD4 T cells become both longer-lived and functionally impaired and they express reduced levels of Bim, a pro-apoptotic Bcl-family member. In this study, we show that reduced Bim expression by naïve CD4 T cells intrinsically mediates their longer lifespan in the periphery. Moreover, using mixed bone marrow chimeras reconstituted with Bim+/+ and Bim+/? bone marrow cells, Bim+/? naïve CD4 T cells exhibit accelerated development of age-associated dysfunctions including reduced proliferation and IL-2 production and defective helper function for B cells, without any increase in their turnover. However, newly generated Bim+/? naïve CD4 T cells in middle aged mice are not defective, indicating an additional requirement for their persistence in the periphery. These age-associated immune defects develop independently of the “aged” host environment and without extensive division, distinguishing them from classic “senescence”. We suggest that the reduction of Bim levels with age in naïve CD4 T cell is the initiating step that leads to increased cellular lifespan and development of age-associated functional defects. PMID:20844198

Tsukamoto, Hirotake; Huston, Gail E.; Dibble, John; Duso, Debra K.; Swain, Susan L.

2012-01-01

122

Regulatory T Cell Ablation Causes Acute T Cell Lymphopenia  

PubMed Central

Regulatory T (Treg) cells enforce T cell homeostasis and maintain peripheral T cell tolerance. Here we report a previously unappreciated phenomenon of acute T cell lymphopenia in secondary lymphoid organs and non-lymphoid tissues triggered by Treg cell depletion that precedes the expansion of self-reactive T cells. Lymphopenia affects both neonates and adults indicating a dominant role of Treg cells in maintaining peripheral T cell numbers regardless of the developmental stage. The lymphopenia was neither triggered by caspase-dependent apoptosis nor macrophage-mediated clearance of T cells, nor diminished survival of naïve or recently activated T cells due to paucity of IL-7. It is possible that transient lymphopenia associated with congenital or acute Treg cell deficiency may contribute to the development of T cell mediated autoimmune disorders. PMID:24466225

Moltedo, Bruno; Hemmers, Saskia; Rudensky, Alexander Y.

2014-01-01

123

Targeted Sos1 deletion reveals its critical role in early T-cell development  

PubMed Central

Activation of the small G protein Ras is required for thymocyte differentiation. In thymocytes, Ras is activated by the Ras guanine exchange factors (RasGEFs) Sos1, Sos2, and RasGRP1. We report the development of a floxed allele of sos1 to assess the role of Sos1 during thymocyte development. Sos1 was required for pre–T-cell receptor (pre-TCR)– but not TCR-stimulated developmental signals. Sos1 deletion led to a partial block at the DN-to-DP transition. Sos1-deficient thymocytes showed reduced pre-TCR–stimulated proliferation, differentiation, and ERK phosphorylation. In contrast, TCR-stimulated positive selection, and negative selection under strong stimulatory conditions, remained intact in Sos1-deficient mice. Comparison of RasGEF expression at different developmental stages showed that relative to Sos2 and RasGRP1, Sos1 is most abundant in DN thymocytes, but least abundant in DP thymocytes. These data reveal that Sos1 is uniquely positioned to affect signal transduction early in thymocyte development. PMID:21746917

Kortum, Robert L.; Sommers, Connie L.; Alexander, Clayton P.; Pinski, John M.; Li, Wenmei; Grinberg, Alex; Lee, Jan; Love, Paul E.; Samelson, Lawrence E.

2011-01-01

124

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

125

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

126

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response  

PubMed Central

Programmed cell death 1 (PD-1) is an inhibitory coreceptor on immune cells and is essential for self-tolerance because mice genetically lacking PD-1 (PD-1?/?) develop spontaneous autoimmune diseases. PD-1?/? mice are also susceptible to severe experimental autoimmune encephalomyelitis (EAE), characterized by a massive production of effector/memory T cells against myelin autoantigen, the mechanism of which is not fully understood. We found that an increased primary response of PD-1?/? mice to heat-killed mycobacteria (HKMTB), an adjuvant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1?/? recombination activating gene (RAG)2?/? mice were found to drive antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1+/+ RAG2?/? mice. This result suggested PD-1’s involvement in the regulation of innate immune responses. Mice reconstituted with PD-1?/? RAG2?/? bone marrow and PD-1+/+ CD4+ T cells developed more severe EAE compared with the ones reconstituted with PD-1+/+ RAG2?/? bone marrow and PD-1+/+ CD4+ T cells. We found that upon recognition of HKMTB, CD11b+ macrophages from PD-1?/? mice produced very high levels of IL-6, which helped promote naive CD4+ T-cell differentiation into IL-17–producing cells. We propose a model in which PD-1 negatively regulates antimycobacterial responses by suppressing innate immune cells, which in turn prevents autoreactive T-cell priming and differentiation to inflammatory effector T cells. PMID:24043779

Rui, Yuxiang; Honjo, Tasuku; Chikuma, Shunsuke

2013-01-01

127

Depletion of m2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo.  

PubMed

Macrophages have key roles in tumor development and invasion in several human cancers, but little is known about their pathogenic role in cutaneous T-cell lymphoma (CTCL). Herein, we used PCR arrays to profile the expression of inflammatory cytokines in 12 patients with mycosis fungoides (MF), the most common variant of CTCL. Compared with normal controls, MF skin displayed increased mRNA levels of macrophage-related cytokines. Moreover, we detected CD163, a reliable marker of tumor-associated macrophages, in the tumor microenvironment of MF biopsies. To demonstrate that macrophages had a role in CTCL tumorigenesis, we xenografted human CTCL tumor cells in immunocompromised mice and compared tumor development using clodronate-containing liposomes to deplete macrophages in mice. Mice treated with clodronate-containing liposomes show markedly less tumor growth compared with mice treated with phosphate-buffered saline-containing liposomes (P<0.001). We also noted a strong correlation between macrophage depletion and decreased expression of vascular marker, CD31, and lymphatic marker, podoplanin, suggesting a role for macrophages in angiogenesis. In vitro, clodronate-containing liposomes killed activated murine M2 macrophages, but not Hut78 cells, demonstrating selective ability to induce apoptosis in macrophages. Our data indicate that macrophages have a critical role in the progression of Hut78 cell tumor formation in skin, thus providing a new therapeutic strategy for CTCL. PMID:24780929

Wu, Xuesong; Schulte, Brian C; Zhou, Youwen; Haribhai, Dipica; Mackinnon, Alexander C; Plaza, Jose A; Williams, Calvin B; Hwang, Sam T

2014-11-01

128

T Cell-Mediated Maintenance of Natural Self-Tolerance: its Breakdown as a Possible Cause of Various Autoimmune Diseases  

Microsoft Academic Search

This paper shows that elimination of a small subpopulation of peripheral T cells can elicit activation\\/expansion of self-reactive T cells from the remaining T cells and produce a wide spectrum of organ-specific and systemic auto-immune diseases in normal mice; reconstitution of the eliminated T-cell population prevents autoimmune development. This regulatory T-cell population expresses the CD25 molecule, apparently includes ‘activated’ T

Shimon Sakaguchi; Masaaki Toda; Masanao Asano; Misako Itoh; Stephen S. Morse; Noriko Sakaguchi

1996-01-01

129

Development of a T cell receptor targeting an HLA-A*0201 restricted epitope from the cancer-testis antigen SSX2 for adoptive immunotherapy of cancer.  

PubMed

The clinical success of adoptive immunotherapy of cancer relies on the selection of target antigens that are highly expressed in tumor cells but absent in essential normal tissues. A group of genes that encode the cancer/testis or cancer germline antigens have been proposed as ideal targets for immunotherapy due to their high expression in multiple cancer types and their restricted expression in immunoprivileged normal tissues. In the present work we report the isolation and characterization of human T cell receptors (TCRs) with specificity for synovial sarcoma X breakpoint 2 (SSX2), a cancer/testis antigen expressed in melanoma, prostate cancer, lymphoma, multiple myeloma and pancreatic cancer, among other tumors. We isolated seven HLA-A2 restricted T cell receptors from natural T cell clones derived from tumor-infiltrated lymph nodes of two SSX2-seropositive melanoma patients, and selected four TCRs for cloning into retroviral vectors. Peripheral blood lymphocytes (PBL) transduced with three of four SSX2 TCRs showed SSX241-49 (KASEKIFYV) peptide specific reactivity, tumor cell recognition and tetramer binding. One of these, TCR-5, exhibited tetramer binding in both CD4 and CD8 cells and was selected for further studies. Antigen-specific and HLA-A*0201-restricted interferon-? release, cell lysis and lymphocyte proliferation was observed following culture of TCR engineered human PBL with relevant tumor cell lines. Codon optimization was found to increase TCR-5 expression in transduced T cells, and this construct has been selected for development of clinical grade viral vector producing cells. The tumor-specific pattern of expression of SSX2, along with the potent and selective activity of TCR-5, makes this TCR an attractive candidate for potential TCR gene therapy to treat multiple cancer histologies. PMID:24681846

Abate-Daga, Daniel; Speiser, Daniel E; Chinnasamy, Nachimuthu; Zheng, Zhili; Xu, Hui; Feldman, Steven A; Rosenberg, Steven A; Morgan, Richard A

2014-01-01

130

Development of a T Cell Receptor Targeting an HLA-A*0201 Restricted Epitope from the Cancer-Testis Antigen SSX2 for Adoptive Immunotherapy of Cancer  

PubMed Central

The clinical success of adoptive immunotherapy of cancer relies on the selection of target antigens that are highly expressed in tumor cells but absent in essential normal tissues. A group of genes that encode the cancer/testis or cancer germline antigens have been proposed as ideal targets for immunotherapy due to their high expression in multiple cancer types and their restricted expression in immunoprivileged normal tissues. In the present work we report the isolation and characterization of human T cell receptors (TCRs) with specificity for synovial sarcoma X breakpoint 2 (SSX2), a cancer/testis antigen expressed in melanoma, prostate cancer, lymphoma, multiple myeloma and pancreatic cancer, among other tumors. We isolated seven HLA-A2 restricted T cell receptors from natural T cell clones derived from tumor-infiltrated lymph nodes of two SSX2-seropositive melanoma patients, and selected four TCRs for cloning into retroviral vectors. Peripheral blood lymphocytes (PBL) transduced with three of four SSX2 TCRs showed SSX241-49 (KASEKIFYV) peptide specific reactivity, tumor cell recognition and tetramer binding. One of these, TCR-5, exhibited tetramer binding in both CD4 and CD8 cells and was selected for further studies. Antigen-specific and HLA-A*0201-restricted interferon-? release, cell lysis and lymphocyte proliferation was observed following culture of TCR engineered human PBL with relevant tumor cell lines. Codon optimization was found to increase TCR-5 expression in transduced T cells, and this construct has been selected for development of clinical grade viral vector producing cells. The tumor-specific pattern of expression of SSX2, along with the potent and selective activity of TCR-5, makes this TCR an attractive candidate for potential TCR gene therapy to treat multiple cancer histologies. PMID:24681846

Abate-Daga, Daniel; Speiser, Daniel E.; Chinnasamy, Nachimuthu; Zheng, Zhili; Xu, Hui; Feldman, Steven A.; Rosenberg, Steven A.; Morgan, Richard A.

2014-01-01

131

The significance of low bcl-2 expression by CD45RO T cells in normal individuals and patients with acute viral infections. The role of apoptosis in T cell memory  

PubMed Central

The bcl-2 gene product has been shown to prevent apoptotic cell death. We have now investigated the bcl-2 protein expression by resting and activated mature T cell populations. Freshly isolated CD45RO+ T cells within CD4+ and CD8+ subsets expressed significantly less bcl-2 than CD45RO- (CD45RA+) T cells (p < 0.001). When CD45RA+ T cells within both CD4+ and CD8+ subsets were activated in vitro, the transition to CD45RO phenotype was associated with a decrease in bcl-2 expression. Patients with acute viral infections such as infectious mononucleosis caused by Epstein-Barr virus infections or chickenpox, resulting from varicella zoster virus infection, had circulating populations of activated CD45RO+ T cells which also showed low bcl-2 expression. In these patients, a significant correlation was seen between low bcl-2 expression by activated T cells and their apoptosis in culture (r = 0.94, p < 0.001). These results suggest that the primary activation of T cells leads to the expansion of a population that is destined to perish unless rescued by some extrinsic event. Thus the suicide of CD45RO+ T cells could be prevented by the addition of interleukin 2 to the culture medium which resulted in a concomitant increase in the bcl- 2 expression of these cells. Alternatively, apoptosis was also prevented by coculturing the activated T lymphocytes with fibroblasts, which maintained the viability of lymphoid cells in a restinglike state but with low bcl-2 expression. The paradox that the CD45RO+ population contains the primed/memory T cell pool yet expresses low bcl-2 and is susceptible to apoptosis can be reconciled by the observations that maintenance of T cell memory may be dependent on the continuous restimulation of T cells, which increases their bcl-2 expression. Furthermore, the propensity of CD45RO+ T cells to extravasate may facilitate encounter with fibroblast-like cells in tissue stroma and thus be an important additional factor which promotes the survival of selected primed/memory T cells in vivo. PMID:8340752

1993-01-01

132

Distribution and development of the postnatal murine V?1 T-cell receptor repertoire  

PubMed Central

Murine ?/? T cells express canonical V?5V?1 chains in the epidermis and V?6V?1 chains at reproductive sites. Both subsets carry an identical V?1-D?2-J?2 chain which completely lacks junctional diversity. These cells are thought to monitor tissue integrity via recognition of stress-induced self antigens. In this study, we showed by reverse transcription–polymerase chain reaction (RT-PCR), complementarity determining region 3 (CDR3) spectratyping and sequencing of the junctional regions of V?1 chains from C57BL/6 mice (aged 1 day to 14 months) that the canonical V?1-D?2-J?2 chain is also consistently present at other sites such as the thymus, gut, lung, liver, spleen and peripheral blood. In addition, we found multiple V?1 chains with fetal type rearrangements which were also shared among organs and among animals. These V?1 chains were typically characterized by a conserved amino acid motif, ‘GGIRA’. Furthermore, by analysing the early postnatal period at days 10 and 16, we demonstrated that the diversification of the thymic V?1 repertoire is not paralleled by a diversification of extrathymic V?1+?/? T cells. This indicates that only fetal type rearrangements survive at extrathymic sites. In conclusion, ?/? T cells expressing the canonical V?1-D?2-J?2 chain are not unique to the skin and reproductive sites. Furthermore, we found other ?/? T cells expressing fetal type V?1 chains which were shared among different organs and animals. Thus, ?/? T cells expressing conserved V?1 chains are likely to have important functions. We suggest a model in which this subset continuously recirculates throughout the organism and rapidly responds to stress-induced self antigens. PMID:20465568

Holtmeier, Wolfgang; Gille, Jens; Zeuzem, Stefan; Sinkora, Marek

2010-01-01

133

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

134

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

135

Human T cell leukemia virus type I and neurologic disease: events in bone marrow, peripheral blood, and central nervous system during normal immune surveillance and neuroinflammation.  

PubMed

Human T cell lymphotropic/leukemia virus type I (HTLV-I) has been identified as the causative agent of both adult T cell leukemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the exact sequence of events that occur during the early stages of infection are not known in detail, the initial route of infection may predetermine, along with host, environmental, and viral factors, the subset of target cells and/or the primary immune response encountered by HTLV-I, and whether an HTLV-I-infected individual will remain asymptomatic, develop ATL, or progress to the neuroinflammatory disease, HAM/TSP. Although a large number of studies have indicated that CD4(+) T cells represent an important target for HTLV-I infection in the peripheral blood (PB), additional evidence has accumulated over the past several years demonstrating that HTLV-I can infect several additional cellular compartments in vivo, including CD8(+) T lymphocytes, PB monocytes, dendritic cells, B lymphocytes, and resident central nervous system (CNS) astrocytes. More importantly, extensive latent viral infection of the bone marrow, including cells likely to be hematopoietic progenitor cells, has been observed in individuals with HAM/TSP as well as some asymptomatic carriers, but to a much lesser extent in individuals with ATL. Furthermore, HTLV-I(+) CD34(+) hematopoietic progenitor cells can maintain the intact proviral genome and initiate viral gene expression during the differentiation process. Introduction of HTLV-I-infected bone marrow progenitor cells into the PB, followed by genomic activation and low level viral gene expression may lead to an increase in proviral DNA load in the PB, resulting in a progressive state of immune dysregulation including the generation of a detrimental cytotoxic Tax-specific CD8(+) T cell population, anti-HTLV-I antibodies, and neurotoxic cytokines involved in disruption of myelin-producing cells and neuronal degradation characteristic of HAM/TSP. PMID:11807819

Grant, Christian; Barmak, Kate; Alefantis, Timothy; Yao, Jing; Jacobson, Steven; Wigdahl, Brian

2002-02-01

136

Numb-dependent integration of pre-TCR and p53 function in T-cell precursor development.  

PubMed

Numb asymmetrically segregates at mitosis to control cell fate choices during development. Numb inheritance specifies progenitor over differentiated cell fates, and, paradoxically, also promotes neuronal differentiation, thus indicating that the role of Numb may change during development. Here we report that Numb nuclear localization is restricted to early thymocyte precursors, whereas timed appearance of pre-T-cell receptor (pre-TCR) and activation of protein kinase C? promote phosphorylation-dependent Numb nuclear exclusion. Notably, nuclear localization of Numb in early thymocyte precursors favors p53 nuclear stabilization, whereas pre-TCR-dependent Numb nuclear exclusion promotes the p53 downmodulation essential for further differentiation. Accordingly, the persistence of Numb in the nucleus impairs the differentiation and promotes precursor cell death. This study reveals a novel regulatory mechanism for Numb function based on its nucleus-cytosol shuttling, coupling the different roles of Numb with different stages of T-cell development. PMID:25321479

Martin-Blanco, N M; Checquolo, S; Del Gaudio, F; Palermo, R; Franciosa, G; Di Marcotullio, L; Gulino, A; Canelles, M; Screpanti, I

2014-01-01

137

Numb-dependent integration of pre-TCR and p53 function in T-cell precursor development  

PubMed Central

Numb asymmetrically segregates at mitosis to control cell fate choices during development. Numb inheritance specifies progenitor over differentiated cell fates, and, paradoxically, also promotes neuronal differentiation, thus indicating that the role of Numb may change during development. Here we report that Numb nuclear localization is restricted to early thymocyte precursors, whereas timed appearance of pre-T-cell receptor (pre-TCR) and activation of protein kinase C? promote phosphorylation-dependent Numb nuclear exclusion. Notably, nuclear localization of Numb in early thymocyte precursors favors p53 nuclear stabilization, whereas pre-TCR-dependent Numb nuclear exclusion promotes the p53 downmodulation essential for further differentiation. Accordingly, the persistence of Numb in the nucleus impairs the differentiation and promotes precursor cell death. This study reveals a novel regulatory mechanism for Numb function based on its nucleus–cytosol shuttling, coupling the different roles of Numb with different stages of T-cell development. PMID:25321479

Martin-Blanco, N M; Checquolo, S; Del Gaudio, F; Palermo, R; Franciosa, G; Di Marcotullio, L; Gulino, A; Canelles, M; Screpanti, I

2014-01-01

138

Characterization of T Cells Immortalized by Taxl of Human T-cell Leukemia Virus Type 1  

Microsoft Academic Search

UMAN T-CELL leukemia virus type 1 (HTLV-l) is etiologically associated with adult T-cell leukemia (ATL) and tropical spastic paraparesis (TSP)\\/HTLV-1 -as- sociated myelopathy (HAM).'.' This virus characteristically has the ability to immortalize normal T cells in vitro.',' HTLV-l-immortalized T cells differ in many ways from normal T cells. The interleukin-2 (IL-2) requirement for cell growth is decreased in many HTLV-1-immortalized

Tsuyoshi Akagi; Hiroaki Ono; Kunitada Shimotohno

1995-01-01

139

Changes in the expression of potassium channels during mouse T cell development  

PubMed Central

In this report we have combined the whole-cell electrophysiological recording technique with flow microfluorometry to isolate phenotypically defined thymocytes and T lymphocytes. Results obtained showed that J11d-/Lyt-2-/L3T4- cells express none or very few delayed rectifier K+ channels, whereas most other Lyt-2-/L3T4- cells, as well as typical cortical thymocytes (Lyt-2+/L3T4+), do express K+ channels. Mature (Lyt-2+/L3T4- or Lyt-2-/L3T4+) thymocytes, which are heterogeneous for J11d expression, were also found to be heterogeneous for K+ channel expression. Consistent with this finding was the observation that the cortisone-resistant subpopulation of thymocytes, which express low levels of J11d, were enriched for cells expressing low levels of K+ channels. Mature phenotype peripheral T lymphocytes expressed very low levels of K+ channels, but upon activation with Con A were found to express high levels of K+ channels. The results suggest that K+ channel expression in T cells is developmentally regulated. Increased expression of the channel is induced in response to mitogenic signals throughout the T cell lineage. Expression of the channel, therefore, serves as a useful marker in defining steps in the T cell differentiation pathway. PMID:2431091

1986-01-01

140

Extracellular Signal-Regulated Kinase (Erk) Activation by the Pre-T Cell Receptor in Developing Thymocytes in Vivo  

PubMed Central

The first checkpoint in T cell development occurs between the CD4?CD8? and CD4+CD8+ stages and is associated with formation of the pre-T cell receptor (TCR). The signaling mechanisms that drive this progression remain largely unknown. Here, we show that extracellular signal–regulated kinases (ERKs)-1/2 are activated upon engagement of the pre-TCR. Using a novel experimental system, we demonstrate that expression of the pre-TCR by developing thymocytes induces ERK-1/2 activation within the thymus. In addition, the activation of this pre-TCR signaling cascade is mediated through Lck. These findings directly link pre-TCR complex formation with specific downstream signaling components in vivo. PMID:10587355

Michie, Alison M.; Trop, Sebastien; Wiest, David L.; Zuniga-Pflucker, Juan Carlos

1999-01-01

141

The Enigmatic Plasmacytoid T Cells Develop into Dendritic Cells with Interleukin (IL)-3 and CD40Ligand  

Microsoft Academic Search

Summary A subset of CD4 1 CD11c 2 CD3 2 blood cells was recently shown to develop into dendritic cells when cultured with monocyte conditioned medium. Here, we demonstrate that CD4 1 CD11c 2 CD3 2 cells, isolated from tonsils, correspond to the so-called plasmacytoid T cells, an obscure cell type that has long been observed by pathologists within secondary

Géraldine Grouard; Marie-Clotilde Rissoan; Luis Filgueira; Isabelle Durand; Jacques Banchereau; Yong-Jun Liu

142

CBFB-MYH11 hinders early T-cell development and induces massive cell death in the thymus  

Microsoft Academic Search

Recent studies suggest that the chromo- some 16 inversion, associated with acute myeloid leukemia M4Eo, takes place in hematopoietic stem cells. If this is the case, it is of interest to know the effects of the resulting fusion gene, CBFB-MYH11, on other lineages. Here we studied T-cell development in mice expressing Cbfb- MYH11 and compared them with mice compound-heterozygous for

Ling Zhao; Jennifer L. Cannons; Stacie Anderson; Martha Kirby; Liping Xu; Lucio H. Castilla; Pamela L. Schwartzberg; Remy Bosselut; P. Paul Liu

2007-01-01

143

Betaglycan (T?RIII) Is Expressed in the Thymus and Regulates T Cell Development by Protecting Thymocytes from Apoptosis  

PubMed Central

TGF-? type III receptor (T?RIII) is a coreceptor for TGF? family members required for high-affinity binding of these ligands to their receptors, potentiating their cellular functions. TGF-? [1]–[3], bone morphogenetic proteins (BMP2/4) and inhibins regulate different checkpoints during T cell differentiation. Although T?RIII is expressed on hematopoietic cells, the role of this receptor in the immune system remains elusive. Here, we provide the first evidence that T?RIII is developmentally expressed during T cell ontogeny, and plays a crucial role in thymocyte differentiation. Blocking of endogenous T?RIII in fetal thymic organ cultures led to a delay in DN-DP transition. In addition, in vitro development of T?RIII?/? thymic lobes also showed a significant reduction in absolute thymocyte numbers, which correlated with increased thymocyte apoptosis, resembling the phenotype reported in Inhibin ? ?/? thymic lobes. These data suggest that Inhibins and T?RIII may function as a molecular pair regulating T cell development. PMID:22952931

Aleman-Muench, German R.; Mendoza, Valentin; Stenvers, Kaye; Garcia-Zepeda, Eduardo A.; Lopez-Casillas, Fernando; Raman, Chander; Soldevila, Gloria

2012-01-01

144

The protein tyrosine phosphatase PTPN4/PTP-MEG1, an enzyme capable of dephosphorylating the TCR ITAMs and regulating NF-?B, is dispensable for T cell development and/or T cell effector functions  

PubMed Central

T cell receptor signaling processes are controlled by the integrated actions of families of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPases). Several distinct cytosolic protein tyrosine phosphatases have been described that are able to negatively regulate TCR signaling pathways, including SHP-1, SHP-2, PTPH1, and PEP. Using PTPase substrate-trapping mutants and wild type enzymes, we determined that PTPN4/PTP-MEG1, a PTPH1-family member, could complex and dephosphorylate the ITAMs of the TCR ? subunit. In addition, the substrate-trapping derivative augmented basal and TCR-induced activation of NF-?B in T cells. To characterize the contribution of this PTPase in T cells, we developed PTPN4-deficient mice. T cell development and TCR signaling events were comparable between wild type and PTPN4-deficient animals. The magnitude and duration of TCR-regulated ITAM phosphorylation, as well as overall protein phosphorylation, was unaltered in the absence of PTPN4. Finally, Th1- and Th2-derived cytokines and in vivo immune responses to Listeria monocytogeneswere equivalent between wild type and PTPN4-deficient mice. These findings suggest that additional PTPases are involved in controlling ITAM phosphorylations. PMID:18614237

Young, Jennifer A.; Becker, Amy M.; Medeiros, Jennifer J.; Shapiro, Virginia S.; Wang, Andrew; Farrar, J. David; Quill, Timothy A.; van Huijsduijnen, Rob Hooft; van Oers, Nicolai S.C.

2008-01-01

145

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

PubMed Central

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

146

Murine Splenic CD4+ T Cells, Induced by Innate Immune Cell Interactions and Secreted Factors, Develop Antileukemia Cytotoxicity.  

PubMed

Inciting the cellular arm of adaptive immunity has been the fundamental goal of cancer immunotherapy strategies, specifically focusing on inducing tumor antigen-specific responses by CD8(+) cytotoxic T lymphocytes (CTL). However, there is an emerging appreciation that the cytotoxic function of CD4(+) T cells can be effective in a clinical setting. Harnessing this potential will require an understanding of how such cells arise. In this study, we use an IL12-transduced variant of the 70Z/3 leukemia cell line in a B6D2F1 (BDF1) murine model system to reveal a novel cascade of cells and soluble factors that activate anticancer CD4(+) killer cells. We show that natural killer T cells play a pivotal role by activating dendritic cells in a contact-dependent manner; soluble products of this interaction, including MCP-1, propagate the activation signal, culminating in the development of CD4(+) CTLs that directly mediate an antileukemia response while also orchestrating a multipronged attack by other effector cells. A more complete picture of the conditions that induce such a robust response will allow us to capitalize on CD4(+) T-cell plasticity for maximum therapeutic effect. Cancer Immunol Res; 2(11); 1113-24. ©2014 AACR. PMID:25154710

Nelles, Megan E; Moreau, Joshua M; Furlonger, Caren L; Berger, Alexandra; Medin, Jeffrey A; Paige, Christopher J

2014-11-01

147

Development of a luciferase based viral inhibition assay to evaluate vaccine induced CD8 T-cell responses.  

PubMed

Emergence of SIV and HIV specific CD8 T cells has been shown to correlate with control of in vivo replication. Poor correlation between IFN-? ELISPOT responses and in vivo control of the virus has triggered the development of more relevant assays to assess functional HIV-1 specific CD8 T-cell responses for the evaluation and prioritization of new HIV-1 vaccine candidates. We previously established a viral inhibition assay (VIA) that measures the ability of vaccine-induced CD8 T-cell responses to inhibit viral replication in autologous CD4 T cells. In this assay, viral replication is determined by measuring p24 in the culture supernatant. Here we describe the development of a novel VIA, referred to as IMC LucR VIA that exploits replication-competent HIV-1 infectious molecular clones (IMCs) in which the complete proviral genome is strain-specific and which express the Renilla luciferase (LucR) gene to determine viral growth and inhibition. The introduction of the luciferase readout does provide significant improvement of the read out time. In addition to switching to the LucR read out, changes made to the overall protocol resulted in the miniaturization of the assay from a 48 to a 96-well plate format, which preserved sample and allowed for the introduction of replicates. The overall assay time was reduced from 13 to 8 days. The assay has a high degree of specificity, and the previously observed non-specific background inhibition in cells from HIV-1 negative volunteers has been reduced dramatically. Importantly, we observed an increase in positive responses, indicating an improvement in sensitivity compared to the original VIA. Currently, only a limited number of "whole-genome" IMC-LucR viruses are available and our efforts will focus on expanding the panel to better evaluate anti-viral breadth. Overall, we believe the IMC LucR VIA provides a platform to assess functional CD8 T-cell responses in large-scale clinical trial testing, which will enhance the ability to select the most promising HIV-1 vaccine candidates capable of controlling HIV-1 replication in vivo. PMID:24291126

Naarding, Marloes A; Fernandez, Natalia; Kappes, John C; Hayes, Peter; Ahmed, Tina; Icyuz, Mert; Edmonds, Tara G; Bergin, Philip; Anzala, Omu; Hanke, Tomas; Clark, Lorna; Cox, Josephine H; Cormier, Emmanuel; Ochsenbauer, Christina; Gilmour, Jill

2014-07-01

148

T-cell receptor gene rearrangements as markers of lineage and clonality in T-cell neoplasms.  

PubMed Central

Ig gene rearrangements represent markers of lineage, clonality, and differentiation of B cells, allowing a molecular diagnosis and immunogenotypic classification of B-cell neoplasms. We sought to apply a similar approach to the study of T-cell populations by analyzing rearrangements of the T-cell receptor beta-chain (T beta) gene. Our analysis, by Southern blotting hybridization using T beta-specific probes of DNAs from polyclonal T cells and from 12 T-cell tumors, indicates that T beta gene rearrangement patterns can be used as markers of (i) lineage, allowing the identification of polyclonal T-cell populations, and (ii) clonality, allowing the detection of monoclonal T-cell tumors. In addition, our data indicate that T beta gene rearrangements represent early and general markers of T-cell differentiation since they are detectable in histologically different tumors at all stages of T-cell development. The ability to determine lineage, clonality, and stage of differentiation has significant implications for future experimental and clinical studies on normal and neoplastic T cells. Images PMID:2987928

Flug, F; Pelicci, P G; Bonetti, F; Knowles, D M; Dalla-Favera, R

1985-01-01

149

T Cell-Tumor Interaction Directs the Development of Immunotherapies in Head and Neck Cancer  

PubMed Central

The competent immune system controls disease effectively due to induction, function, and regulation of effector lymphocytes. Immunosurveillance is exerted mostly by cytotoxic T-lymphocytes (CTLs) while specific immune suppression is associated with tumor malignancy and progression. In squamous cell carcinoma of the head and neck, the presence, activity, but also suppression of tumor-specific CTL have been demonstrated. Functional CTL may exert a selection pressure on the tumor cells that consecutively escape by a combination of molecular and cellular evasion mechanisms. Certain of these mechanisms target antitumor effector cells directly or indirectly by affecting cells that regulate CTL function. This results in the dysfunction or apoptosis of lymphocytes and dysregulated lymphocyte homeostasis. Another important tumor-escape mechanism is to avoid recognition by dysregulation of antigen processing and presentation. Thus, both induction of functional CTL and susceptibility of the tumor and its microenvironment to become T cell targets should be considered in CTL-based immunotherapy. PMID:21234340

Albers, A. E.; Strauss, L.; Liao, T.; Hoffmann, T. K.; Kaufmann, A. M.

2010-01-01

150

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

151

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

152

Recognition of Glioma Stem Cells by Genetically Modified T Cells Targeting EGFRvIII and Development of Adoptive Cell Therapy for Glioma  

PubMed Central

Abstract 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

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.

2012-01-01

153

Angioimmunoblastic T-Cell Lymphoma  

MedlinePLUS

Angioimmunoblastic T-Cell Lymphoma Overview Lymphoma is the most common blood cancer. The two main forms of lymphoma are ... develop into lymphomas: B-lymphocytes (B-cells) and T-lymphocytes (T-cells). Cancerous lymphocytes can travel to ...

154

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

PubMed

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

2013-08-01

155

The inter-relatedness and interdependence of mouse T cell receptor gammadelta+ and alphabeta+ cells.  

PubMed

Although T cell receptor (TCR)gammadelta+ and TCRalphabeta+ cells are commonly viewed as functionally independent, their relatedness and potential interdependence remain enigmatic. Here we have identified a gene profile that distinguishes mouse gammadelta cell populations from conventional alphabeta T cells. However, this profile was also expressed by sets of unconventional alphabeta T cells. Therefore, whereas TCR specificity determines the involvement of a T cell in an immune response, the cell's functional potential, as assessed by gene expression, does not segregate with the TCR. By monitoring the described gene profile, we show that gammadelta T cell development and function in TCRbeta-deficient mice was impaired because of the absence of alphabeta T cell progenitors. Thus, normal gammadelta cell development is dependent on the development of conventional alphabeta T cells. PMID:14502287

Pennington, Daniel J; Silva-Santos, Bruno; Shires, John; Theodoridis, Efstathios; Pollitt, Christopher; Wise, Emma L; Tigelaar, Robert E; Owen, Michael J; Hayday, Adrian C

2003-10-01

156

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

PubMed Central

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

2010-01-01

157

Rhizoctonia Bataticola Lectin (RBL) Induces Caspase-8-Mediated Apoptosis in Human T-Cell Leukemia Cell Lines but Not in Normal CD3 and CD34 Positive Cells  

PubMed Central

We have previously demonstrated immunostimulatory activity of a fungal lectin, Rhizoctonia bataticola lectin (RBL), towards normal human peripheral blood mononuclear cells. The present study aimed to explore the anticancer activities of RBL using human leukemic T-cell lines, Molt-4, Jurkat and HuT-78. RBL exhibited significant binding (>90%) to the cell membrane that was effectively inhibited by complex glycoproteins such as mucin (97% inhibition) and asialofetuin (94% inhibition) but not simple sugars such as N-acetyl-D-galactosamine, glucose and sucrose. RBL induced a dose and time dependent inhibition of proliferation and induced cytotoxicity in the cell lines. The percentage of apoptotic cells, as determined by hypodiploidy, was 33% and 42% in Molt-4 and Jurkat cells, respectively, compared to 3.11% and 2.92% in controls. This effect was associated with a concomitant decrease in the G0/G1 population. Though initiator caspase-8 and -9 were activated upon exposure to RBL, inhibition of caspase-8 but not caspase-9 rescued cells from RBL-induced apoptosis. Mechanistic studies revealed that RBL induced cleavage of Bid, loss of mitochondrial membrane potential and activation of caspase-3. The expression of the anti-apoptotic proteins Bcl-2 and Bcl-X was down regulated without altering the expression of pro-apoptotic proteins- Bad and Bax. In contrast to leukemic cells, RBL did not induce apoptosis in normal PBMC, isolated CD3+ve cells and undifferentiated CD34+ve hematopoietic stem and progenitor cells (HSPCs). The findings highlight the differential effects of RBL on transformed and normal hematopoietic cells and suggest that RBL may be explored for therapeutic applications in leukemia. PMID:24244478

Pujari, Radha; Eligar, Sachin M.; Kumar, Natesh; Barkeer, Srikanth; Reddy, Vishwanath; Swamy, Bale M.; Inamdar, Shashikala R.; Shastry, Padma

2013-01-01

158

Thymic Damage, Impaired Negative Selection, and Development of Chronic Graft-versus-Host Disease Caused by Donor CD4+ and CD8+ T Cells  

PubMed Central

Prevention of chronic graft-versus-host disease (cGVHD) remains a major challenge in allogeneic hematopoietic cell transplantation (HCT), due to limited understanding of cGVHD pathogenesis and lack of appropriate animal models. Here, we report that, in classical acute GVHD models with C57BL/6 donors and MHC-mismatched BALB/c recipients and with C3H.SW donors and MHC-matched C57BL/6 recipients, GVHD recipients surviving for more than 60 days after HCT developed cGVHD characterized by cutaneous fibrosis, tissue damage in the salivary gland and the presence of serum autoantibodies. Donor CD8+ T cells were more potent than CD4+ T cells for inducing cGVHD. The recipient thymus and de novo-generated, donor-derived CD4+ T cells were required for induction of cGVHD by donor CD8+ T cells but not by donor CD4+ T cells. Donor CD8+ T cells preferentially damaged recipient medullary thymic epithelial cells and impaired negative selection, resulting in production of autoreactive CD4+ T cells that perpetuated damage to the thymus and augmented the development of cGVHD. Short-term anti-CD4 monoclonal antibody treatment early after HCT enabled recovery from thymic damage and prevented cGVHD. These results demonstrate that donor CD8+ T cells cause cGVHD solely through thymic-dependent mechanisms, while CD4+ T cells can cause cGVHD through either thymic-dependent or independent mechanisms. PMID:23709681

Wu, Tao; Young, James S.; Johnston, Heather; Ni, Xiong; Deng, Ruishu; Racine, Jeremy; Wang, Miao; Wang, Audrey; Todorov, Ivan; Wang, Jianmin; Zeng, Defu

2013-01-01

159

Molecular Evidence for a Thymus-Independent Partial T Cell Development in a FOXN1?/? Athymic Human Fetus  

PubMed Central

The thymus is the primary organ able to support T cell ontogeny, abrogated in FOXN1?/? human athymia. Although evidence indicates that in animal models T lymphocytes may differentiate at extrathymic sites, whether this process is really thymus-independent has still to be clarified. In an athymic FOXN1?/? fetus, in which we previously described a total blockage of CD4+ and partial blockage of CD8+ cell development, we investigated whether intestine could play a role as extrathymic site of T-lymphopoiesis in humans. We document the presence of few extrathymically developed T lymphocytes and the presence in the intestine of CD3+ and CD8+, but not of CD4+ cells, a few of them exhibiting a CD45RA+ naïve phenotype. The expression of CD3??pT?, RAG1 and RAG2 transcripts in the intestine and TCR gene rearrangement was also documented, thus indicating that in humans the partial T cell ontogeny occurring at extrathymic sites is a thymus- and FOXN1-independent process. PMID:24349129

Fusco, Anna; Panico, Luigi; Gorrese, Marisa; Bianchino, Gabriella; Barone, Maria V.; Grieco, Vitina; Vitiello, Laura; D'Assante, Roberta; Romano, Rosa; Palamaro, Loredana; Scalia, Giulia; Vecchio, Luigi Del; Pignata, Claudio

2013-01-01

160

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

PubMed Central

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). Pharmacological studies utilizing inhibitors have suggested that Mnk1/2 play 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 demonstrated here that T-cell receptor (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 Freud's adjuvant, correlating with milder experimental autoimmune encephalitis scores, it does not affect T helper cell differentiation in vitro. Together, these data suggest that Mnk1/2 play a minimal role in T-cell development and activation but may regulate non-T-cell lineages to control Th1/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

2012-01-01

161

Cytokines from activated T cells induce normal endothelial cells to acquire the phenotypic and functional features of AIDS-Kaposi's sarcoma spindle cells.  

PubMed Central

Kaposi's sarcoma (KS) is a proliferative disease of vascular origin particularly frequent in HIV-1-infected homosexual men (AIDS-KS) and characterized by proliferating spindle-shaped cells, angiogenesis, and inflammatory cell infiltration. Previous work has suggested that KS spindle cells are of endothelial cell origin and that chronic immune activation via the release of inflammatory cytokines may cooperate with basic fibroblast growth factor (bFGF) and the HIV-1 Tat protein in the induction and progression of AIDS-KS. Here we show that KS spindle cells have features of activated endothelial cells, and that conditioned media from activated T cells, rich in the same inflammatory cytokines increased in HIV-1-infected individuals, induce normal endothelial cells to acquire the phenotypic and functional features of KS cells. These include (a) acquisition of a similar pattern of cell surface antigen expression; (b) similar proliferative response to bFGF; (c) induction of the responsiveness to the mitogenic effect of extracellular HIV-1 Tat protein that is now able to promote the G1-S transition of endothelial cell cycle; and (d) induction in nude mice of vascular lesions closely resembling early KS as well as the lesions induced by inoculation of KS cells. These results suggest that chronic immune activation, via release of inflammatory cytokines, may play a role in the induction of KS. Images PMID:7535796

Fiorelli, V; Gendelman, R; Samaniego, F; Markham, P D; Ensoli, B

1995-01-01

162

microRNAs at the regulatory frontier: an investigation into how microRNAs impact the development and effector functions of CD4 T cells  

Microsoft Academic Search

CD4 T cells are an integral part of adaptive immunity. microRNAs have been identified as fundamental regulators of post-transcriptional\\u000a programs and to play roles in T lymphocytes’ development, differentiation, and effector functions. To better understand the\\u000a role of miRNAs in T cells and to identify potential therapeutic tools and targets, we have undertaken studies of miRNAs that\\u000a modulate or are

Erik Allen Lykken; Qi-Jing Li

2011-01-01

163

[Towards novel tuberculosis and leprosy vaccine development: the role of Th1-inducing peptide in cytotoxic T cell differentiation].  

PubMed

The effectiveness of a vaccine against tuberculosis and leprosy is mainly judged by its capability to induce memory CD8 cytotoxic T cells (CTL). It has been reported that 'help' from CD4+ T cells is required to induce memory CTL. However, how CD4+ T cells instruct or support memory CTL during priming phase has not been resolved in detail. Therefore, we examined the helper function of CD4+ T cells in CTL differentiation. Peptide-25 is the major T cell epitope of Ag85B of Mycobacterium tuberculosis. We found that this peptide induced the expression of T-bet and TATA box binding protein-associated factor that can induce the chromatin remodeling of ifn-gamma gene, and as a result induced Th1 differentiation even in the absence of IFN-gamma and IL-12. Next, we established an in vitro CTL differentiation system using Peptide-25, Peptide-25 specific CD4+ T cells, OVA specific CD8+ T cells and splenic DC. By using this system, we found that CD4+ T cells activated DC even in the absence of IFN-gamma and CD40 ligand association, and the activated DC induced the functional differentiation of CTL. To identify the regulatory factors for DC activation, we analyzed the gene expression profile of helper CD4 T cells and identified 27 genes. Taken together, these results suggest that the inducing factors for Th1 differentiation are not indispensable to induce the functional differentiation of CTL. PMID:24579458

Tamura, Toshiki; Shimohakamada, Yoko; Makino, Masahiko

2013-12-01

164

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; Omede, Paola; Palumbo, Antonio; Boccadoro, Mario; Massaia, Massimo

2014-01-01

165

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

166

Hepatosplenic T cell lymphoma.  

PubMed

A 26 year old lady came with intermittent fever since eight months. She also complained of abdominal pain and decreased appetite for six months. She had swelling of feet and distension of abdomen due to ascites since one month. There was history of jaundice one month back. On radiological examination, hepatomegaly with dilated portal vein, massive splenomegaly and ascites without any lymphadenopathy was noted. Chest X-ray was normal. Blood examination and bone marrow studies were inconclusive. We received her liver biopsy, which showed normal architecture and sinusoidal infiltration by a monomorphic population of small to intermediate sized lymphoid cells. Portal tracts were free of such infiltrate. These lymphoid cells were LCA, CD3, CD43 positive and negative for CD20, CD34, CD4, CD8 and c-kit. Based on all these features, a diagnosis of Hepatosplenic T cell lymphoma was made. She was treated symptomatically, however she died within two months of diagnosis. PMID:25332524

Khan, Nadeem Noor Mohammad; Jijina, Farah F; Joshi, Amita S; Gupte, Prajakta A; Chaturvedi, Rachana A

2014-09-01

167

MicroRNA regulation of T-lymphocyte immunity: modulation of molecular networks responsible for T-cell activation, differentiation, and development.  

PubMed

MicroRNAs (miRNA) are a class of small non-coding RNAs that constitute an essential and evolutionarily conserved mechanism for post-transcriptional gene regulation. Multiple miRNAs have been described to play key roles in T-lymphocyte development, differentiation, and function. In this review, we highlight the current literature regarding the differential expression of miRNAs in various models of murine and human T-cell biology. We emphasize mechanistic understandings of miRNA regulation of thymocyte development, T-cell activation, and differentiation into effector and memory subsets. We describe the participation of miRNAs in complex regulatory circuits shaping T-cell proteomes in a context-dependent manner. It is striking that some miRNAs regulate multiple processes, while others only appear in limited functional contexts. It is also evident that the expression and function of specific miRNAs can differ between murine and human systems. Ultimately, it is not always correct to simplify the complex events of T-cell biology into a model driven by only one or two master regulator miRNAs. In reality, T-cell activation and differentiation involve the expression of multiple miRNAs with many mRNA targets; thus, the true extent of miRNA regulation of T-cell biology is likely far more vast than currently appreciated. PMID:24099302

Podshivalova, Katie; Salomon, Daniel R

2013-01-01

168

Characterizing T-Cell Autoimmunity  

Microsoft Academic Search

\\u000a Immunological mechanisms which precipitate autoimmune diabetes involve the influence of a genetic footprint on the phenotype\\u000a of the T-cell response to self-antigens, and on development of pathological outcomes in immune responses resulting in T1D.\\u000a For one of the human diabetes antigens, proinsulin, recent findings allow the emergence of a model in which elements of genetically\\u000a biased T-cell development and peptide

Ivana Durinovic-Belló; Gerald T. Nepom

169

Oxidative Stress, T Cell DNA Methylation and Lupus  

PubMed Central

Objective Lupus develops when genetically predisposed people encounter environmental agents such as UV light, silica, infections and cigarette smoke that cause oxidative stress, but how oxidative damage modifies the immune system to cause lupus flares is unknown. We reported that inhibiting DNA methylation in CD4+ T cells by blocking ERK pathway signaling is sufficient to alter gene expression, and that the modified cells cause lupus-like autoimmunity in mice. We also reported that T cells from patients with active lupus have decreased ERK pathway signaling, decreased DNA methylation, and overexpress genes normally suppressed by DNA methylation. We therefore tested whether oxidizing agents decrease T cell ERK pathway signaling, decrease DNA methyltransferase levels, and cause demethylation and overexpression of T cell genes similar to that found in T cells from patients with active lupus. Methods CD4+ T cells were treated with the oxidizers H2O2 or ONOO?. Effects on ERK pathway signaling were measured by immunoblotting, Dnmt1 levels by RT-PCR, and the methylation and expression of T cell genes were measured using flow cytometry, RT-PCR and bisulfite sequencing. Results H2O2 and ONOO? inhibited T cell ERK pathway signaling by inhibiting the upstream regulator PKC?, decreased Dnmt1 levels, and caused demethylation and overexpression genes previously shown to suppressed by DNA methylation in T cells from patients with active lupus. Conclusions Oxidative stress may contribute to human lupus flares by inhibiting T cell ERK pathway signaling to decrease Dnmt1 and cause DNA demethylation. PMID:24577881

Li, YePeng; Gorelik, Gabriela; Strickland, Faith M.; Richardson, Bruce C.

2014-01-01

170

3-Hydroxykynurenine Suppresses CD4+ T-Cell Proliferation, Induces T-Regulatory-Cell Development, and Prolongs Corneal Allograft Survival  

PubMed Central

Purpose. IDO (indoleamine 2,3-dioxygenase) modulates the immune response by depletion of the essential amino acid tryptophan, and IDO overexpression has been shown to prolong corneal allograft survival. This study was conducted to examine the effect of kynurenines, the products of tryptophan breakdown and known to act directly on T lymphocytes, on corneal graft survival. Methods. The effects of kynurenines on T-cell proliferation and death, T-regulatory-cell development, and dendritic cell function, phenotype, and viability were analyzed in vitro. The effect of topical and systemic administration of 3-hydroxykynurenine (3HK) on orthotopic murine corneal allograft survival was examined. Results. T-lymphocyte proliferation was inhibited by two of the four different kynurenines: 3HK and 3-hydroxyanthranilic acid (3HAA). This effect was accompanied by significant T-cell death. Neither 3HK nor 3HAA altered dendritic cell function, nor did they induce apoptosis or pathogenicity to corneal endothelial cells. Administration of systemic and topical 3HK to mice receiving a fully mismatched corneal graft resulted in significant prolongation of graft survival (median survival of control grafts, 12 days; of treated, 19 and 15 days, respectively; P < 0.0003). While systemic administration of 3HK was associated with a significant depletion of CD4+ T, CD8+ T, and B lymphocytes in peripheral blood, no depletion was found after topical administration. Conclusions. The production of kynurenines, in particular 3HK and 3HAA, may be one mechanism (in addition to tryptophan depletion) by which IDO prolongs graft survival. These molecules have potential as specific agents for preventing allograft rejection in patients at high rejection risk. PMID:21212175

Zaher, Sarah S.; Germain, Conrad; Fu, Hongmei; Larkin, Daniel F. P.

2011-01-01

171

Thymic epithelial requirement for ?? T cell development revealed in the cell ablation transgenic system with TSCOT promoter.  

PubMed

In order to investigate the role of thymic epithelial cell (TEC) subsets during T-cell development, we established a new transgenic system, enabling inducible cell-specific ablation as well as marking the TEC subsets using bicistronic bacterial nitroreductase and EGFP genes. Two different lengths of the TSCOT promoter in transgenic mice, named 3.1T-NE and 9.1T-NE, drive EGFP expression into TECs. In adult life, EGFP expression was located in the medulla with a smaller 3.1 kb TSCOT promoter, while it was maintained in the cortex with a 9.1 kb promoter, suggesting putative TEC specific as well as compartment specific cis elements within two promoters. Nitroreductase induced cell death was specific without bystander killing upon the treatment of prodrugs such as nitrofurantoin and metronidazol. The degree of cell death was dependent on the dose of the prodrug in the cell and the fetal thymic organ cultures (FTOCs). Fetal thymic stromal populations were analyzed based on the expression levels of EpCAM, MHCII, CDR1 and/or UEA-1. EGFP expression patterns varied among subsets indicating the differential TSCOT promoter activity in each TEC subset. Prodrug treatment in FTOCs reduced the numbers of total and subsets of thymocytes. A CD4(+)CD8(+) double positive cell population was highly susceptible in both transgenic lines. Surprisingly, there was a distinct reduction in ?? T cell population only in the 9.1T-NE thymus, indicating that they require a NTREGFP expressing TEC population. Therefore, these results support a division of labor within TEC subsets for the ?? and ?? lineage specification. PMID:23178972

Lee, Gwanghee; Kim, Ki Yeon; Chang, Cheong-Hee; Kim, Moon Gyo

2012-11-01

172

Natural killer T cells are dispensable in the development of allergen-induced airway hyperresponsiveness, inflammation and remodelling in a mouse model of chronic asthma.  

PubMed

Natural killer T (NK T) cells have been shown to play an essential role in the development of allergen-induced airway hyperresponsiveness (AHR) and/or airway inflammation in mouse models of acute asthma. Recently, NK T cells have been reported to be required for the development of AHR in a virus induced chronic asthma model. We investigated whether NK T cells were required for the development of allergen-induced AHR, airway inflammation and airway remodelling in a mouse model of chronic asthma. CD1d-/- mice that lack NK T cells were used for the experiments. In the chronic model, AHR, eosinophilic inflammation, remodelling characteristics including mucus metaplasia, subepithelial fibrosis and increased mass of the airway smooth muscle, T helper type 2 (Th2) immune response and immunoglobulin (Ig)E production were equally increased in both CD1d-/- mice and wild-type mice. However, in the acute model, AHR, eosinophilic inflammation, Th2 immune response and IgE production were significantly decreased in the CD1d-/- mice compared to wild-type. CD1d-dependent NK T cells may not be required for the development of allergen-induced AHR, eosinophilic airway inflammation and airway remodelling in chronic asthma model, although they play a role in the development of AHR and eosinophilic inflammation in acute asthma model. PMID:20456411

Koh, Y-I; Shim, J-U; Lee, J-H; Chung, I-J; Min, J-J; Rhee, J H; Lee, H C; Chung, D H; Wi, J-O

2010-07-01

173

CD47 ligation selectively inhibits the development of human naive T cells into Th1 effectors.  

PubMed

The CD47 Ag, also named integrin-associated protein, was recently reported to regulate the production of IL-12 by human monocytes and dendritic cells. The present study shows that CD47 ligation by CD47 mAb in primary cultures of cord blood mononuclear cells inhibits IL-12-driven Th1 cell development, as revealed by the cytokine secretion profile at restimulation and IFN-gamma production at the single-cell level. F(ab')(2) fragments of CD47 mAb or the synthetic peptide 4N1K, corresponding to the CD47 binding site of thrombospondin, display the same activity. CD47 engagement does not change the phenotype of IL-12-primed cells from Th1 to Th2 or affect IL-4-induced Th2 cell development. Moreover, CD47 mAb inhibits IL-12- but not IL-4-induced IL-2 production as well as IFN-gamma in primary cultures, which was correlated with a decrease of the IL-12Rbeta2 chain expression. Inclusion of exogenous IL-2 at priming corrects IL-12R expression as well as the inhibition of Th1 cell development. The data thus underline the role of IL-2 in Th1 cell development and further suggest that targeting IL-2 and IL-12 simultaneously may have some therapeutic advantage in Th1 autoimmune diseases. PMID:11035105

Avice, M N; Rubio, M; Sergerie, M; Delespesse, G; Sarfati, M

2000-10-15

174

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

175

Development, cytokine profile and function of human interleukin 17–producing helper T cells  

Microsoft Academic Search

TH-17 cells are a distinct lineage of proinflammatory T helper cells that are essential for autoimmune disease. In mice, commitment to the TH-17 lineage is dependent on transforming growth factor-? and interleukin 6 (IL-6). Here we demonstrate that IL-23 and IL-1? induced the development of human TH-17 cells expressing IL-17A, IL-17F, IL-22, IL-26, interferon-?, the chemokine CCL20 and transcription factor

Nicholas J Wilson; Katia Boniface; Jason R Chan; Brent S McKenzie; Wendy M Blumenschein; Jeanine D Mattson; Beth Basham; Kathleen Smith; Taiying Chen; Franck Morel; Jean-Claude Lecron; Robert A Kastelein; Daniel J Cua; Terrill K McClanahan; Edward P Bowman; Rene de Waal Malefyt

2007-01-01

176

Role of SMAD and non-SMAD signals in the development of Th17 and regulatory T cells.  

PubMed

Whereas TGF-beta is essential for the development of peripherally induced Foxp3(+) regulatory T cells (iTreg cells) and Th17 cells, the intracellular signaling mechanism by which TGF-beta regulates development of both cell subsets is less understood. In this study, we report that neither Smad2 nor Smad3 gene deficiency abrogates TGF-beta-dependent iTreg induction by a deacetylase inhibitor trichostatin A in vivo, although the loss of the Smad2 or Smad3 gene partially reduces iTreg induction in vitro. Similarly, SMAD2 and SMAD3 have a redundant role in development of Th17 in vitro and in experimental autoimmune encephalomyelitis. In addition, ERK and/or JNK pathways were shown to be involved in regulating iTreg cells, whereas the p38 pathway predominately modulated Th17 and experimental autoimmune encephalomyelitis induction. Therefore, selective targeting of these intracellular TGF-beta signaling pathways during iTreg and Th17 cell development might lead to the development of therapies in treating autoimmune and other chronic inflammatory diseases. PMID:20304828

Lu, Ling; Wang, Julie; Zhang, Feng; Chai, Yang; Brand, David; Wang, Xuehao; Horwitz, David A; Shi, Wei; Zheng, Song Guo

2010-04-15

177

The role of nonclassical MHC class I products in the development and function of CD8+ T cells  

E-print Network

Major histocompatibility complex (MHC) class I products present pathogen-derived peptides to CD8+ cytotoxic T cells. This interaction mediates the detection and clearance of intracellular infections. Emphasis has been ...

Halme, Dina Gould, 1974-

2002-01-01

178

Induced and Natural Regulatory T Cells in the Development of Inflammatory Bowel Disease  

PubMed Central

The mucosal immune system mediates contact between the host, and the trillions of microbes that symbiotically colonize the gastrointestinal tract. Failure to tolerate the antigens within this “extended self” can result in inflammatory bowel disease (IBD). Within the adaptive immune system, the most significant cells modulating this interaction are Foxp3+ regulatory T (Treg) cells. Treg cells can be divided into two primary subsets: “natural” Treg (nTreg) cells, and “adaptive” or “induced” Treg (iTreg). Recent research suggests that these subsets serve to play both independent and synergistic roles in mucosal tolerance. Studies from both mouse models and human patients suggest defects in Treg cells can play distinct causative roles in IBD. Numerous genetic, microbial, nutritional, and environmental factors that associate with IBD may also affect Treg cells. In this review we summarize the development and function of Treg cells, and how their regulatory mechanisms may fail, leading to a loss of mucosal tolerance. We discuss both animal models and studies of IBD patients suggesting Treg cell involvement in IBD, and consider how Treg cells may be used in future therapies. PMID:23656897

Mayne, Christopher G.; Williams, Calvin B.

2013-01-01

179

Cutting edge: in the absence of TGF-? signaling in T cells, fewer CD103+ regulatory T cells develop, but exuberant IFN-? production renders mice more susceptible to helminth infection.  

PubMed

Multiple factors control susceptibility of C57BL/6 mice to infection with the helminth Heligmosomoides polygyrus, including TGF-? signaling, which inhibits immunity in vivo. However, mice expressing a T cell-specific dominant-negative TGF-? receptor II (TGF-?RII DN) show dampened Th2 immunity and diminished resistance to infection. Interestingly, H. polygyrus-infected TGF-?RII DN mice show greater frequencies of CD4(+)Foxp3(+)Helios(+) Tregs than infected wild-type mice, but levels of CD103 are greatly reduced on both these cells and on the CD4(+)Foxp3(+)Helios(-) population. Although Th9 and Th17 levels are comparable between infected TGF-?RII DN and wild-type mice, the former develop exaggerated CD4(+) and CD8(+) T cell IFN-? responses. Increased susceptibility conferred by TGF-?RII DN expression was lost in IFN-?-deficient mice, although they remained unable to completely clear infection. Hence, overexpression of IFN-? negatively modulates immunity, and the presence of Helios(+) Tregs may maintain susceptibility on the C57BL/6 background. PMID:22753928

Reynolds, Lisa A; Maizels, Rick M

2012-08-01

180

Impaired development of CD4+ CD25+ regulatory T cells in the absence of STAT1: increased susceptibility to autoimmune disease.  

PubMed

Type I and II interferons (IFNs) exert opposing effects on the progression of multiple sclerosis, even though both IFNs use the signal transducer and activator of transcription 1 (STAT1) as a signaling mediator. Here we report that STAT1-deficient mice expressing a transgenic T cell receptor against myelin basic protein spontaneously develop experimental autoimmune encephalomyelitis with dramatically increased frequency. The heightened susceptibility to this autoimmune disease appears to be triggered by a reduced number as well as a functional impairment of the CD4+ CD25+ regulatory T cells in STAT1-deficient animals. Adoptive transfer of wild-type regulatory T cells into STAT1-deficient hosts is sufficient to prevent the development of autoimmune disease. These results demonstrate an essential role of STAT1 in the maintenance of immunological self-tolerance. PMID:14699080

Nishibori, Takeaki; Tanabe, Yoshinari; Su, Leon; David, Michael

2004-01-01

181

Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy?  

PubMed

Epidemiological evidence confirmed that raw cow's milk consumption in the first year of life protects against the development of atopic diseases and increases the number of regulatory T-cells (Tregs). However, milk's atopy-protective mode of action remains elusive.This review supported by translational research proposes that milk-derived microRNAs (miRs) may represent the missing candidates that promote long-term lineage commitment of Tregs downregulating IL-4/Th2-mediated atopic sensitization and effector immune responses. Milk transfers exosomal miRs including the ancient miR-155, which is important for the development of the immune system and controls pivotal target genes involved in the regulation of FoxP3 expression, IL-4 signaling, immunoglobulin class switching to IgE and Fc?RI expression. Boiling of milk abolishes milk's exosomal miR-mediated bioactivity. Infant formula in comparison to human breast- or cow's milk is deficient in bioactive exosomal miRs that may impair FoxP3 expression. The boost of milk-mediated miR may induce pivotal immunoregulatory and epigenetic modifications required for long-term thymic Treg lineage commitment explaining the atopy-protective effect of raw cow's milk consumption.The presented concept offers a new option for the prevention of atopic diseases by the addition of physiological amounts of miR-155-enriched exosomes to infant formula for mothers incapable of breastfeeding. PMID:24521175

Melnik, Bodo C; John, Swen Malte; Schmitz, Gerd

2014-01-01

182

Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy?  

PubMed Central

Epidemiological evidence confirmed that raw cow’s milk consumption in the first year of life protects against the development of atopic diseases and increases the number of regulatory T-cells (Tregs). However, milk’s atopy-protective mode of action remains elusive. This review supported by translational research proposes that milk-derived microRNAs (miRs) may represent the missing candidates that promote long-term lineage commitment of Tregs downregulating IL-4/Th2-mediated atopic sensitization and effector immune responses. Milk transfers exosomal miRs including the ancient miR-155, which is important for the development of the immune system and controls pivotal target genes involved in the regulation of FoxP3 expression, IL-4 signaling, immunoglobulin class switching to IgE and Fc?RI expression. Boiling of milk abolishes milk’s exosomal miR-mediated bioactivity. Infant formula in comparison to human breast- or cow’s milk is deficient in bioactive exosomal miRs that may impair FoxP3 expression. The boost of milk-mediated miR may induce pivotal immunoregulatory and epigenetic modifications required for long-term thymic Treg lineage commitment explaining the atopy-protective effect of raw cow’s milk consumption. The presented concept offers a new option for the prevention of atopic diseases by the addition of physiological amounts of miR-155-enriched exosomes to infant formula for mothers incapable of breastfeeding. PMID:24521175

2014-01-01

183

c-Rel Controls Multiple Discrete Steps in the Thymic Development of Foxp3+ CD4 Regulatory T Cells  

PubMed Central

The development of natural Foxp3+ CD4 regulatory T cells (nTregs) proceeds via two steps that involve the initial antigen dependent generation of CD25+GITRhiFoxp3?CD4+ nTreg precursors followed by the cytokine induction of Foxp3. Using mutant mouse models that lack c-Rel, the critical NF-?B transcription factor required for nTreg differentiation, we establish that c-Rel regulates both of these developmental steps. c-Rel controls the generation of nTreg precursors via a haplo-insufficient mechanism, indicating that this step is highly sensitive to c-Rel levels. However, maintenance of c-Rel in an inactive state in nTreg precursors demonstrates that it is not required for a constitutive function in these cells. While the subsequent IL-2 induction of Foxp3 in nTreg precursors requires c-Rel, this developmental transition does not coincide with the nuclear expression of c-Rel. Collectively, our results support a model of nTreg differentiation in which c-Rel generates a permissive state for foxp3 transcription during the development of nTreg precursors that influences the subsequent IL-2 dependent induction of Foxp3 without a need for c-Rel reactivation. PMID:22066012

Grumont, Raelene; Overall, Sarah; Gleeson, Paul; Shannon, Frances; Gerondakis, Steve

2011-01-01

184

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

185

Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic\\/suppressive state  

Microsoft Academic Search

Elimination of CD25 F T cells, which constitute 5-10% of peripheral CD4 F T cells in normal naive mice, leads to spontaneous development of various autoimmune diseases. These immunoregulatory CD25 F CD4 F T cells are naturally unresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation, suppress proliferation of CD25 - CD4 F T cells and CD8 F T

Takeshi Takahashi; Yuhshi Kuniyasu; Masaaki Toda; Noriko Sakaguchi; Misako Itoh; Makoto Iwata; Jun Shimizu; Shimon Sakaguchi

1998-01-01

186

Human RSV-specific T cells  

Microsoft Academic Search

Respiratory syncytial virus (RSV) is the most common cause of hospitalization due to lower respiratory tract infection in infants. While the majority of infants experience symptoms of a normal common cold, three percent of the entire birth cohort requires hospitalization due to severity of symptoms. While both CD4+ T cells and CD8+ T cells play an important role in clearing

J. Heidema

2006-01-01

187

CD8+ T cells eliminate liver-stage Plasmodium berghei parasites without detectable bystander effect.  

PubMed

Immunization with attenuated Plasmodium sporozoites or viral vectored vaccines can induce protective CD8(+) T cells that can find and eliminate liver-stage malaria parasites. A key question is whether CD8(+) T cells must recognize and eliminate each parasite in the liver or whether bystander killing can occur. To test this, we transferred antigen-specific effector CD8(+) T cells to mice that were then coinfected with two Plasmodium berghei strains, only one of which could be recognized directly by the transferred T cells. We found that the noncognate parasites developed normally in these mice, demonstrating that bystander killing of parasites does not occur during the CD8(+) T cell response to malaria parasites. Rather, elimination of infected parasites is likely mediated by direct recognition of infected hepatocytes by antigen-specific CD8(+) T cells. PMID:24421043

Cockburn, Ian A; Tse, Sze-Wah; Zavala, Fidel

2014-04-01

188

T cell-dependence of Lassa fever pathogenesis.  

PubMed

Lassa virus (LASV), the causative agent of Lassa fever (LF), is endemic in West Africa, accounting for substantial morbidity and mortality. In spite of ongoing research efforts, LF pathogenesis and mechanisms of LASV immune control remain poorly understood. While normal laboratory mice are resistant to LASV, we report that mice expressing humanized instead of murine MHC class I (MHC-I) failed to control LASV infection and develop severe LF. Infection of MHC-I knockout mice confirmed a key role for MHC-I-restricted T cell responses in controlling LASV. Intriguingly we found that T cell depletion in LASV-infected HHD mice prevented disease, irrespective of high-level viremia. Widespread activation of monocyte/macrophage lineage cells, manifest through inducible NO synthase expression, and elevated IL-12p40 serum levels indicated a systemic inflammatory condition. The absence of extensive monocyte/macrophage activation in T cell-depleted mice suggested that T cell responses contribute to deleterious innate inflammatory reactions and LF pathogenesis. Our observations in mice indicate a dual role for T cells, not only protecting from LASV, but also enhancing LF pathogenesis. The possibility of T cell-driven enhancement and immunopathogenesis should be given consideration in future LF vaccine development. PMID:20360949

Flatz, Lukas; Rieger, Toni; Merkler, Doron; Bergthaler, Andreas; Regen, Tommy; Schedensack, Mariann; Bestmann, Lukas; Verschoor, Admar; Kreutzfeldt, Mario; Brück, Wolfgang; Hanisch, Uwe-Karsten; Günther, Stephan; Pinschewer, Daniel D

2010-03-01

189

?? 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

190

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

191

Regulating regulatory T cells  

Microsoft Academic Search

Regulatory T cells (Tregs) are a specialized subpopulation of T cells that act to suppress activation of other immune cells and thereby maintain immune system homeostasis, self-tolerance as well as control excessive response to foreign antigens. The mere concept of Tregs was the subject of significant controversy among immunologists for many years owing to the paucity of reliable markers for

N T Le; N Chao

2007-01-01

192

Intradermal application of vitamin D3 increases migration of CD14+ dermal dendritic cells and promotes the development of Foxp3+ regulatory T cells  

PubMed Central

The active form of vitamin D3 (VitD) is a potent immunosuppressive drug. Its effects are mediated in part through dendritic cells (DCs) that promote the development of regulatory T cells (Tregs). However, it remains elusive how VitD would influence the different human skin DC subsets, e.g., CD1a+/langerin+ Langerhans cells, CD14+ DDCs and CD1a+ DDCs upon administration through the skin route in their natural environment. We addressed this issue by intradermal (ID) administration of VitD in a human skin explant system that closely resembles physiological conditions. ID injection of VitD selectively enhanced the migration of CD14+ DDCs, a subset known for the induction of tolerance. Moreover, ID injection of VitD repressed the LPS-induced T cell stimulatory capacity of migrating DCs. These migrating DCs collectively induced T cells with suppressive activity and abolished IFN-? productivity. Those induced T cells were characterized by the expression of Foxp3. Thus, we report the novel finding that ID injection of VitD not only modifies skin DC migration, but also programs these DCs in their natural milieu to promote the development of Foxp3+ Tregs. PMID:23291929

Bakdash, Ghaith; Schneider, Laura P.; van Capel, Toni M. M.; Kapsenberg, Martien L.; Teunissen, Marcel B. M.; de Jong, Esther C.

2013-01-01

193

T Cell Immune Reconstitution Following Lymphodepletion  

PubMed Central

T cell reconstitution following lymphopenia from chemotherapy or stem cell transplant is often slow and incompetent, contributing to the development of infectious diseases, relapse, and graft-versus-host disease. This is due to the fact that de novo T cell production is impaired following cytoreductive regimens. T cells can be generated from two pathways: 1) thymus derived through active thymopoiesis and 2) peripherally expanded clones through homeostatic proliferation. In the development of lymphopenia, the thymic pathway is commonly compromised in adults and T cells rely upon peripheral expansion to recover T cell numbers. This homeostatic proliferation exploits the high cytokine levels following lymphopenia to rapidly generate T cells in the periphery. Moreover, this early peripheral expansion of T cells can also be driven by exogenous antigen. This results in loss of T cell repertoire diversity and may predispose to auto- or alloimmunity. Alternatively, the high homeostatic proliferation following lymphopenia may facilitate expansion of anti-tumor immunity. Murine and human studies have provided insight into the cytokine and cellular regulators of these two pathways of T cell generation and the disparate portraits of T cell immunity created through robust thymopoiesis or peripheral expansion following lymphopenia. This insight has permitted the manipulation of the immune system to maximize anti-tumor immunity through lymphopenia and led to an appreciation of mechanisms that underlie graft vs. host disease. PMID:18023361

Williams, Kirsten; Hakim, Frances T.; Gress, Ronald E.

2007-01-01

194

Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome  

PubMed Central

Mutations of forkhead box p3 (FOXP3), the master gene for naturally occurring regulatory T cells (nTregs), are responsible for the impaired function of nTregs, resulting in an autoimmune disease known as the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. The relevance of other peripheral tolerance mechanisms, such as the presence and function of type 1 regulatory T (Tr1) cells, the major adaptive IL-10-producing Treg subset, in patients with IPEX syndrome remains to be clarified. FOXP3mutated Tr1-polarized cells, differentiated in vitro from CD4+ T cells of four IPEX patients, were enriched in IL-10+IL-4?IFN-?+ T cells, a cytokine production profile specific for Tr1 cells, and expressed low levels of FOXP3 and high levels of Granzyme-B. IPEX Tr1 cells were hypoproliferative and suppressive, thus indicating that FOXP3 mutations did not impair their function. Furthermore, we isolated Tr1 cell clones from the peripheral blood of one FOXP3null patient, demonstrating that Tr1 cells are present in vivo and they can be expanded in vitro in the absence of WT FOXP3. Overall, our results (i) show that functional Tr1 cells differentiate independently of FOXP3, (ii) confirm that human Tr1 and nTregs are distinct T-cell lineages, and (iii) suggest that under favorable conditions Tr1 cells could exert regulatory functions in IPEX patients. PMID:21400500

Passerini, Laura; Di Nunzio, Sara; Gregori, Silvia; Gambineri, Eleonora; Cecconi, Massimiliano; Seidel, Markus G; Cazzola, Giantonio; Perroni, Lucia; Tommasini, Alberto; Vignola, Silvia; Guidi, Luisa; Roncarolo, Maria G; Bacchetta, Rosa

2011-01-01

195

Development of a Highly Quantitative, Reproducible Assay for Determination of Chicken T Cell Growth Factor Biological Activity  

Microsoft Academic Search

This report examines optimal culture conditions necessary for accurate and sensitive quantifi- cation of chicken T Cell Growth Factor (TCGF) activity. With this bioassay, TCGF is quantified by measuring its ability to cause proliferation of splenocytes prestimu- lated with mitogen. Proliferation is quantified by determining the optical density (OD) or \\

J. L. PFOHL; J. B. HESTER; V. W. DOELLING; R. S. GIRARDI; J. E. HUTCHINS; D. L. MURRAY; C. A. RICKS; R. M. POSTON

196

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

197

Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity  

Microsoft Academic Search

Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8+ T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine

Ahmed N Hegazy; Andreas Bergthaler; Admar Verschoor; Christina Claus; Marylise Fernandez; Luca Gattinoni; Susan Johnson; Florian Kreppel; Stefan Kochanek; Maries van den Broek; Andreas Radbruch; Frédéric Lévy; Paul-Henri Lambert; Claire-Anne Siegrist; Nicholas P Restifo; Max Löhning; Adrian F Ochsenbein; Gary J Nabel; Lukas Flatz; Daniel D Pinschewer

2010-01-01

198

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

199

Skewed T-cell receptor V ?8.2 expression in transgenic CD2-myc induced thymic lymphoma: a role for antigen stimulation in tumour development?  

Microsoft Academic Search

Transgenic mice expressing the c-myc proto-oncogene under the control of the CD2-dominant control region show stochastic development of mainly clonal thymic lymphoma with long latency, indicating that cooperative events are needed for the development of the fully malignant phenotype. Previous studies have suggested that T-cell receptor-associated signals can contribute to tumour development. We have therefore used this transgenic model of

G Webster; DE Onions; JC Neil; ER Cameron

1997-01-01

200

Quantitative assessment concerning the contribution of IL2R  for superantigen-mediated T cell responses in vivo  

Microsoft Academic Search

IL-2- and IL-2R-deficient mice readily develop T cell-dependent immune responses in vivo, but the relevance of this finding is complicated by severe concurrent autoimmunity. Furthermore, the detection of such responses does not address whether under normal circumstances IL-2 dominates T cell immunity. In the present report, we investigated the extent IL-2-independent T cell growth is mediated by other cytokines in

Haoli Jin; Dapeng Gong; Dennis Adeegbe; Allison L. Bayer; Cleo Rolle; Aixin Yu; Thomas R. Malek

2006-01-01

201

Variable CD7 Expression on T Cells in the Leukemic Phase of Cutaneous T Cell Lymphoma (Sézary Syndrome)  

Microsoft Academic Search

CD7, a molecule normally expressed on 90% of normal CD4+ T cells, is often deficient on the malignant T cells of cutaneous T cell lymphoma. To investigate the clinical and biologic implications of CD7 expression, blood lymphocytes from 42 patients with the leukemic phase of cutaneous T cell lymphoma (CD4\\/CD8 ratio of 10 or more with evidence of a T

Eric C Vonderheid; Robert D Bigler; Amy Kotecha; Christine M Boselli; Stuart R Lessin; Maria Grazia Bernengo; Marcia Polansky

2001-01-01

202

Follicular T-cell lymphoma: a member of an emerging family of follicular helper T-cell derived T-cell lymphomas.  

PubMed

Unlike B-cell lymphomas, where knowledge of normal B-cell origin and differentiation has greatly contributed to their classification, the current classification of peripheral T-cell lymphomas is limited by a lack of understanding of their cellular origin. In the current World Health Organization classification of lymphomas, follicular T-cell lymphoma was formally recognized as a morphologic variant of peripheral T-cell lymphoma, not otherwise specified. There is growing evidence, however, that follicular T-cell lymphoma may be a unique clinicopathologic entity based on its morphologic features and derivation from follicular helper T-cells. In addition, there are abundant recent data supporting the concept that follicular helper T-cells can give rise to other types of T-cell lymphoma, including angioimmunoblastic T-cell lymphoma, primary cutaneous CD4+ small/medium T-cell lymphoma, and a subset of neoplasms, in addition to follicular T-cell lymphoma, currently classified as peripheral T-cell lymphoma, not otherwise specified. In this review, we focus primarily on the clinicopathologic, immunophenotypic, and molecular features of follicular T-cell lymphoma and discuss its potential relationship with other types of T-cell lymphoma thought to be derived from follicular helper T-cells. PMID:22959759

Hu, Shimin; Young, Ken H; Konoplev, Sergej N; Medeiros, L Jeffrey

2012-11-01

203

Essential flexibility in the T-cell recognition of antigen  

NASA Astrophysics Data System (ADS)

?? T cells specifically recognize a ligand composed of a peptide bound to a self-major-histocompatibility-complex molecule, but the recognition of slightly altered ligands by T cells can lead to a partial activation. This flexibility is crucial for T-cell development and can have both beneficial and harmful effects on peripheral T cells.

Kersh, Gilbert J.; Allen, Paul M.

1996-04-01

204

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

205

Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages  

Microsoft Academic Search

CD4+ T cells producing interleukin 17 (IL-17) are associated with autoimmunity, although the precise mechanisms that control their development are undefined. Here we present data that challenge the idea of a shared developmental pathway with T helper type 1 (TH1) or TH2 lineages and instead favor the idea of a distinct effector lineage we call 'TH-17'. The development of TH-17

Laurie E Harrington; Robin D Hatton; Paul R Mangan; Henrietta Turner; Theresa L Murphy; Kenneth M Murphy; Casey T Weaver

2005-01-01

206

Development of a coordinated allo T cell and auto B cell response against autosomal PTK2B after allogeneic hematopoietic stem cell transplantation  

PubMed Central

It is well known that allo-reactive T cells play a crucial role in graft-versus-leukemia and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (alloSCT). Allo-reactive CD4+ T cells can mediate direct cytolysis, but may also stimulate production of IgG antibodies as helper cells. Immune complexes may subsequently be processed and presented by professional antigen presenting cells and stimulate induction of specific CD8+ T cells. As such, proteins targeted in coordinated T- and B-cell responses may represent a class of immunodominant antigens in clinical responses after alloSCT. We previously identified LB-PTK2B-1T as HLA class II restricted polymorphic antigen in a patient treated with donor lymphocyte infusion for relapsed chronic myeloid leukemia after HLA-matched alloSCT. Since PTK2B has also been described as antibody target, we here investigated whether a coordinated T- and B-cell response against PTK2B was induced. Patient serum before and after alloSCT and donor lymphocyte infusion (DLI) was screened for antibodies, and we indeed observed development of a humoral immune response against PTK2B. Antibodies against PTK2B were only found after DLI and, in contrast to the CD4+ T cells, recognized a monomorphic region of the protein. To our knowledge, this is the first description of a coordinated allo-reactive CD4+ T-cell and auto-reactive antibody response against an autosomal antigen. PMID:24097630

Kremer, Anita N.; van der Griendt, Judith C.; van der Meijden, Edith D.; Honders, M. Willy; Ayoglu, Burcu; Schwenk, Jochen M.; Nilsson, Peter; Falkenburg, J.H. Frederik; Griffioen, Marieke

2014-01-01

207

Development of a coordinated allo T cell and auto B cell response against autosomal PTK2B after allogeneic hematopoietic stem cell transplantation.  

PubMed

It is well known that allo-reactive T cells play a crucial role in graft-versus-leukemia and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (alloSCT). Allo-reactive CD4(+) T cells can mediate direct cytolysis, but may also stimulate production of IgG antibodies as helper cells. Immune complexes may subsequently be processed and presented by professional antigen presenting cells and stimulate induction of specific CD8(+) T cells. As such, proteins targeted in coordinated T- and B-cell responses may represent a class of immunodominant antigens in clinical responses after alloSCT. We previously identified LB-PTK2B-1T as HLA class II restricted polymorphic antigen in a patient treated with donor lymphocyte infusion for relapsed chronic myeloid leukemia after HLA-matched alloSCT. Since PTK2B has also been described as antibody target, we here investigated whether a coordinated T- and B-cell response against PTK2B was induced. Patient serum before and after alloSCT and donor lymphocyte infusion (DLI) was screened for antibodies, and we indeed observed development of a humoral immune response against PTK2B. Antibodies against PTK2B were only found after DLI and, in contrast to the CD4(+) T cells, recognized a monomorphic region of the protein. To our knowledge, this is the first description of a coordinated allo-reactive CD4(+) T-cell and auto-reactive antibody response against an autosomal antigen. PMID:24097630

Kremer, Anita N; van der Griendt, Judith C; van der Meijden, Edith D; Honders, M Willy; Ayoglu, Burcu; Schwenk, Jochen M; Nilsson, Peter; Falkenburg, J H Frederik; Griffioen, Marieke

2014-02-01

208

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

Microsoft Academic Search

In cocultures of human plancental 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

Karine A. Smans; Marc F. Hoylaerts; Marc E. De Broe

1994-01-01

209

Regulatory CD4+ T Cells Expressing Endogenous T Cell Receptor Chains Protect Myelin Basic Protein-specific Transgenic Mice from Spontaneous Autoimmune Encephalomyelitis  

PubMed Central

The development of T cell–mediated autoimmune diseases hinges on the balance between effector and regulatory mechanisms. Using two transgenic mouse lines expressing identical myelin basic protein (MBP)–specific T cell receptor (TCR) genes, we have previously shown that mice bearing exclusively MBP-specific T cells (designated T/R?) spontaneously develop experimental autoimmune encephalomyelitis (EAE), whereas mice bearing MBP-specific T cells as well as other lymphocytes (designated T/R+) did not. Here we demonstrate that T/R? mice can be protected from EAE by the early transfer of total splenocytes or purified CD4+ T cells from normal donors. Moreover, whereas T/R+ mice crossed with B cell–deficient, ?/? T cell–deficient, or major histocompatibility complex class I–deficient mice did not develop EAE spontaneously, T/R+ mice crossed with TCR-? and -? knockout mice developed EAE with the same incidence and severity as T/R? mice. In addition, MBP-specific transgenic mice that lack only endogenous TCR-? chains developed EAE with high incidence but reduced severity. Surprisingly, two-thirds of MBP-specific transgenic mice lacking only endogenous TCR-? chains also developed EAE, suggesting that in T/R+ mice, cells with high protective activity escape TCR-? chain allelic exclusion. Our study identifies CD4+ T cells bearing endogenous ? and ? TCR chains as the lymphocytes that prevent spontaneous EAE in T/R+ mice. PMID:9815266

Olivares-Villagomez, Danyvid; Wang, Yijie; Lafaille, Juan J.

1998-01-01

210

TGF-?: Guardian of T Cell Function  

PubMed Central

A fundamental aspect of the adaptive immune system is the generation and maintenance of a diverse and self-tolerant T cell repertoire. Through its regulation of T cell development, homeostasis, tolerance, and differentiation, the highly evolutionarily conserved cytokine transforming growth factor-? (TGF-?) critically supports a functional T cell pool. The pleiotropic nature of this regulation is likely due to the elaborate control of TGF-? production and activation in the immune system, and the intricacy of TGF-? signaling pathways. This review discusses our current understanding of TGF-? regulation of T cells. PMID:24098055

Oh, Soyoung A.; Li, Ming O.

2013-01-01

211

Regulatory T Cells in B Cell Follicles  

PubMed Central

Understanding germinal center reactions is crucial not only for the design of effective vaccines against infectious agents and malignant cells but also for the development of therapeutic intervention for the treatment of antibody-mediated immune disorders. Recent advances in this field have revealed specialized subsets of T cells necessary for the control of B cell responses in the follicle. These cells include follicular regulatory T cells and Qa-1-restricted cluster of differentiation (CD)8+ regulatory T cells. In this review, we discuss the current knowledge related to the role of regulatory T cells in the B cell follicle.

Chang, Jae-Hoon

2014-01-01

212

Mst1/Mst2 regulate development and function of regulatory T cells through modulation of Foxo1/Foxo3 stability in autoimmune disease.  

PubMed

Foxp3 expression and regulatory T cell (Treg) development are critical for maintaining dominant tolerance and preventing autoimmune diseases. Human MST1 deficiency causes a novel primary immunodeficiency syndrome accompanied by autoimmune manifestations. However, the mechanism by which Mst1 controls immune regulation is unknown. In this article, we report that Mst1 regulates Foxp3 expression and Treg development/function and inhibits autoimmunity through modulating Foxo1 and Foxo3 (Foxo1/3) stability. We have found that Mst1 deficiency impairs Foxp3 expression and Treg development and function in mice. Mechanistic studies reveal that Mst1 enhances Foxo1/3 stability directly by phosphorylating Foxo1/3 and indirectly by attenuating TCR-induced Akt activation in peripheral T cells. Our studies have also shown that Mst1 deficiency does not affect Foxo1/3 cellular localization in CD4 T cells. In addition, we show that Mst1(-/-) mice are prone to autoimmune disease, and mutant phenotypes, such as overactivation of naive T cells, splenomegaly, and autoimmune pathological changes, are suppressed in Mst1(-/-) bone marrow chimera by cotransplanted wt Tregs. Finally, we demonstrate that Mst1 and Mst2 play a partially redundant role in Treg development and autoimmunity. Our findings not only identify Mst kinases as the long-searched-for factors that simultaneously activate Foxo1/3 and inhibit TCR-stimulated Akt downstream of TCR signaling to promote Foxp3 expression and Treg development, but also shed new light on understanding and designing better therapeutic strategies for MST1 deficiency-mediated human immunodeficiency syndrome. PMID:24453252

Du, Xingrong; Shi, Hao; Li, Jiang; Dong, Yongli; Liang, JieLiang; Ye, Jian; Kong, Shanshan; Zhang, Shujing; Zhong, Tao; Yuan, Zengqiang; Xu, Tian; Zhuang, Yuan; Zheng, Biao; Geng, Jian-Guo; Tao, Wufan

2014-02-15

213

IFN-?-producing CD4+ T cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the brain.  

PubMed

It is well established that IFN-? is required for the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the temporal and tissue-specific cellular sources of IFN-? during P. berghei ANKA infection have not been investigated, and it is not known whether IFN-? production by a single cell type in isolation can induce cerebral pathology. In this study, using IFN-? reporter mice, we show that NK cells dominate the IFN-? response during the early stages of infection in the brain, but not in the spleen, before being replaced by CD4(+) and CD8(+) T cells. Importantly, we demonstrate that IFN-?-producing CD4(+) T cells, but not innate or CD8(+) T cells, can promote the development of ECM in normally resistant IFN-?(-/-) mice infected with P. berghei ANKA. Adoptively transferred wild-type CD4(+) T cells accumulate within the spleen, lung, and brain of IFN-?(-/-) mice and induce ECM through active IFN-? secretion, which increases the accumulation of endogenous IFN-?(-/-) CD8(+) T cells within the brain. Depletion of endogenous IFN-?(-/-) CD8(+) T cells abrogates the ability of wild-type CD4(+) T cells to promote ECM. Finally, we show that IFN-? production, specifically by CD4(+) T cells, is sufficient to induce expression of CXCL9 and CXCL10 within the brain, providing a mechanistic basis for the enhanced CD8(+) T cell accumulation. To our knowledge, these observations demonstrate, for the first time, the importance of and pathways by which IFN-?-producing CD4(+) T cells promote the development of ECM during P. berghei ANKA infection. PMID:22723523

Villegas-Mendez, Ana; Greig, Rachel; Shaw, Tovah N; de Souza, J Brian; Gwyer Findlay, Emily; Stumhofer, Jason S; Hafalla, Julius C R; Blount, Daniel G; Hunter, Christopher A; Riley, Eleanor M; Couper, Kevin N

2012-07-15

214

Elevated CXCL12 expression in the bone marrow of NOD mice is associated with altered T cell and stem cell trafficking and diabetes development  

Microsoft Academic Search

BACKGROUND: Type I diabetes (TID) is an autoimmune disease resulting from destruction of the insulin-producing ?-cells by autoreactive T cells. Studies have shown that polymorphisms of chemokine CXCL12 gene are linked to TID in humans. In non-obese diabetic (NOD) mice, which are predisposed to develop the disease, reduction of CXCL12 level leads to significant delays in the onset of diabetes.

Qibin Leng; Yuchun Nie; Yongrui Zou; Jianzhu Chen

2008-01-01

215

Development of Inflammatory Bowel Disease in Long-Evans Cinnamon Rats Based on CD4CD25Foxp3 Regulatory T Cell Dysfunction1  

Microsoft Academic Search

A mutant strain with defective thymic selection of the Long-Evans Cinnamon (LEC) rat was found to spontaneously develop inflammatory bowel disease (IBD)-like colitis. The secretion of Th1-type cytokines including IFN- and IL-2 from T cells of mesenteric lymph node cells (MLNs) and lamina propria mononuclear cells, but not spleen cells, in LEC rats was significantly increased more than that of

Naozumi Ishimaru; Akiko Yamada; Masayuki Kohashi; Rieko Arakaki; Tetsuyuki Takahashi; Keisuke Izumi; Yoshio Hayashi

216

Properties of reticulum cell sarcomas in SJL/J mice. V. Nature of reticulum cell sarcoma surface antigen which induces proliferation of normal SJL/J T cells.  

PubMed

The results of studies on the reticulum cell sarcoma (RCS) tumors of SJL/J mice presented here, indicate that spontaneous tumors, which arise in older mice, also possess the capacity to induce the vigorous proliferative response in syngenetic T lymphocytes that are characteristic of the transplantable RCS lines. Analysis of cell surface antigens revealed the presence of Ia determinats on gradient-purified transplantable RCS tumor cells; however, these cells did not express Thy 1.2, nIg, or, any of the viral proteins that were tested for by specific antisera. Pretreatment of RCS cells with anti-Ia sera and complement-deleted cells that were stimulatory for syngenetic T lymphocytes, and addition of anti-Ia sera directly to cultures blocked the proliferative response at the stimulator (RCS) cell level. Lymph node cells from H-2(8) strains other than SJL/J, including A.SW and B10.S also gave proliferative responses to RCS cells, although lower in magnitude. A requirement on the part of responding cells for identity with RCS cells at the Ir region was indicated by the finding that A.TH but not A.TL lymph node cells responded to RCS. It is concluded that RCS cells stimulate Ir-region identical T cells (without evidence of presensitization) through a modification in the expression of Ia antigens on the surface of the tumor cells. PMID:68988

Ponzio, N M; David, C S; Shreffler, D C; Thorbecke, G J

1977-07-01

217

Properties of reticulum cell sarcomas in SJL/J mice. V. Nature of reticulum cell sarcoma surface antigen which induces proliferation of normal SJL/J T cells  

PubMed Central

The results of studies on the reticulum cell sarcoma (RCS) tumors of SJL/J mice presented here, indicate that spontaneous tumors, which arise in older mice, also possess the capacity to induce the vigorous proliferative response in syngenetic T lymphocytes that are characteristic of the transplantable RCS lines. Analysis of cell surface antigens revealed the presence of Ia determinats on gradient- purified transplantable RCS tumor cells; however, these cells did not express Thy 1.2, nIg, or, any of the viral proteins that were tested for by specific antisera. Pretreatment of RCS cells with anti-Ia sera and complement-deleted cells that were stimulatory for syngenetic T lymphocytes, and addition of anti-Ia sera directly to cultures blocked the proliferative response at the stimulator (RCS) cell level. Lymph node cells from H-2(8) strains other than SJL/J, including A.SW and B10.S also gave proliferative responses to RCS cells, although lower in magnitude. A requirement on the part of responding cells for identity with RCS cells at the Ir region was indicated by the finding that A.TH but not A.TL lymph node cells responded to RCS. It is concluded that RCS cells stimulate Ir-region identical T cells (without evidence of presensitization) through a modification in the expression of Ia antigens on the surface of the tumor cells. PMID:68988

1977-01-01

218

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

219

Eosinophils affect functions of in vitro-activated human CD3-CD4+ T cells  

PubMed Central

Background The recent development of eosinophil-targeting agents has raised enthusiasm for management of patients with hypereosinophilic syndromes. Roughly half of anti-IL-5-treated patients with corticosteroid-responsive lymphocytic (L-HES) and idiopathic disease variants can be tapered off corticosteroids. Potential consequences of corticosteroid-withdrawal on clonal expansion of pre-malignant CD3-CD4+ T-cells associated with L-HES are a subject of concern. Indeed, corticosteroid treatment inhibits T-cell activation and may lower blood CD3-CD4+ cell counts. On the other hand, previous studies have shown that eosinophils support CD4 T-cell activation, suggesting that targeted eosinophil depletion may negatively regulate these cells. Objectives Effects of eosinophils on CD4 T-cell activation in vitro were investigated as an indirect means of exploring whether treatment-induced eosinophil depletion may affect pathogenic T-cells driving L-HES. Methods Helper (CD4) T-cells and CD3-CD4+ cells from healthy controls and L-HES patients, respectively, were cultured in vitro in presence of anti-CD3/CD28 or dendritic cells. Effects of eosinophils on T-cell proliferation and cytokine production were investigated. Results Eosinophils enhanced CD3-driven proliferation of CD4 T-cells from healthy subjects in vitro, while inhibiting TCR-independent proliferation and IL-5 production by CD3-CD4+ T-cells. Conclusions While this study confirms previous work showing that eosinophils support activation of normal helper T-cells, our in vitro findings with CD3-CD4+ T-cells suggest that eosinophil-depletion may favor activation and expansion of this pathogenic lymphocyte subset. With the ongoing development of eosinophil-targeted therapy for various eosinophilic conditions, the indirect consequences of treatment on the underlying immune mechanisms of disease should be investigated in detail in the setting of translational research programs. PMID:23642304

2013-01-01

220

CD8 + T cells in systemic sclerosis  

Microsoft Academic Search

Systemic sclerosis (SSc) is a progressive and highly debilitating autoimmune disorder characterized by inflammation, fibrosis,\\u000a and vascular damage of the connective tissue. T cell-derived cytokines have been implicated in the induction of fibrosis. We found that high levels of the profibrotic type-2 cytokine IL-13 are produced by peripheral blood effector CD8+ T cells from SSc patients compared to normal controls.

Patrizia Fuschiotti

2011-01-01

221

Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity.  

PubMed

Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8(+) T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine antigens to create replication-defective vaccine vectors. These rLCMV vaccines elicited CTL responses that were equivalent to or greater than those elicited by recombinant adenovirus 5 or recombinant vaccinia virus in their magnitude and cytokine profiles, and they exhibited more effective protection in several models. In contrast to recombinant adenovirus 5, rLCMV failed to elicit vector-specific antibody immunity, which facilitated re-administration of the same vector for booster vaccination. In addition, rLCMV elicited T helper type 1 CD4+ T cell responses and protective neutralizing antibodies to vaccine antigens. These features, together with low seroprevalence in humans, suggest that rLCMV may show utility as a vaccine platform against infectious diseases and cancer. PMID:20139992

Flatz, Lukas; Hegazy, Ahmed N; Bergthaler, Andreas; Verschoor, Admar; Claus, Christina; Fernandez, Marylise; Gattinoni, Luca; Johnson, Susan; Kreppel, Florian; Kochanek, Stefan; Broek, Maries van den; Radbruch, Andreas; Lévy, Frédéric; Lambert, Paul-Henri; Siegrist, Claire-Anne; Restifo, Nicholas P; Löhning, Max; Ochsenbein, Adrian F; Nabel, Gary J; Pinschewer, Daniel D

2010-03-01

222

Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity  

PubMed Central

Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8+ T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine antigens to create replication-defective vaccine vectors. These rLCMV vaccines elicited CTL responses that were equivalent to or greater than those elicited by recombinant adenovirus 5 or recombinant vaccinia virus in their magnitude and cytokine profiles, and they exhibited more effective protection in several models. In contrast to recombinant adenovirus 5, rLCMV failed to elicit vector-specific antibody immunity, which facilitated re-administration of the same vector for booster vaccination. In addition, rLCMV elicited T helper type 1 CD4+ T cell responses and protective neutralizing antibodies to vaccine antigens. These features, together with low seroprevalence in humans, suggest that rLCMV may show utility as a vaccine platform against infectious diseases and cancer. PMID:20139992

Flatz, Lukas; Hegazy, Ahmed N; Bergthaler, Andreas; Verschoor, Admar; Claus, Christina; Fernandez, Marylise; Gattinoni, Luca; Johnson, Susan; Kreppel, Florian; Kochanek, Stefan; van den Broek, Maries; Radbruch, Andreas; Levy, Frederic; Lambert, Paul-Henri; Siegrist, Claire-Anne; Restifo, Nicholas P; Lohning, Max; Ochsenbein, Adrian F; Nabel, Gary J; Pinschewer, Daniel D

2011-01-01

223

CD4 T cell cooperation is required for the in vivo activation of CD4 T cells  

Microsoft Academic Search

We address here the role of CD4 T cell cooperation in the activation of CD4 T cells. Administration of aggregated hen egg lysozyme (HEL) without microbial adjuvant to BALB\\/c mice normally generates cytokine-producing CD4 T cells specific for the HEL major peptide, HEL105-120, as well as CD4 T cells specific for HEL non-major peptides. The prior administration of HEL105-120 ablates

Nathan C. Peters; David R. Kroeger; Steven Mickelwright; Peter A. Bretscher

2009-01-01

224

Immunoregulatory T Cell Function in Multiple Myeloma  

PubMed Central

Multiple myeloma is a malignancy characterized by uncontrolled monoclonal B cell differentiation and immunoglobulin production. In most instances, there is concomitant reduction in polyclonal differentiation and immunoglobulin synthesis both in vivo and in vitro. In in vitro pokeweed mitogen-induced B cell differentiation assays, proliferation and polyclonal immunoglobulin secretion optimally requires T cell help and can be inhibited both by monocytes and suppressor T cells. Helper function and monocyte-mediated suppression are relatively radio-resistant whereas T suppressor function is sensitive to 2,000 rad x-irradiation. We have examined myeloma T cell subset function in this assay using recombinations of isolated patient and normal B cells, T cells, and T cell subsets. Monocytes were removed by a carbonyl iron ingestion technique, normal and myeloma T cells were fractionated on the basis of Fc receptors for immunoglobulin (Ig) G (T?) or IgM (T? or T non-?), and proliferation and IgG secretion after co-culture determined by [3H]thymidine incorporation and radio-immunoassay, respectively. Myeloma B cells demonstrate quantitatively and qualitatively normal blastogenic responses and are appropriately regulated by either autologous or allogeneic T helper and suppressor subsets. Despite normal proliferation, however, myeloma B cells remain deficient in subsequent differentiation and immunoglobulin secretion even when co-cultured in the absence of monocytes or suppressor T cells and the presence of normal helper cells. Myeloma T cell populations, in contrast, are entirely normal in helper capacity over a range of T:B ratios but are markedly deficient in radiosensitive and concanavalin A-induced suppressor activity. T suppressor cell dysfunction in multiple myeloma is apparently due to a deficit in the T non-? suppressor subset, whereas T? cells, although proportionately reduced, are functionally normal. This unique T suppressor deficit reflects the heterogeneity of suppressor mechanisms in this disease and may represent a compensatory response to the monoclonal proliferation or the involvement of regulatory T cells in the pathogenesis of the malignancy. PMID:6451635

Ozer, H.; Han, T.; Henderson, E. S.; Nussbaum, A.; Sheedy, D.

1981-01-01

225

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

226

A Th1 cytokine-enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells  

PubMed Central

In this study, we investigated whether activated T cells (ATC) armed with bispecific antibodies (aATC) can inhibits tumor growth and MDSC development in a Th1 cytokine–enriched (IL-2 and IFN-?) microenvironment. Cytotoxicity mediated by aATC was significantly higher (P <0.001) against breast cancer cell lines in the presence of Th1 cytokines as compared with control co-cultures. In the presence of aATC, CD33+/CD11b+/CD14?/HLA-DR?MDSC population was reduced significantly under both control (P <0.03) and Th1-enriched (P <0.036) culture conditions. Cytokine analysis in the culture supernatants showed high levels of MDSC suppressive chemokines CXCL9 and CXCL10 in Th1-enriched culture supernatants with highly significant increase (P <0.001) in the presence of aATC. Interestingly, MDSC recovered from co-cultures without aATC showed potent ability to suppress activated T-cell-mediated cytotoxicity (P <0.001), IFN-? production (P <0.01) and T-cell proliferation (P <0.05) compared to those recovered from aATC-containing co-cultures. These data suggest that aATC can mediate enhanced killing of tumor cells and may suppress MDSC and Treg differentiation, and presence of Th1 cytokines potentiates aATC-induced suppression of MDSC, sug-gesting that Th1-enriching immunotherapy may be benefi-cial in cancer treatment. PMID:21971587

Schalk, Dana; Sarkar, Sanila H.; Al-Khadimi, Zaid; Sarkar, Fazlul H.; Lum, Lawrence G.

2013-01-01

227

Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell–mediated immunotherapy  

PubMed Central

Activation of invariant CD1d-dependent NK T cells (iNKT cells) in vivo through administration of the glycolipid ligand ?-galactosylceramide (?-GalCer) or the sphingosine-truncated ?-GalCer analog OCH leads to CD40 signaling as well as the release of soluble molecules including type 1 and ? interferons that contribute to DC maturation. This process enhances T cell immunity to antigens presented by the DC. The adjuvant activity is further amplified if APCs are stimulated through Toll-like receptor 4, suggesting that iNKT cell signals can amplify maturation induced by microbial stimuli. The adjuvant activity of ?-GalCer enhances both priming and boosting of CD8+ T cells to coadministered peptide or protein antigens, including a peptide encoding the clinically relevant, HLA-A2–restricted epitope of the human tumor antigen NY-ESO-1. Importantly, ?-GalCer was used to induce CD8+ T cells to antigens delivered orally, despite the fact that this route of administration is normally associated with blunted responses. Only T cell responses induced in the presence of iNKT cell stimulation, whether by the i.v. or oral route, were capable of eradicating established tumors. Together these data highlight the therapeutic potential of iNKT cell ligands in vaccination strategies, particularly “heterologous prime-boost” strategies against tumors, and provide evidence that iNKT cell stimulation may be exploited in the development of oral vaccines. PMID:15599405

Silk, Jonathan D.; Hermans, Ian F.; Gileadi, Uzi; Chong, Tsung Wen; Shepherd, Dawn; Salio, Mariolina; Mathew, Bini; Schmidt, Richard R.; Lunt, Sarah Jane; Williams, Kaye J.; Stratford, Ian J.; Harris, Adrian L.; Cerundolo, Vincenzo

2004-01-01

228

T-cell lymphomas.  

PubMed

T-cell malignancies are related to various stages of T-lymphocyte differentiation and, consequently, bear diverse immunological and cytochemical markers. The processes may have different malignant potential. Thymus, thymus-dependent areas of lymphatic organs, skin and central nervous system are frequently involved. The histological descriptions of the lesions in question are given. PMID:317426

Mioduszewska, O

1979-01-01

229

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.

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

2014-01-01

230

CD8+ memory T cells appear exhausted within hours of acute virus infection  

PubMed Central

CD8+ memory T cells are abundant, and are activated in a near-synchronous manner by infection, thereby providing a unique opportunity to evaluate the coordinate functional and phenotypic changes that occur in vivo within hours of viral challenge. Using two disparate virus challenges of mice, we show that splenic CD8+ memory T cells rapidly produced IFN? in vivo, but, within 18–24 hours, IFN? synthesis was terminated, and remained undetectable for ?48 hours. A similar on/off response was observed in CD8+ memory T cells in the peritoneal cavity. Cessation of IFN? production in vivo occurred despite the continued presence of immunostimulatory viral antigen, indicating that the initial IFN? response had been actively down-regulated and that the cells had been rendered refractory to subsequent in vivo antigen contact. Down-regulation of IFN? synthesis was accompanied by the upregulation of inhibitory receptor expression on the T cells, and ex vivo analyses using synthetic peptides revealed a concurrent hierarchical loss of cytokine responsiveness (IL-2, then TNF, then IFN?) taking place during the first 24 hours following antigen contact. Thus, within hours of virus challenge, CD8+ memory T cells display the standard hallmarks of T cell exhaustion, a phenotype that has previously been associated only with chronic diseases, and that is generally viewed as a gradually-developing and pathological change in T cell function. Our data suggest that, instead, the “exhaustion” phenotype is a rapid and normal physiological T cell response. PMID:24026080

Hosking, Martin P.; Flynn, Claudia T.; Botten, Jason; Whitton, J. Lindsay

2013-01-01

231

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

232

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

233

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

234

Polarity gene discs large homolog 1 regulates the generation of memory T cells  

PubMed Central

SUMMARY Mammalian ortholog of Drosophila cell polarity protein, Dlg1, plays a critical role in neural synapse formation, epithelial cell homeostasis, and urogenital development. More recently, it has been proposed that Dlg1 may also be involved in the regulation of T-cell proliferation, migration, and antigen receptor signaling. However, a requirement for Dlg1 in development and function of T lineage cells remains to be established. In this study, we investigated a role for Dlg1 during T-cell development and function using a combination of conditional Dlg1 knockout and two different Cre expression systems where Dlg1 deficiency is restricted to the T-cell lineage only, or all hematopoietic cells. Here, using three different TCR models, we show that Dlg1 is not required during development and selection of thymocytes bearing functionally rearranged TCR transgenes. Moreover, Dlg1 is dispensable in the activation and proliferative expansion of antigen specific TCR transgenic CD4+ and CD8+ T cells in vitro and in vivo. Surprisingly, however, we show that Dlg1 is required for normal generation of memory T cells during endogenous response to cognate antigen. Thus, Dlg1 is not required for the thymocyte selection or the activation of primary T cells, however it is involved in the generation of memory T cells. PMID:23436244

Gmyrek, Grzegorz B.; Graham, Daniel B.; Sandoval, Gabriel; Blaufuss, Gregory S.; Akilesh, Holly M.; Fujikawa, Keiko; Xavier, Ramnik J.; Swat, Wojciech

2013-01-01

235

Using T-Cells for Transplantation and Autoimmune Therapy  

Cancer.gov

Transplant complications and autoimmune diseases are primarily caused by T-cell immune responses against normal host tissue or transplanted tissues. Current treatment for these disorders is often not effective, and is typically associated with significant side effects, including global immune suppression. Researchers at NCI's Experimental Transplantation and Immunology Branch have developed a cellular therapy to treat graft-vs.-host disease (GVHD) that results from hematopoetic transplant and other autoimmune disorders.

236

T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice  

PubMed Central

Many autoimmune diseases exhibit familial aggregation, indicating that they have genetic determinants. Single nucleotide polymorphisms in PTPN2, which encodes T cell protein tyrosine phosphatase (TCPTP), have been linked with the development of several autoimmune diseases, including type 1 diabetes and Crohn’s disease. In this study, we have identified TCPTP as a key negative regulator of TCR signaling, which might explain the association of PTPN2 SNPs with autoimmune disease. We found that TCPTP dephosphorylates and inactivates Src family kinases to regulate T cell responses. Using T cell–specific TCPTP-deficient mice, we established that TCPTP attenuates T cell activation and proliferation in vitro and blunts antigen-induced responses in vivo. TCPTP deficiency lowered the in vivo threshold for TCR-dependent CD8+ T cell proliferation. Consistent with this, T cell–specific TCPTP-deficient mice developed widespread inflammation and autoimmunity that was transferable to wild-type recipient mice by CD8+ T cells alone. This autoimmunity was associated with increased serum levels of proinflammatory cytokines and anti-nuclear antibodies, T cell infiltrates in non-lymphoid tissues, and liver disease. These data indicate that TCPTP is a critical negative regulator of TCR signaling that sets the threshold for TCR-induced naive T cell responses to prevent autoimmune and inflammatory disorders arising. PMID:22080863

Wiede, Florian; Shields, Benjamin J.; Chew, Sock Hui; Kyparissoudis, Konstantinos; van Vliet, Catherine; Galic, Sandra; Tremblay, Michel L.; Russell, Sarah M.; Godfrey, Dale I.; Tiganis, Tony

2011-01-01

237

Natural killer T cells are essential for the development of contact hypersensitivity in BALB/c mice.  

PubMed

Contact hypersensitivity (CHS) has been widely used to study cutaneous immune responses, as a prototype of delayed-type hypersensitivity. Although natural killer T (NKT) cells have been assumed to have an important role in CHS, their role is controversial. Here, we report the role of NKT cells in the sensitization phase of CHS, by promoting the survival and maturation of dendritic cells (DCs) in the draining lymph nodes (LNs). The CHS response was attenuated with Cd1d1(-/-) and Traj18(-/-) BALB/c mice in which NKT cells were absent. In the draining LNs, the number of effector T cells and cytokine production were significantly reduced with NKT cell-deficient mice. NKT cells activated and colocalized with DCs in the draining LNs after sensitization. The number of migrated and mature DCs was reduced in NKT cell-deficient mice 72?hours after FITC application. In in vitro experiments, activated NKT cells enhanced bone marrow-derived DC (BMDC) survivability via tumor necrosis factor (TNF) production from BMDCs. In addition, TNF production from BMDCs was partially suppressed by the neutralizing anti-CD54 or CD154 antibodies. Our data demonstrate that DC-NKT interaction has a pivotal role in the sensitization phase of CHS. PMID:24756110

Shimizuhira, Chihiro; Otsuka, Atsushi; Honda, Tetsuya; Kitoh, Akihiko; Egawa, Gyohei; Nakajima, Saeko; Nakashima, Chisa; Watarai, Hiroshi; Miyachi, Yoshiki; Kabashima, Kenji

2014-11-01

238

Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway  

PubMed Central

CD4+Foxp3+ regulatory T cells (Treg cells) are largely autoreactive yet escape clonal deletion in the thymus. We demonstrate here that CD27–CD70 co-stimulation in the thymus rescues developing Treg cells from apoptosis and thereby promotes Treg cell generation. Genetic ablation of CD27 or its ligand CD70 reduced Treg cell numbers in the thymus and peripheral lymphoid organs, whereas it did not alter conventional CD4+Foxp3? T cell numbers. The CD27–CD70 pathway was not required for pre-Treg cell generation, Foxp3 induction, or mature Treg cell function. Rather, CD27 signaling enhanced positive selection of Treg cells within the thymus in a cell-intrinsic manner. CD27 signals promoted the survival of thymic Treg cells by inhibiting the mitochondrial apoptosis pathway. CD70 was expressed on Aire? and Aire+ medullary thymic epithelial cells (mTECs) and on dendritic cells (DCs) in the thymic medulla. CD70 on both mTECs and DCs contributed to Treg cell development as shown in BM chimera experiments with CD70-deficient mice. In vitro experiments indicated that CD70 on the CD8?+ subset of thymic DCs promoted Treg cell development. Our data suggest that mTECs and DCs form dedicated niches in the thymic medulla, in which CD27–CD70 co-stimulation rescues developing Treg cells from apoptosis, subsequent to Foxp3 induction by TCR and CD28 signals. PMID:23547099

Coquet, Jonathan M.; Ribot, Julie C.; Babala, Nikolina; Middendorp, Sabine; van der Horst, Gerda; Xiao, Yanling; Neves, Joana F.; Fonseca-Pereira, Diogo; Jacobs, Heinz; Pennington, Daniel J.; Silva-Santos, Bruno

2013-01-01

239

Pharmacologic suppression of target cell recognition by engineered T cells expressing chimeric T-cell receptors.  

PubMed

Adoptive therapy with autologous T cells expressing chimeric T-cell receptors (chTCRs) is of potential interest for the treatment of malignancy. To limit possible T-cell-mediated damage to normal tissues that weakly express the targeted tumor antigen (Ag), we have tested a strategy for the suppression of target cell recognition by engineered T cells. Jurkat T cells were transduced with an anti-hapten chTCR tinder the control of a tetracycline-suppressible promoter and were shown to respond to Ag-positive (hapten-coated) but not to Ag-negative target cells. The engineered T cells were then reacted with hapten-coated target cells at different effector to target cell ratios before and after exposure to tetracycline. When the engineered T cells were treated with tetracycline, expression of the chTCR was greatly decreased and recognition of the hapten-coated target cells was completely suppressed. Tetracycline-mediated suppression of target cell recognition by engineered T cells may be a useful strategy to limit the toxicity of the approach to cancer gene therapy. PMID:10811469

Alvarez-Vallina, L; Yañez, R; Blanco, B; Gil, M; Russell, S J

2000-04-01

240

Roles of dosage, pharmacokinetics, and cellular sensitivity to damage in the selective toxicity of cyclophosphamide towards B and T cells in development.  

PubMed

Cyclophosphamide (CP) is a known immunomodulating agent. When presented to either late stage chick embryos (e.g. 18 days of incubation (DI] or neonatal chicks. CP induces selective B cell damage resulting in humoral immunosuppression in chickens. The present study was undertaken in order to provide further insights into CP's selective immunotoxic effects. We investigated the influences of age, CP-dose, and drug distribution on CP-induced cytotoxicity in the B and T cell compartments of the developing chick. In this test system, differential immunotoxicity was strongly dosage-dependent; at all ages tested, B cell depletion predominated at low CP dosages (50 and 100 mg/kg) whereas equally extensive lymphocyte toxicity was observed in both thymus and bursa at 200 mg/kg drug levels. Furthermore, while immunotoxicity profiles were similar at the two later developmental timepoints (18 DI and 1 day post-hatch), significantly higher CP dosages were required to induce lymphoid damage at 12 DI. Pharmacokinetic studies with radiolabeled CP revealed that approximately two-fold higher levels of CP and its metabolites are taken up in bursal tissue as compared to the thymus. Experiments concerning the possible inherent differences in susceptibility to CP-induced mitotic inhibition and cell killing mediating selective toxicity towards B cells versus T cells showed that B cell mitosis was inhibited at CP dosages as low as 5 mg/kg. No such inhibition of T cell mitosis was observed at this same low dosage. However, mitosis was completely arrested in both B and T cells at 50 mg/kg CP. Observations of cellularity in immune organs shortly after CP exposure revealed that the bursa is at least ten times more sensitive than the thymus to CP-induced mitotic inhibition and killing of resident lymphocytes. These studies reveal that multiple factors are involved in modulating CP selective immunotoxicity in the developing embryo. These include the dosage level, preferential distribution of the drug to the bursa, and a much greater sensitivity of B cells to CP-mediated mitotic inhibition and cell killing. PMID:2011850

Misra, R R; Bloom, S E

1991-03-11

241

Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells  

Microsoft Academic Search

Nedd4 and Itch are E3 ubiquitin ligases that ubiquitinate similar targets in vitro and thus are thought to function similarly. T cells lacking Itch show spontaneous activation and T helper type 2 polarization. To test whether loss of Nedd4 affects T cells in the same way, we generated Nedd4+\\/+ and Nedd4?\\/? fetal liver chimeras. Nedd4?\\/? T cells developed normally but

Baoli Yang; Denise L Gay; Megan K L MacLeod; Xiao Cao; Tamara Hala; Eileen M Sweezer; John Kappler; Philippa Marrack; Paula M Oliver

2008-01-01

242

Regulatory T cells in radiotherapeutic responses.  

PubMed

Radiation therapy (RT) can extend its influence in cancer therapy beyond what can be attributed to in-field cytotoxicity by modulating the immune system. While complex, these systemic effects can help tip the therapeutic balance in favor of treatment success or failure. Engagement of the immune system is generally through recognition of damage-associated molecules expressed or released as a result of tumor and normal tissue radiation damage. This system has evolved to discriminate pathological from physiological forms of cell death by signaling "danger." The multiple mechanisms that can be evoked include a shift toward a pro-inflammatory, pro-oxidant microenvironment that can promote maturation of dendritic cells and, in cancer treatment, the development of effector T cell responses to tumor-associated antigens. Control over these processes is exerted by regulatory T cells (Tregs), suppressor macrophages, and immunosuppressive cytokines that act in consort to maintain tolerance to self, limit tissue damage, and re-establish tissue homeostasis. Unfortunately, by the time RT for cancer is initiated the tumor-host relationship has already been sculpted in favor of tumor growth and against immune-mediated mechanisms for tumor regression. Reversing this situation is a major challenge. However, recent data show that removal of Tregs can tip the balance in favor of the generation of radiation-induced anti-tumor immunity. The clinical challenge is to do so without excessive depletion that might precipitate serious autoimmune reactions and increase the likelihood of normal tissue complications. The selective modulation of Treg biology to maintain immune tolerance and control of normal tissue damage, while releasing the "brakes" on anti-tumor immune responses, is a worthy aim with promise for enhancing the therapeutic benefit of RT for cancer. PMID:22912933

Schaue, Dörthe; Xie, Michael W; Ratikan, Josephine A; McBride, William H

2012-01-01

243

Tumor Evasion from T Cell Surveillance  

PubMed Central

An intact immune system is essential to prevent the development and progression of neoplastic cells in a process termed immune surveillance. During this process the innate and the adaptive immune systems closely cooperate and especially T cells play an important role to detect and eliminate tumor cells. Due to the mechanism of central tolerance the frequency of T cells displaying appropriate arranged tumor-peptide-specific-T-cell receptors is very low and their activation by professional antigen-presenting cells, such as dendritic cells, is frequently hampered by insufficient costimulation resulting in peripheral tolerance. In addition, inhibitory immune circuits can impair an efficient antitumoral response of reactive T cells. It also has been demonstrated that large tumor burden can promote a state of immunosuppression that in turn can facilitate neoplastic progression. Moreover, tumor cells, which mostly are genetically instable, can gain rescue mechanisms which further impair immune surveillance by T cells. Herein, we summarize the data on how tumor cells evade T-cell immune surveillance with the focus on solid tumors and describe approaches to improve anticancer capacity of T cells. PMID:22190859

Topfer, Katrin; Kempe, Stefanie; Muller, Nadja; Schmitz, Marc; Bachmann, Michael; Cartellieri, Marc; Schackert, Gabriele; Temme, Achim

2011-01-01

244

The development and functions of CD4+ T cells expressing a transgenic TCR specific for an MHC-I-restricted tumor antigenic epitope  

PubMed Central

It has been reported that the ratio of CD4+ to CD8+ T cells has no bias in a few class I major histocompatibility complex (MHC-I)-restricted T-cell receptor (TCR)-transgenic mice specific for alloantigens or autoantigens, in which most CD4+ T cells express an MHC-I-restricted TCR. In this study, we further showed that more than 50% of CD4+ T cells in MHC-I-restricted P1A tumor antigen-specific TCR (P1ATCR)-transgenic mice could specifically bind to MHC-I/P1A peptide complex. P1A peptide could stimulate the transgenic CD4+ T cells to proliferate and secrete both type 1 helper T cell and type 2 helper T cell cytokines. The activated CD4+ T cells also showed cytotoxicity against P1A-expressing tumor cells. The analysis of TCR ?-chains showed that these CD4+ T cells were selected by co-expressing endogenous TCRs. Our results show that CD4+ T cells from P1ATCR transgenic mice co-expressed an MHC-I-restricted transgenic TCR and another rearranged endogenous TCRs, both of which were functional. PMID:21643003

Han, Xue; Ye, Peiying; Luo, Liqun; Zheng, Linghua; Liu, Yang; Chen, Lieping; Wang, Shengdian

2011-01-01

245

A Comparative Study of N-glycolylneuraminic Acid (Neu5Gc) and Cytotoxic T Cell (CT) Carbohydrate Expression in Normal and Dystrophin-Deficient Dog and Human Skeletal Muscle  

PubMed Central

The expression of N-glycolylneuraminic acid (Neu5Gc) and the cytotoxic T cell (CT) carbohydrate can impact the severity of muscular dystrophy arising from the loss of dystrophin in mdx mice. Here, we describe the expression of these two glycans in skeletal muscles of dogs and humans with or without dystrophin-deficiency. Neu5Gc expression was highly reduced (>95%) in muscle from normal golden retriever crosses (GR, n?=?3) and from golden retriever with muscular dystrophy (GRMD, n?=?5) dogs at multiple ages (3, 6 and 13 months) when compared to mouse muscle, however, overall sialic acid expression in GR and GRMD muscles remained high at all ages. Neu5Gc was expressed on only a minority of GRMD satellite cells, CD8+ T lymphocytes and macrophages. Human muscle from normal (no evident disease, n?=?3), Becker (BMD, n?=?3) and Duchenne (DMD, n?=?3) muscular dystrophy individuals had absent to very low Neu5Gc staining, but some punctate intracellular muscle staining was present in BMD and DMD muscles. The CT carbohydrate was localized to the neuromuscular junction in GR muscle, while GRMD muscles had increased expression on a subset of myofibers and macrophages. In humans, the CT carbohydrate was ectopically expressed on the sarcolemmal membrane of some BMD muscles, but not normal human or DMD muscles. These data are consistent with the notion that altered Neu5Gc and CT carbohydrate expression may modify disease severity resulting from dystrophin deficiency in dogs and humans. PMID:24505439

Martin, Paul T.; Golden, Bethannie; Okerblom, Jonathan; Camboni, Marybeth; Chandrasekharan, Kumaran; Xu, Rui; Varki, Ajit; Flanigan, Kevin M.; Kornegay, Joe N.

2014-01-01

246

T cell–directed therapies: lessons learned and future prospects  

Microsoft Academic Search

Agents interfering with T cell function are therapeutic mainstays for various autoimmune diseases and for transplant approaches to organ failure. The understanding of T cell biology has blossomed since the development of most agents now in use. Here we discuss T cell–specific agents now in use, others recently added to the therapeutic armamentarium and promising agents being investigated in clinical

Eric H Liu; Richard M Siegel; David M Harlan; John J O'Shea

2007-01-01

247

Development of an Artificial-Antigen-Presenting-Cell-Based Assay for the Detection of Low-Frequency Virus-Specific CD8+ T Cells in Whole Blood, with Application for Measles Virus?  

PubMed Central

Evaluation of the immune responses induced by childhood vaccines requires measurement of T-cell, as well as antibody, responses. However, cellular immune responses are often not analyzed because of technical hurdles and the volume of blood required. Therefore, a sensitive and specific assay for antigen-specific T cells that utilizes a small volume of blood would facilitate new vaccine evaluation. We developed a novel assay for quantifying virus-specific CD8+ T cells that combines the use of HLA-A2 immunoglobulin-based artificial antigen-presenting cells (aAPCs) for stimulation of antigen-specific CD8+ T cells in whole blood with quantitative real-time reverse transcription-PCR (qRT-PCR) to detect gamma interferon (IFN-?) mRNA. This assay was optimized using a well-established cytomegalovirus (CMV) CD8+ T-cell system. The aAPC-qRT-PCR assay had comparable sensitivity to intracellular cytokine staining (ICS) in detecting CMV-specific CD8+ T cells with a detection limit of less than 0.004%. The assay was applied to the detection of low-frequency measles virus (MV)-specific CD8+ T cells by stimulating blood from five MV-immune HLA-A*0201 donors with four different MV-specific peptides (MV peptide aAPCs). Stimulation with three of the MV peptide aAPCs resulted in significant increases in IFN-? mRNA ranging from 3.3- to 13.5-fold. Our results show that the aAPC-qRT-PCR assay is highly sensitive and specific and can be standardized for screening MV-specific CD8+ T cells in vaccine trials. The technology should be transferable to analysis of CD8+ T-cell responses to other antigens. PMID:19494085

Ndhlovu, Zaza M.; Angenendt, Monika; Heckel, Diana; Schneck, Jonathan P.; Griffin, Diane E.; Oelke, Mathias

2009-01-01

248

Immunoregulatory T cells in autoimmunity  

Microsoft Academic Search

The aim of this work was to discuss the current knowledge concerning regulatory T cells in the pathogenesis of autoimmune diseases. CD4+ T cells that constitutively express CD25 exhibit powerful suppressive properties. Such cells have been denominated regulatory T cells (TR). Alterations in TR cells are known to cause organ-specific autoimmune disease in animal models. These cells are anergic when

Jose C Crispin; Maria Ines Vargas; Jorge Alcocer-Varela

2004-01-01

249

Expression of NK cell receptors on decidual T cells in human pregnancy  

Microsoft Academic Search

Specific receptors enable NK cells to discriminate between cells with normal expression of MHC class I and cells that have low or absent expression of MHC class I molecules. In addition to NK cells, these receptors can be expressed on T cell subsets, mainly on CD8+ T cells but also on ??TCR+ T cells and CD4+ T cells. Although the

Tamara Tilburgs; Barbara J. van der Mast; Nicole M. A. Nagtzaam; Dave L. Roelen; Sicco A. Scherjon; Frans H. J. Claas

2009-01-01

250

Transnuclear Mice with Pre-defined T Cell Receptor Specificities Against Toxoplasma gondii Obtained via SCNT  

E-print Network

Mice that are transgenic for rearranged antigen-specific T cell receptors (TCRs) are essential tools to study T cell development and function. Such TCRs are usually isolated from the relevant T cells after long-term culture, ...

Suh, Heikyung

251

Adult T-Cell Leukemia/Lymphoma (HTLV-1)  

MedlinePLUS

... gentic material made of DNA, but instead carry RNA. These viruses selectively infect only T-cells. Only ... potential to inject its genetic material (DNA or RNA) into normal cells. Once inside the normal cells, ...

252

Roscovitine Suppresses CD4+ T Cells and T Cell-Mediated Experimental Uveitis  

PubMed Central

Background T cells are essential for the development of uveitis and other autoimmune diseases. After initial activation, CD4+ lymphocytes express the co-stimulatory molecule OX40 that plays an important role in T cell proliferation. Cyclin dependent kinase 2 (CdK2) plays a pivotal role in the cell cycle transition from G1 to S phase. In addition, recent research has implicated CdK2 in T cell activation. Thus, we sought to test the immunosuppressive effect of roscovitine, a potent CdK2 inhibitor, on CD4+ T cell activation, proliferation, and function. Design and Methods Mouse CD4+ T cells were activated by anti-CD3 and anti-CD28 antibodies. The expression of OX40, CD44, and CdK2 were analyzed by flow cytometry. In addition, cell cycle progression and apoptosis of control and roscovitine-treated T lymphocytes were measured by BrdU incorporation and annexin V assay, respectively. Furthermore, the immunoregulatory effect of roscovitine was evaluated in both ovalbumin-induced uveitis and experimental autoimmune uveitis (EAU) models. Results In this study, we found that T cell activation induced OX40 expression. Cell cycle analysis showed that more CD4+OX40+ cells entered S phase than OX40- T cells. Concurrently, CD4+OX40+ cells had a higher level of CdK2 expression. Roscovitine treatment blocked activated CD4+ cells from entering S phase. In addition, roscovitine not only reduced the viability of CD4+ lymphocytes but also suppressed T cell activation and cytokine production. Finally, roscovitine significantly attenuated the severity of T cell-dependent, OX40-enhanced uveitis. Conclusion These results implicate CdK2 in OX40-augmented T cell response and expansion. Furthermore, this study suggests that roscovitine is a novel, promising, therapeutic agent for treating T cell-mediated diseases such as uveitis. PMID:24260551

Zhang, Zili; Liu, Qi; Leskov, Konstantin S.; Wu, Xiumei; Duan, Jie; Zhang, Gary L.; Hall, Mark; Rosenbaum, James T.

2013-01-01

253

Mechanisms of T-Cell Activation by Human T-Cell Lymphotropic Virus Type I  

PubMed Central

The interactions between human T-cell lymphotropic virus type I (HTLV-I) and the cellular immune system can be divided into viral interference with functions of the infected host T cell and the subsequent interactions between the infected T cell and the cellular immune system. HTLV-I-mediated activation of the infected host T cell is induced primarily by the viral protein Tax, which influences transcriptional activation, signal transduction pathways, cell cycle control, and apoptosis. These properties of Tax may well explain the ability of HTLV-I to immortalize T cells. It is not clear, though, how HTLV-I induces T-cell transformation (interleukin-2 [IL-2] independence). Recent evidence suggests that Tax may promote the G1- to S-phase transition, although this may involve additional proteins. A role for other viral proteins that may constitutively activate the IL-2 receptor pathway has also been suggested. By virtue of their activated state, HTLV-I-infected T cells can nonspecifically activate resting, uninfected T cells via virus-mediated upregulation of adhesion molecules. This may favor viral dissemination. Moreover, the induction of a remarkably high frequency of antiviral CD8+ T cells does not appear to eliminate the infection. Indeed, individuals with a high frequency of virus-specific CD8+ T cells have a high viral load, indicating a state of chronic immune system stimulation. Thus, while an activated immune system is needed to eradicate the infection, the spread of the HTLV-I is also accelerated under these conditions. A detailed knowledge of the molecular interactions between virus-specific CD8+ T cells and immunodominant viral epitopes holds promise for the development of specific antiviral therapy. PMID:10357853

Hollsberg, Per

1999-01-01

254

Foxp3+ CD25+ regulatory T cells specific for a neo-self-antigen develop at the double-positive thymic stage  

Microsoft Academic Search

Thymus-derived regulatory T cells (Tregs) expressing CD4, CD25, and the transcription factor Foxp3 play major roles in preventing autoimmunity. The Treg population is enriched in T cells expressing high-avidity self-reactive T cell receptors, and thymic epithelial cells expressing self-antigens (Ag) have been implicated in their induction and\\/or selection. However, the thymic selection events leading to Treg lineage commitment remain unclear.

Julie Cabarrocas; Cécile Cassan; Fay Magnusson; Eliane Piaggio; Lennart Mars; Jens Derbinski; Bruno Kyewski; David-Alexandre Gross; Benoit L. Salomon; Khashayarsha Khazaie; Abdelhadi Saoudi; Roland S. Liblau

2006-01-01

255

A Variable CD3+ T-Cell Frequency in Peripheral Blood Lymphocytes Associated with Type 1 Diabetes Mellitus Development in the LEW.1AR1-iddm Rat  

PubMed Central

Purpose The LEW.1AR1-iddm rat is an animal model of human type 1 diabetes mellitus (T1DM), which arose through a spontaneous mutation within the MHC-congenic inbred strain LEW.1AR1 (RT1r2). In contrast to the diabetes-resistant LEW.1AR1 background strain in LEW.1AR1-iddm rats a highly variable T-cell frequency could be observed in peripheral blood lymphocytes (PBLs). Methods In this study we therefore characterised the T-cell repertoire within the PBLs of the two strains by flow cytometry analysis and identified the CD3+ T-cell phenotype and its possible linkage to diabetes susceptibility. To map loci conferring susceptibility to variable CD3+ T-cell frequency, backcross strains (N2) were generated with the genetically divergent BN and PAR rats for microsatellite analysis. Results The LEW.1AR1-iddm rat strain was characterised by a higher variability of CD3+ T-cells in PBLs along with a slightly decreased mean value compared to the LEW.1AR1 background strain. The reason for this reduction was a decrease in the CD4+ T-cell count while the CD8+ T-cell proportion remained unchanged. However, both T-cell subpopulations showed a high variability. This resulted in a lower CD4+/CD8+ T-cell ratio than in LEW.1AR1 rats. Like LEW.1AR1-iddm rats all animals of the backcross populations, N2 BN and N2 PAR rats, also showed large variations of the CD3+ T-cell frequency. The phenotype of variable CD3+ T-cell frequency mapped to the telomeric region of chromosome 1 (RNO1), which is identical with the already known Iddm8 diabetes susceptibility region. The data indicate that a variable CD3+ T-cell frequency in PBLs is genetically linked to diabetes susceptibility in the LEW.1AR1-iddm rat. Conclusion The T-cell variability in PBLs could be related to the previously reported imbalance between regulatory and effector T-cell populations which results in beta-cell autoimmunity. Since similar T-cell phenotypes have also been described in human T1DM the identification of the functional role of the observed variable CD3+ T-cell frequency may help to understand the mechanisms of autoimmunity in T1DM. PMID:23717591

Arndt, Tanja; Jörns, Anne; Weiss, Heike; Tiedge, Markus; Hedrich, Hans-Jürgen; Lenzen, Sigurd; Wedekind, Dirk

2013-01-01

256

Memory T Cells in Transplantation  

PubMed Central

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.

Su, Charles A.; Fairchild, Robert L.

2014-01-01

257

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

PubMed

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

2014-09-01

258

Differential lymphopenia-induced homeostatic proliferation for CD4+ and CD8+ T cells following septic injury  

PubMed Central

Sepsis is a severe, life-threatening infection and a leading cause of death in hospitals. A hallmark of sepsis is the profound apoptosis-induced depletion of lymphocytes generating a lymphopenic environment. As lymphopenia can induce nonantigen-driven homeostatic proliferation (HP), we examined this process during sepsis. CD4+ and CD8+ T cells, which were depleted within 24 h of sepsis induction, remained at significantly reduced levels until Day 21 when normal numbers were detected. When HP was examined, naïve CD8+ T cells proliferated between Day 7 and Day 21 post-cecal ligation and puncture, developing into memory cells with relatively few cells expressing an activation phenotype. Conversely, naïve CD4+ T cells did not undergo HP, but proportionally higher numbers expressed activation markers. Adoptive transfer studies revealed that T cells from mice that had recovered from sepsis were not protective when transferred to naïve mice undergoing sepsis. In addition, the TCR repertoire was not skewed toward any specific V? type but resembled the repertoire found in normal mice, suggesting that T cells were not primed to antigens resulting from the infection. Interestingly, depletion of endogenous CD8+ but not CD4+ T cells restored the ability of naive CD4+ T cells to undergo HP, increasing the number of CD4+ T cells with memory but not activation markers. We conclude that homeostatic control in the postseptic environment permits recovery of the T cell repertoire to normal levels without generating antigen-specific memory or aberrant T cell specificities. Restoration of homeostatic control mechanisms might be a rational therapy for this disorder. PMID:19088177

Unsinger, Jacqueline; Kazama, Hirotaka; McDonough, Jacquelyn S.; Hotchkiss, Richard S.; Ferguson, Thomas A.

2009-01-01

259

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

260

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

261

[CD30-positive anaplastic large cell T-cell lymphoma developing during immunosuppressive therapy of pityriasis rubra pilaris with ustekinumab].  

PubMed

The development of malignancies during therapy with biologics has been discussed controversially. A patient with extensive pityriasis rubra pilaris failed to respond to standard therapeutic approaches. While receiving immunomodulatory therapy, lastly with ustekinumab, the patient developed a CD30(+) anaplastic large cell lymphoma. PMID:23322178

Humme, D; Beyer, M; Röwert-Huber, H-J; Sterry, W; Philipp, S

2013-03-01

262

Peritoneal Cavity Regulatory B Cells (B10 Cells) Modulate IFN-?+CD4+ T Cell Numbers During Colitis Development in Mice  

PubMed Central

The spleen regulatory B cell subset with the functional capacity to express IL-10 (B10 cells) modulates both immune responses and autoimmune disease severity. However, the peritoneal cavity also contains relatively high frequencies of functionally-defined IL-10-competent B10 cells. In this study, peritoneal cavity B10 cells shared similar cell surface phenotypes with their spleen counterparts. However, peritoneal cavity B10 cells were 10-fold more frequent among B cells than occurred within the spleen, intestinal track or mesenteric lymph nodes and were present at higher proportions among the phenotypically-defined peritoneal B1a>B1b>B2 cell subpopulations. The development or localization of B10 cells within the peritoneal cavity was not dependent on the presence of commensal microbiota, T cells, IL-10 or B10 cell IL-10 production, or differences between their fetal liver or adult bone marrow progenitor cell origins. The BCR repertoire of peritoneal cavity B10 cells was diverse, as occurs in the spleen, and predominantly included germline-encoded VH and VL regions commonly found in either the conventional or B1 B cell compartments. Thereby, the capacity to produce IL-10 appears to be an intrinsic functional property acquired by clonally diverse B cells. Importantly, IL-10 production by peritoneal cavity B cells significantly reduced disease severity in spontaneous and induced models of colitis by regulating neutrophil infiltration, colitogenic CD4+ T cell activation and pro-inflammatory cytokine production during colitis onset. Thus, the numerically small B10 cell subset within the peritoneal cavity has regulatory function and is important for maintaining homeostasis within gastrointestinal tissues and the immune system. PMID:23918988

Smith, Susan H.; Kalampokis, Ioannis; Weaver, Casey T.; Plevy, Scott E.; Poe, Jonathan C.; Tedder, Thomas F.

2013-01-01

263

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

264

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

PubMed

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

2014-02-18

265

Peritoneal cavity regulatory B cells (B10 cells) modulate IFN-?+CD4+ T cell numbers during colitis development in mice.  

PubMed

The spleen regulatory B cell subset with the functional capacity to express IL-10 (B10 cells) modulates both immune responses and autoimmune disease severity. However, the peritoneal cavity also contains relatively high frequencies of functionally defined IL-10-competent B10 cells. In this study, peritoneal cavity B10 cells shared similar cell surface phenotypes with their spleen counterparts. However, peritoneal cavity B10 cells were 10-fold more frequent among B cells than occurred within the spleen, intestinal tract, or mesenteric lymph nodes and were present at higher proportions among the phenotypically defined peritoneal B1a > B1b > B2 cell subpopulations. The development or localization of B10 cells within the peritoneal cavity was not dependent on the presence of commensal microbiota, T cells, IL-10 or B10 cell IL-10 production, or differences between their fetal liver or adult bone marrow progenitor cell origins. The BCR repertoire of peritoneal cavity B10 cells was diverse, as occurs in the spleen, and predominantly included germline-encoded VH and VL regions commonly found in either the conventional or B1 B cell compartments. Thereby, the capacity to produce IL-10 appears to be an intrinsic functional property acquired by clonally diverse B cells. Importantly, IL-10 production by peritoneal cavity B cells significantly reduced disease severity in spontaneous and induced models of colitis by regulating neutrophil infiltration, colitogenic CD4(+) T cell activation, and proinflammatory cytokine production during colitis onset. Thus, the numerically small B10 cell subset within the peritoneal cavity has regulatory function and is important for maintaining homeostasis within gastrointestinal tissues and the immune system. PMID:23918988

Maseda, Damian; Candando, Kathleen M; Smith, Susan H; Kalampokis, Ioannis; Weaver, Casey T; Plevy, Scott E; Poe, Jonathan C; Tedder, Thomas F

2013-09-01

266

MAPKAP kinase 3 suppresses Ifng gene expression and attenuates NK cell cytotoxicity and Th1 CD4 T-cell development upon influenza A virus infection.  

PubMed

MK2 and MK3 are downstream targets of p38 and ERK1/2. They control the mRNA stability of several inflammatory cytokines, including TNF-? and IL-10. Whereas MK2 is expressed ubiquitously, the expression of MK3 is restricted to muscle, liver, and heart tissues and T and NK cells. Using Mk-deficient and wild-type (WT) mice, we demonstrated an inhibitory effect of MK3, but not of MK2, on interferon (IFN)-? expression in T and NK lymphocytes. The results provided evidence that the inhibitory effect of MK3 is based on negative feedback phosphorylation of p38 and ERK1/2, which causes decreased binding of Stat4 to the IFN-? promoter and reduced expression of IFN-? mRNA and protein. Consequently, all Mk3(-/-) mice challenged with the Th1-inducing influenza A virus (IAV) survived the WT LD50 virus dose. The reduced disease severity in the Mk3(-/-) mice was accompanied by a >10-fold reduction in viral lung titer and an increase in the number of activated NK cells and enhanced Th1 activation of CD4 T cells. Thus, our data describe the protein kinase MK3 as a novel regulator of the innate and adaptive immune responses.-Köther, K., Nordhoff, C., Masemann, D., Varga, G., Bream, J. H., Gaestel, M., Wixler, V., Ludwig, S. MAPKAP kinase 3 suppresses Ifng gene expression and attenuates NK cell cytotoxicity and Th1 CD4 T-cell development upon influenza A virus infection. PMID:24935968

Köther, Katharina; Nordhoff, Carolin; Masemann, Dörthe; Varga, Georg; Bream, Jay H; Gaestel, Matthias; Wixler, Viktor; Ludwig, Stephan

2014-10-01

267

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

268

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

269

G Protein-Coupled Receptor 83 Is Dispensable for the Development and Function of Regulatory T Cells  

Microsoft Academic Search

Global analyses of gene expression in regulatory T (Treg) cells, whose development is critically dependent upon the transcription factor Foxp3, have provided many clues as to the molecular mechanisms these cells employ to control immune responses and establish immune tolerance. Through these studies, G protein- coupled receptor 83 (GPR83) was found to be expressed at high levels in Treg-cell populations.

Li-Fan Lu; Marc A. Gavin; Jeffrey P. Rasmussen; Alexander Y. Rudensky

2007-01-01

270

B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase.  

PubMed

A discrete population of splenocytes with attributes of dendritic cells (DCs) and coexpressing the B-cell marker CD19 is uniquely competent to express the T-cell regulatory enzyme indoleamine 2,3-dioxygenase (IDO) in mice treated with TLR9 ligands (CpGs). Here we show that IDO-competent cells express the B-lineage commitment factor Pax5 and surface immunoglobulins. CD19 ablation abrogated IDO-dependent T-cell suppression by DCs, even though cells with phenotypic attributes matching IDO-competent cells developed normally and expressed IDO in response to interferon gamma. Consequently, DCs and regulatory T cells (Tregs) did not acquire T-cell regulatory functions after TLR9 ligation, providing an alternative perspective on the known T-cell regulatory defects of CD19-deficient mice. DCs from B-cell-deficient mice expressed IDO and mediated T-cell suppression after TLR9 ligation, indicating that B-cell attributes were not essential for B-lymphoid IDO-competent cells to regulate T cells. Thus, IDO-competent cells constitute a distinctive B-lymphoid cell type with quintessential T-cell regulatory attributes and phenotypic features of both B cells and DCs. PMID:20498068

Johnson, Burles A; Kahler, David J; Baban, Babak; Chandler, Phillip R; Kang, Baolin; Shimoda, Michiko; Koni, Pandelakis A; Pihkala, Jeanene; Vilagos, Bojan; Busslinger, Meinrad; Munn, David H; Mellor, Andrew L

2010-06-01

271

Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7R? mutant mice  

PubMed Central

Loss of interleukin (IL)-7 or the IL-7 receptor alpha (IL-7R?, CD127) results in severe immunodeficiencies in mice and humans. To more precisely identify signals governing IL-7 function in vivo, we have disrupted the IL-7R? Y449XXM motif in mice by knock-in mutagenesis (IL-7R?449F). Thymic precursors were reduced in number in IL-7R?449F mice, but in marked contrast to IL-7R??/? knockout mice, thymocytes and peripheral T cells developed normally. Strikingly, Listeria infection revealed that CD4 and CD8 T cells had different requirements for IL-7R? signals. CD4 T cells failed to mount a primary response, but despite normal CD8 primary responses, maintenance of CD8 memory was impaired in IL-7R?449F mice. Furthermore, we show that Bcl-2 is IL-7R? Y449 independent and insufficient for IL-7–mediated maintenance of CD8 memory. PMID:17325202

Osborne, Lisa C.; Dhanji, Salim; Snow, Jonathan W.; Priatel, John J.; Ma, Melissa C.; Miners, M. Jill; Teh, Hung-Sia; Goldsmith, Mark A.; Abraham, Ninan

2007-01-01

272

Assessing the replicative history of human T cells.  

PubMed

Upon encountering antigen, T cells clonally expand and differentiate into effector cells that directly or indirectly eliminate antigen-bearing pathogens. When renewed contact with the same pathogen occurs the immune response is mounted in a faster and more accurate way, a process that is referred to as immunological memory. The basis for T-cell memory is at least partially provided by an enhanced precursor frequency of antigen-specific T cells, and an increased responsiveness of primed T cells to activation signals. In contrast to B cells, which acquire mutations in the immunoglobulin genes after antigenic challenge, somatic markers are lacking that distinguish unprimed (or naive) from primed (encompassing memory and effector) T cells. Instead, differential expression of cell surface molecules on subsets of T cells and measures for replicative history can be used to obtain insight into the antigen-driven development of the T-cell compartment. Apart from fundamental issues addressing lineage relationships between naive, memory and effector T cells and the cellular basis for long-term T-cell memory, these types of studies have proved to be valuable in understanding T-cell reconstitution in situations of severe T-cell depletion, i.e., after chemotherapy, treatment with depleting CD4 monoclonal antibodies or during HIV infection. PMID:10635984

Van Lier, R A; Baars, P A

1999-12-17

273

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

274

PPAR? Negatively Regulates T Cell Activation to Prevent Follicular Helper T Cells and Germinal Center Formation  

PubMed Central

Peroxisome proliferator-activated receptor gamma (PPAR?) is a transcription factor that regulates lipid and glucose metabolism. Although studies of PPAR? ligands have demonstrated its regulatory functions in inflammation and adaptive immunity, its intrinsic role in T cells and autoimmunity has yet to be fully elucidated. Here we used CD4-PPAR?KO mice to investigate PPAR?-deficient T cells, which were hyper-reactive to produce higher levels of cytokines and exhibited greater proliferation than wild type T cells with increased ERK and AKT phosphorylation. Diminished expression of I?B?, Sirt1, and Foxo1, which are inhibitors of NF-?B, was observed in PPAR?-deficient T cells that were prone to produce all the signature cytokines under Th1, Th2, Th17, and Th9 skewing condition. Interestingly, 1-year-old CD4-PPAR?KO mice spontaneously developed moderate autoimmune phenotype by increased activated T cells, follicular helper T cells (TFH cells) and germinal center B cells with glomerular inflammation and enhanced autoantibody production. Sheep red blood cell immunization more induced TFH cells and germinal centers in CD4-PPAR?KO mice and the T cells showed increased of Bcl-6 and IL-21 expression suggesting its regulatory role in germinal center reaction. Collectively, these results suggest that PPAR? has a regulatory role for TFH cells and germinal center reaction to prevent autoimmunity. PMID:24921943

Park, Hong-Jai; Kim, Do-Hyun; Choi, Jin-Young; Kim, Won-Ju; Kim, Ji Yun; Senejani, Alireza G.; Hwang, Soo Seok; Kim, Lark Kyun; Tobiasova, Zuzana; Lee, Gap Ryol; Craft, Joseph; Bothwell, Alfred L. M.; Choi, Je-Min

2014-01-01

275

Functional activation of myelin-specific T cells by virus-induced molecular mimicry.  

PubMed

Molecular mimicry is the process by which T cells activated in response to determinants on an infecting microorganism cross-react with self epitopes, leading to an autoimmune disease. Normally, infection of SJL/J mice with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) results in a persistent CNS infection, leading to a chronic progressive, CD4(+) T cell-mediated demyelinating disease. Myelin damage is initiated by T cell responses to virus persisting in CNS APCs, and progressive demyelinating disease (50 days postinfection) is perpetuated by myelin epitope-specific CD4(+) T cells activated by epitope spreading. We developed an infectious model of molecular mimicry by inserting a sequence encompassing the immunodominant myelin epitope, proteolipid protein (PLP) 139-151, into the coding region of a nonpathogenic TMEV variant. PLP139-TMEV-infected mice developed a rapid onset paralytic inflammatory, demyelinating disease paralleled by the activation of PLP139-151-specific CD4(+) Th1 responses within 10-14 days postinfection. The current studies demonstrate that the early onset demyelinating disease induced by PLP139-TMEV is the direct result of autoreactive PLP139-151-specific CD4(+) T cell responses. PLP139-151-specific CD4(+) T cells from PLP139-TMEV-infected mice transferred demyelinating disease to naive recipients and PLP139-151-specific tolerance before infection prevented clinical disease. Finally, infection with the mimic virus at sites peripheral to the CNS induced early demyelinating disease, suggesting that the PLP139-151-specific CD4(+) T cells could be activated in the periphery and traffic to the CNS. Collectively, infection with PLP139-151 mimic encoding TMEV serves as an excellent model for molecular mimicry by inducing pathologic myelin-specific CD4(+) T cells via a natural virus infection. PMID:12193746

Olson, Julie K; Eagar, Todd N; Miller, Stephen D

2002-09-01

276

Regulatory T Cells as Immunotherapy  

PubMed Central

Regulatory T cells (Tregs) suppress exuberant immune system activation and promote immunologic tolerance. Because Tregs modulate both innate and adaptive immunity, the biomedical community has developed an intense interest in using Tregs for immunotherapy. Conditions that require clinical tolerance to improve outcomes – autoimmune disease, solid organ transplantation, and hematopoietic stem cell transplantation – may benefit from Treg immunotherapy. Investigators have designed ex vivo strategies to isolate, preserve, expand, and infuse Tregs. Protocols to manipulate Treg populations in vivo have also been considered. Barriers to clinically feasible Treg immunotherapy include Treg stability, off-cell effects, and demonstration of cell preparation purity and potency. Clinical trials involving Treg adoptive transfer to treat graft versus host disease preliminarily demonstrated the safety and efficacy of Treg immunotherapy in humans. Future work will need to confirm the safety of Treg immunotherapy and establish the efficacy of specific Treg subsets for the treatment of immune-mediated disease. PMID:24575095

Singer, Benjamin D.; King, Landon S.; D'Alessio, Franco R.

2014-01-01

277

The Gut Microbiota and Mucosal T Cells  

PubMed Central

It is intuitive that immune cells in the gut may require microbiota-derived cues for their differentiation. The proximity between host and microbe in the intestine would seemingly necessitate co-adaptation. However, it has been challenging to determine the members and features of the gut microbiota that influence immune system development and function. The recent identification of immunomodulatory members of the commensal microbiota is providing insight into the dependence of select, intestinal immune cell subsets on specific microbial species. In this review, we focus on the gut microbiota's influence on the development and function of mucosal T cells subsets, specifically intraepithelial lymphocytes and lamina propria CD4 T cells. PMID:21833339

Smith, Patrick M.; Garrett, Wendy S.

2011-01-01

278

Kinase Suppressor of Ras 1 Is Not Required for the Generation of Regulatory and Memory T Cells  

PubMed Central

The mammalian target of rapamycin (mTOR) kinase is a critical regulator of the differentiation of helper and regulatory CD4+ T cells, as well as memory CD8+ T cells. In this study, we investigated the role of the ERK signaling pathway in regulating mTOR activation in T cells. We showed that activation of ERK following TCR engagement is required for sustained mTOR complex 1 (mTORC1) activation. Absence of kinase suppressor of Ras 1 (KSR1), a scaffold protein of the ERK signaling pathway, or inhibition of ERK resulted in decreased mTORC1 activity following T cell activation. However, KSR1-deficient mice displayed normal regulatory CD4+ T cell development, as well as normal memory CD8+ T cell responses to LCMV and Listeria monocytogenes infection. These data indicate that despite its role in mTORC1 activation, KSR1 is not required in vivo for mTOR-dependent T cell differentiation. PMID:23431403

Le Borgne, Marie; Filbert, Erin L.; Shaw, Andrey S.

2013-01-01

279

Development and therapeutic effect of adoptively transferred T cells primed by tumor lysate-pulsed autologous dendritic cells in a patient with metastatic endometrial cancer.  

PubMed

We describe a 65-year-old woman with a large surgically unresectable and chemoresistant liver metastasis of endometrial carcinoma who was treated by infusion with peripheral blood T cells stimulated with tumor lysate-pulsed autologous dendritic cells (DC). Extensive in vitro characterization of the DC-activated T cells included phenotypic analysis, cytotoxicity, and intracellular cytokine secretion. High cytotoxicity was observed against autologous tumor cells, but not against NK-sensitive K562 cells, autologous Con-A lymphoblasts, or autologous Epstein-Barr virus-transformed lymphoblastoid cells. Blocking studies demonstrated that lytic activity was HLA class I restricted. Two-color flow cytometric analysis revealed that a significant proportion of CD8+ T cells was also CD56+, and analysis of intracellular IFN-gamma and IL-4 expression suggested a type 1 cytokine bias. The patient was treated by three infusions of tumor-specific T cells at 3- to 4-week intervals, and in vivo distribution of the T cells was followed by (111)In oxine labeling and serial gamma camera imaging. Tumor localization and accumulation of labeled lymphocytes was consistently detected at serial time points following each injection. However, deep infiltration of the large tumor mass by activated T cells was minimal, as evaluated in 3 dimensions by single photon emission computerized tomography (SPECT) imaging. Transient serum increases of the tumor marker lactate dehydrogenase (LDH), were detectable after each injection. Similar posttreatment elevations were seen for serum uric acid and potassium. Clinically, stabilization of the large liver metastasis was obtained during treatment. Collectively, these results indicate that tumor-specific CD8+ cytotoxic T-cell responses can be generated in patients with endometrial cancer, and suggest that T-cell immunotherapy may be of therapeutic value in patients harboring metastatic disease. PMID:10729762

Santin, A D; Hermonat, P L; Ravaggi, A; Bellone, S; Cowan, C; Coke, C; Pecorelli, S; Cannon, M J; Parham, G P

2000-01-01

280

Murine CD4 T Cells Produce a New Form of TGF-beta as Measured by a Newly Developed TGF-beta Bioassay  

Microsoft Academic Search

BackgroundIt is generally assumed that T cells do not produce active TGF-? since active TGF-? as measured in supernatants by ELISA without acidification is usually not detectable. However, it is possible that active TGF-? from T cells may take a special form which is not detectable by ELISA.Methodology\\/Principal FindingsWe constructed a TGF-? bioassay which can detect both soluble and membrane-bound

Takatoku Oida; Howard L. Weiner; Jean Kanellopoulos

2011-01-01

281

A T-cell subpopulation committed to help B cells for immune responses restricted to IgM type.  

PubMed Central

Immune responses againt bovine serum albumin by chicken were dependent upon thymus-derived cells. Thirty-five of seventy chickens that had been neonatally thymectomized and subsequently immunized with bovine serum albumin produced IgM antibodies, but not IgG antibodies, against the antigen. T cells (IgM-T cells) of such chickens were able to help B cells to produce IgM antibody responses but were not able to help them to switch IgM- to IgG-antibody responses. Helper activity of the IgM-T cells was much less susceptible to the cytotoxic effect of anti-thymus cell serum and complement than was that of normal T cells. The introduction of the IgM-T cells into normal chickens at the same time as the initiation of immunization of the chickens did not affect immune responses by them at all, indicating the absence of suppressor T cells in the IgM-T cell preparations. Injection of chicken thymus factor into immunodeficient chickens transplanted with normal B cells and IgM-T cells developed the capability to help B cells to switch IgM- to IgG-antibody responses. On the basis of these findings the authors propose the existence of helper T cells which are characterized by peripheralization in early periods of ontogeny, the possession of helper activity for only IgM-antibody responses, the lack of helper activity for the switch from IgM- to IgG-antibody responses and relative insusceptibility to the cytotoxic effect of anti-thymus cell serum and complement. PMID:6967854

Naito, I; Bito, Y

1980-01-01

282

Abnormalities of T cell maturation and regulation in human beings with immunodeficiency disorders.  

PubMed Central

A series of monoclonal antibodies to T cell surface antigens were used to characterize peripheral lymphoid populations from patients with a variety of immunodeficiency diseases. Several disorders of T cell differentiation were observed to occur in severe combined immunodeficiency. One subtype of severe combined immunodeficiency was associated with failure to develop lymphocytes that express any thymus specific antigens, another with failure to differentiate beyond the early prothymocyte-thymocyte (T9+, T10+) stage, while a third subtype was associated with failure to differentiate beyond a late thymocyte (T3+, T4+, T5+/T8+, T10+) stage. In contrast, patients with thymic aplasia (DiGeorge syndrome) had a diminished but detectable population of mature T cells. Imbalances in immunoregulatory T cells with a relative excess of suppressor cells were found in 9 of 17 patients with spontaneously occurring acquired agammaglobulinemia. In one of the latter individuals, there was an activated suppressor T cell population expressing Ia antigens (T+/T8+, Ia+). Another had no inducer T4+ cells. Patients with X-linked agammaglobulinemia frequently had an abnormal ratio of inducer to suppressor cells as well as an absence of circulating surface immunoglobulin-bearing cells. No such abnormalities were noted in normals or individuals with selective immunoglobulin (Ig)A deficiency. Taken together, these findings support the notion that several immunodeficiency states may occur as a consequence of defective T cell maturation or imbalances in immunoregulatory T lymphocyte subpopulations. PMID:6974177

Reinherz, E L; Cooper, M D; Schlossman, S F; Rosen, F S

1981-01-01

283

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

284

Antigen-Specific CD25?Foxp3?IFN-?highCD4+ T Cells Restrain the Development of Experimental Allergic Encephalomyelitis by Suppressing Th17  

PubMed Central

The current study identifies within the Th1 subtype two distinct CD4+ populations: those capable of transferring inflammatory autoimmunity and others that regulate its development by suppressing Th17 in an interferon (IFN)-?-dependent manner. These CD4+IFN-?highIL-4lowIL-10lowTGF-?lowFOXp3? cells in fact function as antigen-specific regulatory cells that restrain the development of autoimmunity by increasing the threshold of Th17 activation. We show that development of autoimmune conditions within the central nervous system is dependent on the Fas ligand-mediated apoptosis of these regulatory cells at early stages of disease. We also show that not only is the function of these cells IFN-? dependent but also that stable over expression of IFN-? in encephalitogenic CD4+ T cells redirects their biological function to become antigen-specific regulatory cells. This may also explain, in part, the pleiotropic role of IFN-? in the regulation of autoimmunity, as previously observed by others. PMID:20382706

Wildbaum, Gizi; Zohar, Yaniv; Karin, Nathan

2010-01-01

285

MRI of normal fetal brain development  

Microsoft Academic Search

Normal fetal brain maturation can be studied by in vivo magnetic resonance imaging (MRI) from the 18th gestational week (GW) to term, and relies primarily on T2-weighted and diffusion-weighted (DW) sequences. These maturational changes must be interpreted with a knowledge of the histological background and the temporal course of the respective developmental steps. In addition, MR presentation of developing and

Daniela Prayer; Gregor Kasprian; Elisabeth Krampl; Barbara Ulm; Linde Witzani; Lucas Prayer; Peter C. Brugger

2006-01-01

286

Effect of Long-Term Anti-CD4 or Anti-CD8 Treatment on the Development of lpr CD4 ?CD8 ?Double Negative T Cells and of the Autoimmune Syndrome in MRL- lpr \\/ lpr Mice  

Microsoft Academic Search

We have determined the effect of anti-CD4 or anti-CD8 monoclonal antibody (mAb) treatment from birth on the generation of thelprCD4?CD8?double-negative (DN) T cell subset and on the development of lupus-like autoimmune syndrome in MRL-lpr\\/lprmice. Both anti-CD4 and anti-CD8 mAb treatments resulted in a marked inhibition of lymphadenopathy, whereas the development of thelprDN T cells and of the lupus-like autoimmune syndrome

Ramón Merino; Liliane Fossati; Masahiro Iwamo to; Satoru Takahashi; Robert Lemoine; Nabila Ibnou-Zekri; Luisella Pugliatti; Jesús Merino; Shozo Izui

1995-01-01

287

Arthritogenic self-reactive CD4+ T cells acquire a FR4hi CD73hi anergic state in the presence of Foxp3+ T regulatory cells1  

PubMed Central

Rheumatoid arthritis develops in association with a defect in peripheral CD4+ T cell homeostasis. T cell lymphopenia has also been shown to be a barrier to CD4+ T cell clonal anergy induction. We, therefore, explored the relationship between clonal anergy induction and the avoidance of autoimmune arthritis by tracking the fate of glucose-6-phosphate isomerase (GPI)-reactive CD4+ T cells in the setting of selective T cell lymphopenia. CD4+ T cell recognition of self GPI peptide/MHCII complexes in normal murine hosts did not lead to arthritis, and instead caused those T cells to develop a Folate receptor 4 (FR4)hi CD73hi anergic phenotype. In contrast, hosts selectively depleted of polyclonal Foxp3+ CD4+ T regulatory cells could not make GPI-specific CD4+ T cells anergic, and failed to control arthritis. This suggests that autoimmune arthritis develops in the setting of lymphopenia when Foxp3+ CD4+ T regulatory cells are insufficient to functionally inactivate all autoreactive CD4+ T cells that encounter self Ag. PMID:22124124

Martinez, Ryan J.; Zhang, Na; Thomas, Stephanie R.; Nandiwada, Sarada L.; Jenkins, Marc K.; Binstadt, Bryce A.; Mueller, Daniel L.

2011-01-01

288

CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2.  

PubMed

Regulatory T cells (Tregs) are engaged in the maintenance of immunological self-tolerance and immune homeostasis. IL-10 has an important role in maintaining the normal immune state. Here, we show that IL-10-secreting Tregs can be delineated in normal mice as CD4(+)CD25(-)Foxp3(-) T cells that express lymphocyte activation gene 3 (LAG-3), an MHC-class-II-binding CD4 homolog. Although approximately 2% of the CD4(+)CD25(-) T cell population consisted of CD4(+)CD25(-)LAG3(+) T cells in the spleen, CD4(+)CD25(-)LAG3(+) T cells are enriched to approximately 8% in the Peyer's patch. They are hypoproliferative upon in vitro antigenic stimulation and suppress in vivo development of colitis. Gene expression analysis reveals that CD4(+)CD25(-)LAG3(+) Tregs characteristically express early growth response gene 2 (Egr-2), a key molecule for anergy induction. Retroviral gene transfer of Egr-2 converts naïve CD4(+) T cells into the IL-10-secreting and LAG-3-expressing phenotype, and Egr-2-transduced CD4(+) T cells exhibit antigen-specific immunosuppressive capacity in vivo. Unlike Foxp3(+) natural Tregs, high-affinity interactions with selecting peptide/MHC ligands expressed in the thymus do not induce the development of CD4(+)CD25(-)LAG3(+) Tregs. In contrast, the number of CD4(+)CD25(-)LAG3(+) Tregs is influenced by the presence of environmental microbiota. Thus, IL-10-secreting Egr-2(+)LAG3(+)CD4(+) Tregs can be exploited for the control of peripheral immunity. PMID:19666526

Okamura, Tomohisa; Fujio, Keishi; Shibuya, Mihoko; Sumitomo, Shuji; Shoda, Hirofumi; Sakaguchi, Shimon; Yamamoto, Kazuhiko

2009-08-18

289

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

290

Key role of regulated upon activation normal T-cell expressed and secreted, nonstructural protein1 and myeloperoxidase in cytokine storm induced by influenza virus PR-8 (A/H1N1) infection in A549 bronchial epithelial cells  

PubMed Central

Influenza virus infection causes severe respiratory disease such as that due to avian influenza (H5N1). Influenza A viruses proliferate in human epithelial cells, which produce inflammatory cytokines/chemokines as a “cytokine storm” attenuated with the viral nonstructural protein 1 (NS1). Cytokine/chemokine production in A549 epithelial cells infected with influenza A/H1N1 virus (PR-8) or nonstructural protein 1 (NS1) plasmid was examined in vitro. Because tumor necrosis factor-? (TNF-?) and regulated upon activation normal T-cell expressed and secreted (RANTES) are predominantly produced from cells infected with PR-8 virus, the effects of mRNA knockdown of these cytokines were investigated. Small interfering (si)TNF-? down-regulated RANTES expression and secretion of RANTES, interleukin (IL)-8, and monocyte chemotactic protein-1 (MCP-1). In addition, siRANTES suppressed interferon (IFN)-? expression and secretion of RANTES, IL-8, and MCP-1, suggesting that TNF-? stimulates production of RANTES, IL-8, MCP-1, and IFN-?, and RANTES also increased IL-8, MCP-1, and IFN-?. Furthermore, administration of TNF-? promoted increased secretion of RANTES, IL-8, and MCP-1. Administration of RANTES enhanced IL-6, IL-8, and MCP-1 production without PR-8 infection. These results strongly suggest that, as an initial step, TNF-? regulates RANTES production, followed by increase of IL-6, IL-8, and MCP-1 and IFNs concentrations. At a later stage, cells transfected with viral NS1 plasmid showed production of a large amount of IL-8 and MCP-1 in the presence of the H2O2-myeloperoxidse (MPO) system, suggesting that NS1 of PR-8 may induce a “cytokine storm” from epithelial cells in the presence of an H2O2-MPO system. PMID:22039999

Phung, Thuy Thi Bich; Sugamata, Ryuichi; Uno, Kazuko; Aratani, Yasuaki; Ozato, Keiko; Kawachi, Shoji; Nguyen, Liem Thanh; Nakayama, Toshinori; Suzuki, Kazuo

2014-01-01

291

Enhanced Response of T Cells from Murine Gammaherpesvirus 68-Infected Mice Lacking the Suppressor of T Cell Receptor Signaling Molecules Sts-1 and Sts-2  

PubMed Central

The human gammaherpesviruses establish life-long infections that are associated with the development of lymphomas and neoplasms, especially in immunocompromised individuals. T cells play a crucial role in the control of gammaherpesvirus infection through multiple functions, including the direct killing of infected cells, production of cytokines such as interferon-? (IFN-?), and costimulation of B cells. Impaired T cell function in mice infected with murine gammaherpesvirus 68 (MHV68) leads to increased reactivation and pathologies, including a higher incidence of lymphoid hyperplasia. Here we report that the absence of Suppressor of TCR signaling ?1 and ?2 (Sts-1-/-/2-/-) during MHV68 infection leads to the generation of T cells with significantly heightened responses. Transient differences in the T and B cell response of infected Sts-1-/-/2-/- (Sts dKO) mice were also observed when compared to WT mice. However, these alterations in the immune response and the overall absence of Sts-1 and Sts-2 did not impact viral pathogenesis or lead to pathology. Acute lytic replication in the lungs, establishment of latency in the spleen and reactivation from latency in the spleen in the Sts dKO mice were comparable to WT mice. Our studies indicate that Sts-1 and Sts-2 are not required for the immune control of MHV68 in a normal course of gammaherpesvirus infection, but suggest that interference with negative regulators of T cell responses might be further explored as a safe and efficacious strategy to improve adoptive T cell therapy. PMID:24587276

Cieniewicz, Brandon; Carpino, Nicholas; Krug, Laurie T.

2014-01-01

292

A Study of T Cell Tolerance to the Tumor-Associated Antigen MDM2: Cytokines Can Restore Antigen Responsiveness, but Not High Avidity T Cell Function  

Microsoft Academic Search

BackgroundMost tumor-associated antigens (TAA) currently used for immunotherapy of cancer are also expressed in normal tissues, which may induce tolerance and impair T cell-mediated immunity. However, there is limited information about how physiological expression in normal tissues alters the function of TAA-specific T cells.Methodology\\/Principal FindingsWe used a T cell receptor transgenic model to study how MDM2 expression in normal tissues

Gavin M. Bendle; Shao-An Xue; Angelika Holler; Hans J. Stauss; Jacques Zimmer

2007-01-01

293

Development of a hypersensitive periodate-cleavable amino acid that is methionine- and disulfide-compatible and its application in MHC exchange reagents for T cell characterisation.  

PubMed

Incorporation of cleavable linkers into peptides and proteins is of particular value in the study of biological processes. Here we describe the synthesis of a cleavable linker that is hypersensitive to oxidative cleavage as the result of the periodate reactivity of a vicinal amino alcohol moiety. Two strategies directed towards the synthesis of a building block suitable for solid-phase peptide synthesis were developed: a chemoenzymatic route, involving L-threonine aldolase, and an enantioselective chemical route; these led to ?,?-diamino-?-hydroxybutanoic acids in diastereoisomerically mixed and enantiopure forms, respectively. Incorporation of the 1,2-amino alcohol linker into the backbone of a peptide generated a conditional peptide that was rapidly cleaved at very low concentrations of sodium periodate. This cleavable peptide ligand was applied in the generation of MHC exchange reagents for the detection of antigen-specific T cells in peripheral blood cells. The extremely low concentration of periodate required to trigger MHC peptide exchange allowed the co-oxidation of methionine and disulfide residues to be avoided. Conditional MHC reagents hypersensitive to periodate can now be applied without limitations when UV irradiation is undesired or less practical. PMID:23280887

Amore, Alessia; Wals, Kim; Koekoek, Evelyn; Hoppes, Rieuwert; Toebes, Mireille; Schumacher, Ton N M; Rodenko, Boris; Ovaa, Huib

2013-01-01

294

Production of tag-free recombinant fusion protein encompassing promiscuous T cell epitope of tetanus toxoid and dog zona pellucida glycoprotein-3 for contraceptive vaccine development.  

PubMed

Affinity tags can interfere in various physicochemical properties and immunogenicity of the recombinant proteins. In the present study, tag-free recombinant fusion protein encompassing promiscuous T cell epitope of tetanus toxoid [TT; amino acid (aa) residues 830-844] followed by dilysine linker and dog zona pellucida glycoprotein-3 (ZP3; aa residues 23-348) (TT-KK-ZP3) was expressed in Escherichia coli. The recombinant protein, expressed as inclusion bodies (IBs), was purified by isolation of IBs, processed to remove host cell proteins, followed by solubilization and refolding. A specific 39 kDa protein including ZP3 was identified by SDS-PAGE. CD spectra showed the presence of ?-helices and ?-sheets, and fluorescent spectroscopy revealed emission maxima of 265 A.U. at 339 nm for refolded protein and showed red shift in the presence of 6 M guanidine hydrochloride. Immunization of inbred FvB/J female mice with purified recombinant TT-KK-ZP3 (25 ?g/animal) led to generation of high antibody titers against the recombinant protein. The antibodies reacted specifically with ZP matrix surrounding mouse oocytes. Immunized mice showed significant reduction in fertility as compared to the control group. The studies described herein provide a simple method to produce and purify tag-free recombinant protein for the development of a contraceptive vaccine. PMID:23242635

Gupta, Neha; Shrestha, Abhinav; Panda, Amulya Kumar; Gupta, Satish Kumar

2013-07-01

295

Diversity and Recognition Efficiency of T Cell Responses to Cancer  

PubMed Central

Background Melanoma patients vaccinated with tumor-associated antigens frequently develop measurable peptide-specific CD8+ T cell responses; however, such responses often do not confer clinical benefit. Understanding why vaccine-elicited responses are beneficial in some patients but not in others will be important to improve targeted cancer immunotherapies. Methods and Findings We analyzed peptide-specific CD8+ T cell responses in detail, by generating and characterizing over 200 cytotoxic T lymphocyte clones derived from T cell responses to heteroclitic peptide vaccination, and compared these responses to endogenous anti-tumor T cell responses elicited naturally (a heteroclitic peptide is a modification of a native peptide sequence involving substitution of an amino acid at an anchor residue to enhance the immunogenicity of the peptide). We found that vaccine-elicited T cells are diverse in T cell receptor variable chain beta expression and exhibit a different recognition profile for heteroclitic versus native peptide. In particular, vaccine-elicited T cells respond to native peptide with predominantly low recognition efficiency—a measure of the sensitivity of a T cell to different cognate peptide concentrations for stimulation—and, as a result, are inefficient in tumor lysis. In contrast, endogenous tumor-associated-antigen-specific T cells show a predominantly high recognition efficiency for native peptide and efficiently lyse tumor targets. Conclusions These results suggest that factors that shape the peptide-specific T cell repertoire after vaccination may be different from those that affect the endogenous response. Furthermore, our findings suggest that current heteroclitic peptide vaccination protocols drive expansion of peptide-specific T cells with a diverse range of recognition efficiencies, a significant proportion of which are unable to respond to melanoma cells. Therefore, it is critical that the recognition efficiency of vaccine-elicited T cells be measured, with the goal of advancing those modalities that elicit T cells with the greatest potential of tumor reactivity. PMID:15578105

2004-01-01

296

EVER2 Deficiency is Associated with Mild T-cell Abnormalities  

PubMed Central

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent flat warts or pityriasis versicolor-like lesions caused by betapapillomaviruses (EV-HPVs). Autosomal recessive EVER1 and EVER2 deficiencies account for EV in most patients. The mechanisms by which mutations in these partners of the Zinc transporter ZnT1 impair host defense against EV-HPVs are still poorly understood. Keratinocytes of EVER-deficient patients display an alteration of zinc homeostasis and an enhanced proliferative activity. Since EVER proteins are highly expressed in T lymphocytes, we aimed to assess the impact of EVER2 deficiency on T-cell development and function. We studied circulating lymphocyte populations in three adult EV patients sharing the same EVER2 mutation (T150fsX3). We found a normal count of CD4+ and CD8+ T cells and a normal proliferative capacity in response to anti-CD3 stimulation. However, we observed a significant increase of memory CD4+ and effector memory CD8+ T cells, a bias of the TCR V?? and V?? repertoires and an increase of skin-homing CD4+ T-cell subsets. Our findings suggest that EVER2-deficient patients display mild T-cell abnormalities. It remains unclear whether these abnormalities result from EVER deficiency, chronic EV-HPV infection, or both. PMID:22903682

Crequer, Amandine; Picard, Capucine; Pedergnana, Vincent; Lim, Annick; Zhang, Shen-Ying; Abel, Laurent; Majewski, Slawomir; Casanova, Jean-Laurent; Jablonska, Stefania; Orth, Gerard; Jouanguy, Emmanuelle

2013-01-01

297

EVER2 deficiency is associated with mild T-cell abnormalities.  

PubMed

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent flat warts or pityriasis versicolor-like lesions caused by betapapillomaviruses (EV-HPVs). Autosomal recessive EVER1 and EVER2 deficiencies account for EV in most patients. The mechanisms by which mutations in these partners of the Zinc transporter ZnT1 impair host defense against EV-HPVs are still poorly understood. Keratinocytes of EVER-deficient patients display an alteration of zinc homeostasis and an enhanced proliferative activity. Since EVER proteins are highly expressed in T lymphocytes, we aimed to assess the impact of EVER2 deficiency on T-cell development and function. We studied circulating lymphocyte populations in three adult EV patients sharing the same EVER2 mutation (T150fsX3). We found a normal count of CD4(+) and CD8(+) T cells and a normal proliferative capacity in response to anti-CD3 stimulation. However, we observed a significant increase of memory CD4(+) and effector memory CD8(+) T cells, a bias of the TCR V?? and V?? repertoires and an increase of skin-homing CD4(+) T-cell subsets. Our findings suggest that EVER2-deficient patients display mild T-cell abnormalities. It remains unclear whether these abnormalities result from EVER deficiency, chronic EV-HPV infection, or both. PMID:22903682

Crequer, Amandine; Picard, Capucine; Pedergnana, Vincent; Lim, Annick; Zhang, Shen-Ying; Abel, Laurent; Majewski, Slawomir; Casanova, Jean-Laurent; Jablonska, Stefania; Orth, Gerard; Jouanguy, Emmanuelle

2013-01-01

298

Master switches of T-cell activation and differentiation  

Microsoft Academic Search

T-cells play a central role in allergic airway diseases such as bronchial asthma. The imbalance between allergen-specific pro-inflammatory and pro-allergic T-cell responses on one hand and regulatory or suppressive T-cell responses on the other may best explain the development of unwanted immune responses against environmental allergens, which lead to immunoglobulin E production and airway inflammation. A key role in the

K. C. Beier; T. Kallinich; E. Hamelmann

2007-01-01

299

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

300

Inhibition of T cell activation and autoimmune diabetes using a B cell surface-linked CTLA-4 agonist  

PubMed Central

CTL-associated antigen 4 (CTLA-4) engagement negatively regulates T cell activation and function and promotes immune tolerance. However, it has been difficult to explore the biology of selective engagement of CTLA-4 in vivo because CTLA-4 shares its ligands, B7-1 and B7-2, with CD28. To address this issue, we developed a Tg mouse expressing a single-chain, membrane-bound anti–CTLA-4 Ab (scFv) on B cells. B and T cells developed normally and exhibited normal phenotype in the steady state and after activation in these mice. However, B cells from scFv Tg+ mice (sc?CTLA4+) prevented T cell proliferation and cytokine production in mixed lymphocyte reactions. Additionally, mice treated with sc?CTLA4+ B cells had decreased T cell–dependent B cell Ab production and class switching in vivo after antigen challenge. Furthermore, expression of this CTLA-4 agonist protected NOD mice from spontaneous autoimmune diabetes. Finally, this disease prevention occurred in Treg-deficient NOD.B7-1/B7-2 double-knockout mice, suggesting that the effect of the CTLA-4 agonist directly attenuates autoreactive T cell activation, not Treg activation. Together, results from this study demonstrate that selective ligation of CTLA-4 attenuates in vivo T cell responses, prevents development of autoimmunity, and represents a novel immunotherapeutic approach for the induction and maintenance of peripheral tolerance. PMID:16886063

Fife, Brian T.; Griffin, Matthew D.; Abbas, Abul K.; Locksley, Richard M.; Bluestone, Jeffrey A.

2006-01-01

301

B Lymphocytes -Development and 1Frankfurt Institute for Advanced Studies (FIAS), Goethe-  

E-print Network

and peripheral T-cell activation. Conversely to LAX and SIT, TRIM appears to be dispensable for normal T-cell development and T-cell function as TRIMÃ?/Ã? mice show no obvious defects. Although the data from knock immune tolerance and lead to the generation/activation of autoreactive T cells. Surprisingly, SIT

Maini, Philip K.

302

T-Cell Signaling in HIV-1 Infection  

PubMed Central

HIV exploits the T-cell signaling network to gain access to downstream cellular components, which serves as effective tools to break the cellular barriers. Multiple host factors and their interaction with viral proteins contribute to the complexity of HIV-1 pathogenesis and disease progression. HIV-1 proteins gp120, Nef, Tat and Vpr alter the T-cell signaling pathways by activating multiple transcription factors including NF-?B, Sp1 and AP-1. HIV-1 evades the immune system by developing a multi-pronged strategy. Additionally, HIV-1 encoded proteins influence the apoptosis in the host cell favoring or blocking T-cell apoptosis. Thus, T-cell signaling hijacked by viral proteins accounts for both viral persistence and immune suppression during HIV-1 infection. Here, we summarize past and present studies on HIV-1 T-cell signaling with special focus on the possible role of T cells in facilitating viral infection and pathogenesis PMID:23986795

Abbas, Wasim; Herbein, Georges

2013-01-01

303

Rare T-Cell Lymphomas  

Microsoft Academic Search

T-Cell lymphomas are a group of rare or, at least uncommon, hematologic malignancies comprising about 10–15% of all non-Hodgkin’s\\u000a lymphomas in North America (6). Overrepresentation of certain subtypes such as natural killer (NK)\\/T-cell lymphoma makes them\\u000a relatively more common in Asia (105, 106). As classification systems for lymphoid malignancies become more sophisticated,\\u000a combining morphology, immunophenotype, molecular, and clinical information, more

Ana Maria Molina; Steven M. Horwitz

304

Islet-Specific T-Cell Clones from Nonobese Diabetic Mice Express Heterogeneous T-Cell Receptors  

Microsoft Academic Search

Nonobese diabetic (NOD) mice spontaneously develop a T-cell-mediated autoimmune disease that is similar in many respects to insulin-dependent diabetes mellitus in humans. T-cell clones that specifically recognize pancreatic islet cell antigens can be derived from NOD mice, and most of these have been diabetogenic upon transfer to healthy recipients. We report herein the sequences of the T-cell receptor alpha and

Serge Candeias; Jonathan Katz; Christophe Benoist; Diane Mathis; Kathryn Haskins

1991-01-01

305

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

306

Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2R?null humanized mice  

PubMed Central

Human hematolymphoid mice have become valuable tools for the study of human hematopoiesis and uniquely human pathogens in vivo. Recent improvements in xenorecipient strains allow for long-term reconstitution with a human immune system. However, certain hematopoietic lineages, for example, the myeloid lineage, are underrepresented, possibly because of the limited cross-reactivity of murine and human cytokines. Therefore, we created a nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor-?–null (NOD-SCID IL2R?null) mouse strain that expressed human stem cell factor, granulocyte-macrophage colony-stimulating factor, and interleukin-3, termed NSG-SGM3. Transplantation of CD34+ human hematopoietic stem cells into NSG-SGM3 mice led to robust human hematopoietic reconstitution in blood, spleen, bone marrow, and liver. Human myeloid cell frequencies, specifically, myeloid dendritic cells, were elevated in the bone marrow of humanized NSG-SGM3 mice compared with nontransgenic NSG recipients. Most significant, however, was the increase in the CD4+FoxP3+ regulatory T-cell population in all compartments analyzed. These CD4+FoxP3+ regulatory T cells were functional, as evidenced by their ability to suppress T-cell proliferation. In conclusion, humanized NSG-SGM3 mice might serve as a useful model to study human regulatory T-cell development in vivo, but this unexpected lineage skewing also highlights the importance of adequate spatiotemporal expression of human cytokines for future xenorecipient strain development. PMID:21252091

Billerbeck, Eva; Barry, Walter T.; Mu, Kathy; Dorner, Marcus; Rice, Charles M.

2011-01-01

307

The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4(+) T-cell compartment.  

PubMed

Some signs of potential autoimmunity, such as the appearance of antinuclear antibodies (ANAs) become prevalent with age. In most cases, elderly people with ANAs remain healthy. Here, we investigated whether the same holds true for inbred strains of mice. Indeed, we show that most mice of the C57BL/6 (B6) strain spontaneously produced IgG ANA at 8-12 months of age, showed IgM deposition in kidneys and lymphocyte infiltrates in submandibular salivary glands. Despite all of this, the mice remained healthy. ANA production is likely CD4(+) T-cell dependent, since old (40-50 weeks of age) B6 mice deficient for MHC class II do not produce IgG ANAs. BM chimeras showed that ANA production was not determined by age-related changes in radiosensitive, hematopoietic progenitor cells, and that the CD4(+) T cells that promote ANA production were radioresistant. Thymectomy of B6 mice at 5 weeks of age led to premature alterations in T-cell homeostasis and ANA production, by 15 weeks of age, similar to that in old mice. Our findings suggest that a disturbed T-cell homeostasis may drive the onset of some autoimmune features. PMID:25044476

Nusser, Anja; Nuber, Natko; Wirz, Oliver F; Rolink, Hannie; Andersson, Jan; Rolink, Antonius

2014-10-01

308

C7a, a Biphosphinic Cyclopalladated Compound, Efficiently Controls the Development of a Patient-Derived Xenograft Model of Adult T Cell Leukemia/Lymphoma  

PubMed Central

Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive disease that occurs in individuals infected with the human T lymphotropic virus type 1 (HTLV-1). Patients with aggressive ATLL have a poor prognosis because the leukemic cells are resistant to conventional chemotherapy. We have investigated the therapeutic efficacy of a biphosphinic cyclopalladated complex {Pd2 [S(?)C2, N-dmpa]2 (?-dppe)Cl2}, termed C7a, in a patient-derived xenograft model of ATLL, and investigated the mechanism of C7a action in HTLV-1-positive and negative transformed T cell lines in vitro. In vivo survival studies in immunocompromised mice inoculated with human RV-ATL cells and intraperitoneally treated with C7a led to significantly increased survival of the treated mice. We investigated the mechanism of C7a activity in vitro and found that it induced mitochondrial release of cytochrome c, caspase activation, nuclear condensation and DNA degradation. These results suggest that C7a triggers apoptotic cell death in both HTLV-1 infected and uninfected human transformed T-cell lines. Significantly, C7a was not cytotoxic to peripheral blood mononuclear cells (PBMC) from healthy donors and HTLV-1-infected individuals. C7a inhibited more than 60% of the ex vivo spontaneous proliferation of PBMC from HTLV-1-infected individuals. These results support a potential therapeutic role for C7a in both ATLL and HTLV-1-negative T-cell lymphomas. PMID:21994769

Guimaraes-Correa, Ana B.; Crawford, Lindsey B.; Figueiredo, Carlos R.; Gimenes, Karina P.; Pinto, Lorena A.; Rios Grassi, Maria Fernanda; Feuer, Gerold; Travassos, Luiz R.; Caires, Antonio C.F.; Rodrigues, Elaine G.; Marriott, Susan J.

2011-01-01

309

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

310

Ageing combines CD4 T cell lymphopenia in secondary lymphoid organs and T cell accumulation in gut associated lymphoid tissue  

PubMed Central

Background CD4 T cell lymphopenia is an important T cell defect associated to ageing. Higher susceptibility to infections, cancer, or autoimmune pathologies described in aged individuals is thought to partly rely on T cell lymphopenia. We hypothesize that such diverse effects may reflect anatomical heterogeneity of age related T cell lymphopenia. Indeed, no data are currently available on the impact of ageing on T cell pool recovered from gut associated lymphoid tissue (GALT), a crucial site of CD4 T cell accumulation. Results Primary, secondary and tertiary lymphoid organs of C57BL/6 animals were analysed at three intervals of ages: 2 to 6 months (young), 10 to 14 months (middle-aged) and 22 to 26 months (old). We confirmed that ageing preferentially impacted CD4 T cell compartment in secondary lymphoid organs. Importantly, a different picture emerged from gut associated mucosal sites: during ageing, CD4 T cell accumulation was progressively developing in colon and small intestine lamina propria and Peyer’s patches. Similar trend was also observed in middle-aged SJL/B6 F1 mice. Interestingly, an inverse correlation was detected between CD4 T cell numbers in secondary lymphoid organs and colonic lamina propria of C57BL/6 mice whereas no increase in proliferation rate of GALT CD4 T cells was detected. In contrast to GALT, no CD4 T cell accumulation was detected in lungs and liver in middle-aged animals. Finally, the concomitant accumulation of CD4 T cell in GALT and depletion in secondary lymphoid organs during ageing was detected both in male and female animals. Conclusions Our data thus demonstrate that T cell lymphopenia in secondary lymphoid organs currently associated to ageing is not sustained in gut or lung mucosa associated lymphoid tissues or non-lymphoid sites such as the liver. The inverse correlation between CD4 T cell numbers in secondary lymphoid organs and colonic lamina propria and the absence of overt proliferation in GALT suggest that marked CD4 T cell decay in secondary lymphoid organs during ageing reflect redistribution of CD4 T cells rather than generalized CD4 T cell decay. Such anatomical heterogeneity may provide an important rationale for the diversity of immune defects observed during ageing. PMID:24829607

2014-01-01

311

Production of pemphigus antibody in vitro and analysis of T-cell subsets  

Microsoft Academic Search

T cells from nine patients in the active stage of pemphigus vulgaris and five in the inactive stage of the disease were studied with Leu-1, Leu-2, and Leu-3 monoclonal antibodies. No significant differences were observed in the proportions of total T cells or T cells expressing either helper or suppressor phenotype in peripheral blood leukocytes of patients compared to normal

A. Razzaque Ahmed; Richard I. Murahata; Robert W. Schroff; Ronald M. Stevens; Andrew S. Saxon

1983-01-01

312

ROQUIN/RC3H1 Alterations Are Not Found in Angioimmunoblastic T-Cell Lymphoma  

E-print Network

frequent T-cell lymphoma entities. Follicular helper T lymphocytes (TFH) are recognized as the normalROQUIN/RC3H1 Alterations Are Not Found in Angioimmunoblastic T-Cell Lymphoma Tiphanie Auguste1-Mondor Albert-Chenevier, Cre´teil, France Abstract Angioimmunoblastic T-cell Lymphoma (AITL) is one of the most

Paris-Sud XI, Université de

313

Local expression of transgene encoded TNF alpha in islets prevents autoimmune diabetes in nonobese diabetic (NOD) mice by preventing the development of auto-reactive islet-specific T cells  

PubMed Central

Lately, TNF alpha has been the focus of studies of autoimmunity; its role in the progression of autoimmune diabetes is, however, still unclear. To analyze the effects of TNF alpha in insulin-dependent diabetes mellitus (IDDM), we have generated nonobese diabetic (NOD) transgenic mice expressing TNF alpha under the control of the rat insulin II promoter (RIP). In transgenic mice, TNF alpha expression on the islets resulted in massive insulitis, composed of CD4+ T cells, CD8+ T cells, and B cells. Despite infiltration of considerable number of lymphoid cells in islets, expression of TNF alpha protected NOD mice from IDDM. To determine the mechanism of TNF alpha action, splenic cells from control NOD and RIP-TNF alpha mice were adoptively transferred to NOD-SCID recipients. In contrast to the induction of diabetes by splenic cells from control NOD mice, splenic cells from RIP- TNF alpha transgenic mice did not induce diabetes in NOD-SCID recipients. Diabetes was induced however, in the RIP-TNF alpha transgenic mice when CD8+ diabetogenic cloned T cells or splenic cells from diabetic NOD mice were adoptively transferred to these mice. Furthermore, expression of TNF alpha in islets also downregulated splenic cell responses to autoantigens. These data establish a mechanism of TNF alpha action and provide evidence that local expression of TNF alpha protects NOD mice from autoimmune diabetes by preventing the development of autoreactive islet-specific T cells. PMID:8920883

1996-01-01

314

Where do T cells stand in rheumatoid arthritis?  

PubMed

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by destruction of cartilage and bone. The destructive lesions result from both immune responses and non-antigen-specific inflammatory processes. Little is known about the primary cause of RA. Although the primacy of T-cell-related events early in the disease remains debated, strong evidence indicates that autoantigen recognition by specific T cells is crucial to the pathophysiology of rheumatoid synovitis. We will discuss evolving concepts about T-cell involvement in RA and the roles for various T cell subsets in the development of joint abnormalities. The hypothesis that RA is a T-cell driven disease was put forward when studies of RA synovium showed numerous T cells carrying activation markers. These T cells were found to participate in the complex network of cell- and mediator-driven events leading to joint destruction. Conceivably, these T cells may be stimulated by an autoantigen (whether specific to the joints or ubiquitous), a highly conserved foreign protein cross-reacting with its human homolog, or a neo-antigen expressed as a result of posttranslational events. For many years, animal models have provided valuable evidence supporting a role for T cells in RA. We will review three murine models of arthritis caused by different mechanisms. In collagen-induced arthritis, the immune response to a joint antigen is mediated by pathogenic Th1 cells that elicit severe inflammatory synovitis. Spontaneous arthritis in K/BxN T-cell-receptor transgenic mice is related to an adaptive immune response against a ubiquitous protein whose end-stage effector mechanisms are heavily dependent on the innate immune system. In the SKG model of autoimmune inflammatory arthritis, a point mutation in the gene encoding a key signal-transduction molecule in T cells causes defective T cell selection in the thymus, which releases polyclonal autoreactive T cells. Studies in these and other animal models have established that a variety of T-cell subsets whose roles vary with cell location and disease stage can contribute to synovitis. Finally, in addition to direct autoimmune attack by effector T cells, arthritis may result from defective homeostatic control of immunity by regulatory T cells. PMID:16087382

Fournier, Catherine

2005-12-01

315

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

316

Telomerase induction in T cells: a cure for aging and disease?  

PubMed

Cells of the immune system are unique among normal somatic cells in that they have the capacity to upregulate the telomere-extending enzyme, telomerase, albeit in a precisely controlled fashion. Kinetic analysis of telomerase activity in long-term T cell cultures has documented that the high level of telomerase induced in concert with activation reaches a peak at 3-5 days, then declines by 3 weeks. The process is recapitulated during secondary antigenic stimulation, but by the third, and all subsequent stimulations in vitro, CD8 T cells are unable to upregulate telomerase. Cell division in the absence of telomerase activity results in progressive telomere shortening, and ultimately, the DNA damage/cell cycle arrest that is signaled by critically short telomeres. Cultures of senescent CD8 T cells show altered cytokine patterns, resistance to apoptosis, and absence of expression of the CD28 costimulatory receptor. CD8 T cells with these and other features of replicative senescence accumulate progressively with age, and at an accelerated rate, during chronic infection with HIV-1. Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8(+)CD28(-) T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically suitable formulation. PMID:17182206

Effros, Rita B

2007-05-01

317

The Dark Side of Regulatory T Cells in Psoriasis  

Microsoft Academic Search

Psoriasis is a hereditary disease elicited by chronic activation of cutaneous T cells. Delineating the mechanistic interplay of the cell subsets involved is key to developing the next generation of effective treatments. In this issue, Bovenschen et al. report that regulatory T cells maintain a fine balance between the transcription factors Foxp3 and ROR?t. In patients with psoriasis, Tregs readily

David C. Soler; Thomas S. McCormick

2011-01-01

318

Studies of T-cell activation in chronic inflammation  

Microsoft Academic Search

CHAPTER SUMMARY: The strong association between specific alleles encoded within the MHC class II region and the development of rheumatoid arthritis (RA) has provided the best evidence to date that CD4+ T cells play a role in the pathogenesis of this chronic inflammatory disease. However, the unusual phenotype of synovial T cells, including their profound proliferative hyporesponsiveness to TCR ligation,

Andrew P Cope

2002-01-01

319

Isolation and Transmission of Human Retrovirus (Human T-Cell Leukemia Virus)  

Microsoft Academic Search

Nine new isolates of human T-cell leukemia-lymphoma virus (HTLV) were obtained from cells of seven patients with malignancies of mature T cells and from two clinically normal relatives of a T-cell leukemia patient. These people were from the United States, Israel, the West Indies, and Japan. The virus was detected in the fresh T cells and was isolated from the

M. Popovic; P. S. Sarin; M. Robert-Gurroff; V. S. Kalyanaraman; D. Mann; J. Minowada; R. C. Gallo

1983-01-01

320

Characterizing T Cells in SCID Patients Presenting with Reactive or Residual T Lymphocytes  

PubMed Central

Introduction. Patients with severe combined immunodeficiency (SCID) may present with residual circulating T cells. While all cells are functionally deficient, resulting in high susceptibility to infections, only some of these cells are causing autoimmune symptoms. Methods. Here we compared T-cell functions including the number of circulating CD3+ T cells, in vitro responses to mitogens, T-cell receptor (TCR) repertoire, TCR excision circles (TREC) levels, and regulatory T cells (Tregs) enumeration in several immunodeficinecy subtypes, clinically presenting with nonreactive residual cells (MHC-II deficiency) or reactive cells. The latter includes patients with autoreactive clonal expanded T cell and patients with alloreactive transplacentally maternal T cells. Results. MHC-II deficient patients had slightly reduced T-cell function, normal TRECs, TCR repertoires, and normal Tregs enumeration. In contrast, patients with reactive T cells exhibited poor T-cell differentiation and activity. While the autoreactive cells displayed significantly reduced Tregs numbers, the alloreactive transplacentally acquired maternal lymphocytes had high functional Tregs. Conclusion. SCID patients presenting with circulating T cells show different patterns of T-cell activity and regulatory T cells enumeration that dictates the immunodeficient and autoimmune manifestations. We suggest that a high-tolerance capacity of the alloreactive transplacentally acquired maternal lymphocytes represents a toleration advantage, yet still associated with severe immunodeficiency. PMID:23243423

Lev, Atar; Simon, Amos J.; Trakhtenbrot, Luba; Goldstein, Itamar; Nagar, Meital; Stepensky, Polina; Rechavi, Gideon; Amariglio, Ninette; Somech, Raz

2012-01-01

321

Regulatory T Cells Modulate Staphylococcal Enterotoxin B-Induced Effector T-Cell Activation and Acceleration of Colitis?  

PubMed Central

Oral administration of bacterial superantigen Staphylococcus aureus enterotoxin B (SEB) activates mucosal T cells but does not cause mucosal inflammation. We examined the effect of oral SEB on the development of mucosal inflammation in mice in the absence of regulatory T (Treg) cells. SCID mice were fed SEB 3 and 7 days after reconstitution with CD4+ CD45RBhigh or CD4+ CD45RBhigh plus CD4+ CD45RBlow T cells. Mice were sacrificed at different time points to examine changes in tissue damage and in T-cell phenotypes. Feeding SEB failed to produce any clinical effect on SCID mice reconstituted with CD4+ CD45RBhigh and CD4+ CD45RBlow T cells, but feeding SEB accelerated the development of colitis in SCID mice reconstituted with CD4+ CD45RBhigh T cells alone. The latter was associated with an increase in the number of CD4+ V?8+ T cells expressing CD69 and a significantly lower number of CD4+ CD25+ Foxp3+ T cells. These changes were not observed in SCID mice reconstituted with both CD45RBhigh and CD45RBlow T cells. In addition, SEB impaired the development of Treg cells in the SCID mice reconstituted with CD4+ CD45RBhigh T cells alone but had no direct effect on Treg cells. In the absence of Treg cells, feeding SEB induced activation of mucosal T cells and accelerated the development of colitis. This suggests that Treg cells prevent SEB-induced mucosal inflammation through modulation of SEB-induced T-cell activation. PMID:19064639

Heriazon, Armando; Zhou, Pengfei; Borojevic, Rajka; Foerster, Katharina; Streutker, Catherine J.; Ng, Terry; Croitoru, Kenneth

2009-01-01

322

TGF-? Signalling Is Required for CD4+ T Cell Homeostasis But Dispensable for Regulatory T Cell Function  

PubMed Central

TGF-? is widely held to be critical for the maintenance and function of regulatory T (Treg) cells and thus peripheral tolerance. This is highlighted by constitutive ablation of TGF-? receptor (TR) during thymic development in mice, which leads to a lethal autoimmune syndrome. Here we describe that TGF-?–driven peripheral tolerance is not regulated by TGF-? signalling on mature CD4+ T cells. Inducible TR2 ablation specifically on CD4+ T cells did not result in a lethal autoinflammation. Transfer of these TR2-deficient CD4+ T cells to lymphopenic recipients resulted in colitis, but not overt autoimmunity. In contrast, thymic ablation of TR2 in combination with lymphopenia led to lethal multi-organ inflammation. Interestingly, deletion of TR2 on mature CD4+ T cells does not result in the collapse of the Treg cell population as observed in constitutive models. Instead, a pronounced enlargement of both regulatory and effector memory T cell pools was observed. This expansion is cell-intrinsic and seems to be caused by increased T cell receptor sensitivity independently of common gamma chain-dependent cytokine signals. The expression of Foxp3 and other regulatory T cells markers was not dependent on TGF-? signalling and the TR2–deficient Treg cells retained their suppressive function both in vitro and in vivo. In summary, absence of TGF-? signalling on mature CD4+ T cells is not responsible for breakdown of peripheral tolerance, but rather controls homeostasis of mature T cells in adult mice. PMID:24115907

Sledzinska, Anna; Hemmers, Saskia; Mair, Florian; Gorka, Oliver; Ruland, Jurgen; Fairbairn, Lynsey; Nissler, Anja; Muller, Werner; Waisman, Ari

2013-01-01

323

UVB radiation and human monocyte accessory function: Differential effects on pre-mitotic events in T-cell activation  

SciTech Connect

Purified T lymphocytes fail to proliferate in response to antigenic and mitogenic stimuli when cultured in the presence of accessory cells that have been exposed in vitro to sublethal doses of UVB radiation. Because proliferation represents a final stage in the T-cell activation process, the present study was conducted to determine whether T cells were able to progress through any of the pre-mitotic stages when UVB-irradiated monocytes were used as model accessory cells. In these experiments, monoclonal anti-CD3 antibodies were employed as the mitogenic stimulus. Culture of T cells with UVB-irradiated monocytes did allow the T cells to undergo an increase in intracellular free calcium, which is one of the first steps in the activation sequence. The T cells expressed interleukin-2 receptors, although at a reduced level. However, T cells failed to produce interleukin-2 above background levels when they were placed in culture with monocytes exposed to UVB doses as low as 50 J/m2. Incubation of T cells with UVB-irradiated monocytes did not affect the subsequent capacity of T cells to proliferate, since they developed a normal proliferative response in secondary culture when restimulated with anti-CD3 antibodies and unirradiated monocytes. These studies indicate that T lymphocytes become partially activated when cultured with UVB-irradiated monocytes and mitogenic anti-CD3 monoclonal antibodies. In addition, they suggest that interleukin-2 production is the T-cell activation step most sensitive to inhibition when UVB-irradiated monocytes are employed as accessory cells.

Krutmann, J.K.; Kammer, G.M.; Toossi, Z.; Waller, R.L.; Ellner, J.J.; Elmets, C.A. (Case Western Reserve Univ., Cleveland, OH (USA))

1990-02-01

324

Human Hepatic Stellate Cells Inhibit T cell Response through B7-H1 Pathway  

PubMed Central

Background The liver is an immunological privileged organ – liver allografts are accepted across major histocompatibility complex barriers in many species; however, hepatocyte transplants are acutely rejected, suggesting a role for liver non-parenchymal cells in regulating the immune response. We have shown potent immune regulatory activity of hepatic stellate cells (HSCs) in mice. The aim of this study was to examine the immune regulatory activity of human HSCs. Methods HSCs were isolated from normal human livers for analyses of their impact on T cell response. Results HSCs expressed low HLA-DR and co-stimulatory molecules CD40, CD80, but constitutively expressed high levels of CD54. IFN? stimulated HSCs to express B7-H1 in a dose dependent manner, and produce the suppressive cytokines IL-6, IL-10 and TGF?, but not affect expression of HLA-DR, CD40 and CD80. Human HSCs did not stimulate allogeneic T cell proliferative response, indicating they are not professional APC. HSCs markedly inhibited T cell response elicited by either allogeneic APC or CD3/CD28 beads, which was associated with increases in activated CD4 and CD8 T cell apoptosis. Addition of anti-B7-H1 blocking Ab significantly reversed the inhibitory effect. Conclusions Human HSCs demonstrate potent immune regulatory activity via B7-H1-mediated induction of apoptosis in activated T cells. Understanding of the involved mechanisms may lead to development of novel therapeutic approaches for treatment of liver diseases. PMID:23756770

Charles, Ronald; Chou, Hong-Shiue; Wang, Lianfu; Fung, John J.; Lu, Lina; Qian, Shiguang

2013-01-01

325

[Panniculitic T-cell lymphoma].  

PubMed

Panniculitic T-cell lymphoma is a rare, aggressive variant of cutaneous T-cell lymphoma, with fewer than 100 cases described. The main problem is its diagnosis, as both the clinical and the histological features may simulate benign panniculitis. We present the case of a 34-year-old male patient, who had presented with an indurated plaque, sclerodermiform in appearance, on the front of the right thigh for 4 months, later accompanied by fever and constitutional symptoms. The initial diagnosis was cellulitis, but no clinical improvement was seen despite systemic antibiotic therapy. After two skin biopsies, the patient was diagnosed with panniculitic cutaneous T-cell lymphoma. The patient was treated with 8 cycles of CHOP chemotherapy, with resolution of the symptoms. PMID:16476344

Rodríguez-Vázquez, María; García-Arpa, Mónica; Martín, Francisco; Calle, Carmen; Marchán, Enrique; Romero, Guillermo; Cortina, Pilar

2005-03-01

326

Evidence for extrathymic T cell maturation after thymectomy in infancy  

PubMed Central

Our previous study showed that children who had been partially or completely thymectomized during heart surgery as infants had lower proportions and numbers of total lymphocytes and reduced proportions of T cells (CD3+), helper T cells (CD4+) and naive T cells (CD3+ CD4+ CD45RA+), but normal proportion of cytotoxic T cells (CD8+). In this study T lymphocytes from a selected group of eight of these children and age- and gender-matched controls were characterized further using flow cytometry to determine phenotypes of T cells and T cell subsets related to T cell regulation and phenotypes suggestive of extrathymic maturation. Immune function was assessed by measuring autoantibodies and antibodies against vaccines. The study group had significantly lower numbers of all the main subsets of T lymphocytes and the composition was different. Thus, the proportions of lymphocytes with the following phenotypes: CD3+, CD2+, CD7+, CD4+, CD62L+, CD4+ CD62L+ and CD4+ CD69? were significantly reduced in the study group compared with the control group, but significantly higher proportions were seen of lymphocytes expressing CD8?+ CD8?? and TCR??+ CD8?+ CD8??. The absolute number and proportion of CD4+ CD25+ cells were reduced but the proportions of the subgroup of naive regulatory T cells (CD4+ CD25+ CD62L+) and non-activated regulatory T cells (CD4+ CD25+ CD69?) were not reduced in the thymectomized children. We conclude that the phenotypic characteristics of T lymphocytes of children who have lost their thymus in infancy are indicative of extrathymic maturation. T regulatory cells appear to be less affected than other subsets by the general reduction in T cell numbers. PMID:16907907

Torfadottir, H; Freysdottir, J; Skaftadottir, I; Haraldsson, A; Sigfusson, G; Ogmundsdottir, H M

2006-01-01

327

Intrathyroidal accumulation of T cell phenotypes in autoimmune thyroid disease.  

PubMed

In this study we have correlated peripheral T cell subset phenotypes with intrathyroidal lymphocyte accumulation in patients with autoimmune thyroid disease (Graves' and Hashimoto's disease). Our study utilized euthyroid family members for one of our control groups (n = 48) thus significantly limiting familial, but not disease-specific, influences on these T cell phenotypes. Our principal new observations were found only in patients with Graves' disease. As previously reported, there was a decrease in CD8+ (suppressor/cytotoxic) T cells in the peripheral blood of patients with untreated hyperthyroid Graves' disease (n = 27) (mean +/- SEM, 19 +/- 1.1% in patients compared with 25 +/- 1.2% in controls, p = 0.03), a finding not observed in treated, euthyroid Graves' disease patients or their relatives. However, the relative number of CD8+ T cells, assessed by CD4:CD8 ratios, was increased in the intrathyroidal T cell populations (n = 10), when compared to normal and patient peripheral blood. There were no consistent changes in total CD4+ (helper) T cells in the peripheral blood of patients with treated and untreated Graves' disease but a reduction in CD4+2H4+ (suppressor-inducer) T cells was seen in patients undergoing surgery for Graves' disease (13 +/- 6.9% compared with 39 +/- 3.4%). Again, however, this T cell subset was increased within the target organ of the same patients (41 +/- 5.9%). These data point to either a selective accumulation, or a specific "homing", of certain T cell subsets within the thyroid gland of patients with Graves' disease where T cell differentiation may be strongly influenced by antithyroid drug treatment and the local immune environment. PMID:1716476

Martin, A; Goldsmith, N K; Friedman, E W; Schwartz, A E; Davies, T F; Roman, S H

1990-01-01

328

Invasivenessof T-Cell Hybridomasin Vitroand Their Metastatic Potentialin Vivo  

Microsoft Academic Search

BW5147 lymphoma cells, which are noninvasive and nonme- tastatic, were fused with normal T-lymphocytes. The invasive- ness of the generated T-cell hybridomas was tested in hepato- cyte cultures, and their metastatic potential was tested by tail vein injection. A total of 29 hybridomas generated from alloanti- gen-activated T-cells were all found to be invasive. One of these cell lines rapidly

Ed Roos; Geertje La; John G. Collard; Marijke J. Stukart; Patrick De Baetselier

1985-01-01

329

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

330

Induction of Rapid T Cell Death and Phagocytic Activity by Fas-Deficient lpr Macrophages  

PubMed Central

Peripheral T cells are maintained by the apoptosis of activated T cells through the Fas–Fas ligand system. Although it is well known that normal T cells fail to survive in the Fas-deficient immune condition, the molecular mechanism for the phenomenon has yet to be elucidated. In this study, we demonstrate that rapid cell death and clearance of normal T cells were induced by Fas-deficient lpr macrophages. Transfer of normal T cells into lpr mice revealed that Fas expression on donor T cells was promptly enhanced through the IFN-?/IFN-?R. In addition, Fas ligand expression and phagocytic activity of lpr macrophages were promoted through increased NF-?B activation. Controlling Fas expression on macrophages plays an essential role in maintaining T cell homeostasis in the peripheral immune system. Our data suggest a critical implication to the therapeutic strategies such as transplantation and immunotherapy for immune disorder or autoimmunity related to abnormal Fas expression. PMID:23255359

Oura, Ritsuko; Arakaki, Rieko; Yamada, Akiko; Kudo, Yasusei; Tanaka, Eiji; Hayashi, Yoshio

2013-01-01

331

T-Cell-Mediated Autoimmunity  

PubMed Central

Histological samples of autopsy or biopsy tissue provide the best available evidence that autoreactive T cells are involved in the immunopathogenesis of many autoimmune diseases. However, morphology alone does not provide information on the antigen-specific T-cell receptor (TCR) of these cells, let alone on their antigen specificity. In this review article we discuss a number of emerging possibilities for identifying TCR sequences directly from biopsy tissue. We also review the methods for expressing presumably autoreactive TCR molecules and speculate on how the expressed TCR might be used to identify target antigens. Such information should eventually provide new insights into disease pathogenesis which lead to better therapies. PMID:14507631

Dornmair, Klaus; Goebels, Norbert; Weltzien, Hans-Ulrich; Wekerle, Hartmut; Hohlfeld, Reinhard

2003-01-01

332

Differential Responses of Human Regulatory T Cells (Treg) and Effector T Cells to Rapamycin  

PubMed Central

Background The immunosuppressive drug rapamycin (RAPA) promotes the expansion of CD4+ CD25highFoxp3+ regulatory T cells via mechanisms that remain unknown. Here, we studied expansion, IL-2R-? chain signaling, survival pathways and resistance to apoptosis in human Treg responding to RAPA. Methodology/Principal Findings CD4+CD25+ and CD4+CD25neg T cells were isolated from PBMC of normal controls (n?=?21) using AutoMACS. These T cell subsets were cultured in the presence of anti-CD3/CD28 antibodies and 1000 IU/mL IL-2 for 3 to 6 weeks. RAPA (1–100 nM) was added to half of the cultures. After harvest, the cell phenotype, signaling via the PI3K/mTOR and STAT pathways, expression of survival proteins and Annexin V binding were determined and compared to values obtained with freshly-separated CD4+CD25high and CD4+CD25neg T cells. Suppressor function was tested in co-cultures with autologous CFSE-labeled CD4+CD25neg or CD8+CD25neg T-cell responders. The frequency and suppressor activity of Treg were increased after culture of CD4+CD25+ T cells in the presence of 1–100 nM RAPA (p<0.001). RAPA-expanded Treg were largely CD4+CD25highFoxp3+ cells and were resistant to apoptosis, while CD4+CD25neg T cells were sensitive. Only Treg upregulated anti-apoptotic and down-regulated pro-apoptotic proteins. Treg expressed higher levels of the PTEN protein than CD4+CD25neg cells. Activated Treg±RAPA preferentially phosphorylated STAT5 and STAT3 and did not utilize the PI3K/mTOR pathway. Conclusions/Significance RAPA favors Treg expansion and survival by differentially regulating signaling, proliferation and sensitivity to apoptosis of human effector T cells and Treg after TCR/IL-2 activation. PMID:19543393

Strauss, Laura; Czystowska, Malgorzata; Szajnik, Marta; Mandapathil, Magis; Whiteside, Theresa L.

2009-01-01

333

Substrate rigidity regulates human T cell activation and proliferation.  

PubMed

Adoptive immunotherapy using cultured T cells holds promise for the treatment of cancer and infectious disease. Ligands immobilized on surfaces fabricated from hard materials such as polystyrene plastic are commonly employed for T cell culture. The mechanical properties of a culture surface can influence the adhesion, proliferation, and differentiation of stem cells and fibroblasts. We therefore explored the impact of culture substrate stiffness on the ex vivo activation and expansion of human T cells. We describe a simple system for the stimulation of the TCR/CD3 complex and the CD28 receptor using substrates with variable rigidity manufactured from poly(dimethylsiloxane), a biocompatible silicone elastomer. We show that softer (Young's Modulus [E] < 100 kPa) substrates stimulate an average 4-fold greater IL-2 production and ex vivo proliferation of human CD4(+) and CD8(+) T cells compared with stiffer substrates (E > 2 MPa). Mixed peripheral blood T cells cultured on the stiffer substrates also demonstrate a trend (nonsignificant) toward a greater proportion of CD62L(neg), effector-differentiated CD4(+) and CD8(+) T cells. Naive CD4(+) T cells expanded on softer substrates yield an average 3-fold greater proportion of IFN-?-producing Th1-like cells. These results reveal that the rigidity of the substrate used to immobilize T cell stimulatory ligands is an important and previously unrecognized parameter influencing T cell activation, proliferation, and Th differentiation. Substrate rigidity should therefore be a consideration in the development of T cell culture systems as well as when interpreting results of T cell activation based upon solid-phase immobilization of TCR/CD3 and CD28 ligands. PMID:22732590

O'Connor, Roddy S; Hao, Xueli; Shen, Keyue; Bashour, Keenan; Akimova, Tatiana; Hancock, Wayne W; Kam, Lance C; Milone, Michael C

2012-08-01

334

Dynamic regulation of functionally distinct virus-specific T cells  

PubMed Central

The functional capacities of CD8+ T cells important for virus clearance are influenced by interactions with antigen presenting cells (APCs) and CD4+ T cells during initial selection, subsequent expansion, and development of memory. Recently, investigators have shown that polyfunctional T cells correlate best with long-term protection, however, it is still unknown how to stimulate T cells to achieve these responses. To study this, we examined the phenotypes and functions of CD8+ T cells specific for two different virus antigens stimulated ex vivo using either autologous monocyte-derived dendritic cells (moDCs) or HLA-A2-Ig-based artificial APCs (aAPCs). Although similar numbers of influenza virus and measles virus tetramer-positive cells were generated by stimulation with peptide-loaded moDCs and aAPCs, T cell function, assessed by expression of IL-2, IFN-?, TNF-?, MIP1?, and CD107a, showed that aAPC-generated CD8+ T cells were multifunctional, whereas moDC-generated cells were mostly monofunctional. aAPC-generated cells also produced more of each cytokine per cell than CD8+ T cells generated with moDCs. These phenotypes were not fixed, as changing the culture conditions of expanding T cells from aAPCs to moDCs, and moDCs to aAPCs, reversed the phenotypes. We conclude that CD8+ T cells are heterogeneous in their functionality and that this is dependent, in a dynamic way, on the stimulating APC. These studies will lead to understanding the factors that influence induction of optimal CD8+ T cell function. PMID:20133680

Ndhlovu, Zaza M.; Oelke, Mathias; Schneck, Jonathan P.; Griffin, Diane E.

2010-01-01

335

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

Microsoft Academic Search

BackgroundCellular 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

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

2010-01-01

336

Congenital rubella. Monoclonal antibody-defined T cell abnormalities in young adults.  

PubMed

In order to determine if congenital rubella infection is associated with persistent T cell abnormalities, T cell subsets were quantitated in 16 non-institutionalized subjects (ages nine to 21) with the clinical stigmata and history of congenital rubella. Flow cytometric analysis revealed a decreased T4/T8 ratio (mean +/- SEM in subjects with rubella, 1.57 +/- 0.15, p less than 0.01; in normal subjects, 2.3 +/- 0.4; in subjects with type I diabetes, 2.3 +/- 0.3), decreased percent of T4-positive "helper" cells (42.6 +/- 2.3) different from that in both normal subjects (52.6 +/- 2.4, p less than 0.01) and subjects with recent-onset diabetes (51.5 +/- 2.4), and increased percent of T8-positive "suppressor/cytotoxic" T cells (29.9 +/- 1.4, p less than 0.02) relative to that in normal subjects (24.2 +/- 1.5) and subjects with type I diabetes (23.9 +/- 1.4). Five of 16 subjects with congenital rubella had an elevation of la-positive T cells. Approximately 20 percent had antimicrosomal antibodies. One subject had diabetes mellitus and hypothyroidism, one had hypoglobulinemia, and one had previously undiagnosed hyperthyroidism. Glycosylated hemoglobin levels were normal in all except the diabetic subject, and none of the subjects was islet cell antibody-positive. The T cell abnormalities documented may predispose persons with congenital rubella to the development of organ-specific autoimmunity. PMID:3490785

Rabinowe, S L; George, K L; Loughlin, R; Soeldner, J S; Eisenbarth, G S

1986-11-01

337

B220 Double-Negative T Cells Suppress Polyclonal T Cell Activation by a Fas-Independent Mechanism That Involves Inhibition of IL2 Production  

Microsoft Academic Search

Fas-mediated apoptosis is a key mechanism for elimination of autoreactive T cells, yet loss of function mutations in the Fas signaling pathway does not result in overt T cell-mediated autoimmunity. Furthermore, mice and humans with homozygous Faslpr or Fas ligandgld mutations develop significant numbers of B220 CD4 CD8 double-negative (DN) T cells (hereafter referred to as B220 DN T cells)

Abdel Rahim; A. Hamad; Abdiaziz S. Mohamood; Crystal J. Trujillo; Ching-Tai Huang; Emily Yuan; Jonathan P. Schneck

338

Low CD4\\/CD8 T-Cell Ratio Associated with Inflammatory Arthropathy in Human T-Cell Leukemia Virus Type I Tax Transgenic Mice  

Microsoft Academic Search

BackgroundHuman T-cell leukemia virus type I (HTLV-1) can cause an aggressive malignancy known as adult T-cell leukemia\\/lymphoma (ATL) as well as inflammatory diseases such as HTLV-1-associated myelopathy\\/tropical spastic paraparesis (HAM\\/TSP). A transgenic mouse that expresses HTLV-1 Tax also develops T-cell leukemia\\/lymphoma and an inflammatory arthropathy that resembles rheumatoid arthritis. The aim of this study was to identify the primary T-cell

Takeo Ohsugi; Toshio Kumasaka

2011-01-01

339

Regulatory T cells and type 1 diabetes  

Microsoft Academic Search

Regulatory T cells are now recognized as important mediators of self-tolerance and may mediate responses to immune therapy.\\u000a The mechanisms of action of these cells are diverse, and some studies suggest that there may be defects in regulatory cells\\u000a in patients with type 1 diabetes. These cells may be expanded by immune therapy, suggesting the possible development of adoptive\\u000a immune

Brygida C. Bisikirska; Kevan C. Herold

2005-01-01

340

Fish T cells: recent advances through genomics  

USGS Publications Warehouse

This brief review is intended to provide a concise overview of the current literature concerning T cells, advances in identifying distinct T cell functional subsets, and in distinguishing effector cells from memory cells. We compare and contrast a wealth of recent progress made in T cell immunology of teleost, elasmobranch, and agnathan fish, to knowledge derived from mammalian T cell studies. From genome studies, fish clearly have most components associated with T cell function and we can speculate on the presence of putative T cell subsets, and the ability to detect their differentiation to form memory cells. Some recombinant proteins for T cell associated cytokines and antibodies for T cell surface receptors have been generated that will facilitate studying the functional roles of teleost T cells during immune responses. Although there is still a long way to go, major advances have occurred in recent years for investigating T cell responses, thus phenotypic and functional characterization is on the near horizon.

Laing, Kerry J.; Hansen, John D.

2011-01-01

341

Roles of ?? T Cells in the Pathogenesis of Autoimmune Diseases  

PubMed Central

? ? T cells are a minor population of T cells that express the TCR ?? chains, mainly distributed in the mucosal and epithelial tissue and accounting for less than 5% of the total T cells in the peripheral blood. By bridging innate and adaptive immunity, ?? T cells play important roles in the anti-infection, antitumor, and autoimmune responses. Previous research on ?? T cells was primarily concentrated on infectious diseases and tumors, whereas their functions in autoimmune diseases attracted much attention. In this paper, we summarized the various functions of ?? T cells in two prototypical autoimmune connective tissue diseases, that is, SLE and RA, elaborating on their antigen-presenting capacity, secretion of proinflammatory cytokines, immunomodulatory effects, and auxiliary function for B cells, which contribute to overproduction of proinflammatory cytokines and pathogenic autoantibodies, ultimately leading to the onset of these autoimmune diseases. Elucidation of the roles of ?? T cells in autoimmune diseases is not only conducive to in-depth understanding of the pathogenesis of these diseases, but also beneficial in providing theoretical support for the development of ?? T-cell-targeted therapy. PMID:23533458

Su, Dinglei; Shen, Minning; Li, Xia; Sun, Lingyun

2013-01-01

342

T regulatory cells maintain intestinal homeostasis by suppressing ?? T cells  

PubMed Central

Immune tolerance against enteric commensal bacteria is important for preventing intestinal inflammation. Deletion of phosphoinositide dependent protein kinase 1 (Pdk1) in T cells using Cd4-Cre induced chronic inflammation of the intestine despite the importance of PDK1 in T cell activation. Analysis of colonic intraepithelial lymphocytes of PDK1-deficient mice revealed markedly increased CD8?+ T cell receptor (TCR)??+ T cells, including an interleukin-17 (IL-17)-expressing population. TCR??+ T cells were responsible for the inflammatory colitis as deletion of Tcrd abolished spontaneous colitis in the PDK1 deficient mice. This dysregulation of intestinal TCR??+ T cells was attributable to a reduction in the number and functional capacity of PDK1-deficient T-regulatory (Treg) cells. Adoptive transfer of wild-type Treg cells abrogated the spontaneous activation and proliferation of intestinal TCR??+ T cells observed in PDK1-deficient mice and prevented the development of colitis. Therefore suppression of intestinal TCR??+ T cells by Treg cells maintains enteric immune tolerance. PMID:21074460

Park, Sung-Gyoo; Mathur, Ramkumar; Long, Meixiao; Hosh, Namiko; Hao, Liming; Hayden, Matthew S.; Ghosh, Sankar

2010-01-01

343

Molecular Insights for Optimizing T Cell Receptor Specificity Against Cancer  

PubMed Central

Cytotoxic CD8 T cells mediate immunity to pathogens and they are able to eliminate malignant cells. Immunity to viruses and bacteria primarily involves CD8 T cells bearing high affinity T cell receptors (TCRs), which are specific to pathogen-derived (non-self) antigens. Given the thorough elimination of high affinity self/tumor-antigen reactive T cells by central and peripheral tolerance mechanisms, anti-cancer immunity mostly depends on TCRs with intermediate-to-low affinity for self-antigens. Because of this, a promising novel therapeutic approach to increase the efficacy of tumor-reactive T cells is to engineer their TCRs, with the aim to enhance their binding kinetics to pMHC complexes, or to directly manipulate the TCR-signaling cascades. Such manipulations require a detailed knowledge on how pMHC-TCR and co-receptors binding kinetics impact the T cell response. In this review, we present the current knowledge in this field. We discuss future challenges in identifying and targeting the molecular mechanisms to enhance the function of natural or TCR-affinity optimized T cells, and we provide perspectives for the development of protective anti-tumor T cell responses. PMID:23801991

Hebeisen, Michael; Oberle, Susanne G.; Presotto, Danilo; Speiser, Daniel E.; Zehn, Dietmar; Rufer, Nathalie

2013-01-01

344

The mediator subunit Med23 contributes to controlling T-cell activation and prevents autoimmunity.  

PubMed

T-cell activation is critical for successful immune responses and is controlled at multiple levels. Although many changes of T-cell receptor-associated signalling molecules affect T-cell activation, the transcriptional mechanisms that control this process remain largely unknown. Here we find that T cell-specific deletion of the mediator subunit Med23 leads to hyperactivation of T cells and aged Med23-deficient mice exhibit an autoimmune syndrome. Med23 specifically and consistently promotes the transcription of multiple negative regulators of T-cell activation. In the absence of Med23, the T-cell activation threshold is lower, which results in enhanced antitumour T-cell function. Cumulatively, our data suggest that Med23 contributes to controlling T-cell activation at the transcriptional level and prevents the development of autoimmunity. PMID:25301163

Sun, Yang; Zhu, Xiaoyan; Chen, Xufeng; Liu, Haifeng; Xu, Yu; Chu, Yajing; Wang, Gang; Liu, Xiaolong

2014-01-01

345

Antibodies targeting human OX40 expand effector T cells and block inducible and natural regulatory T cell function  

PubMed Central

Current cancer vaccines induce tumor-specific T cell responses without sustained tumor regression because immunosuppressive elements within the tumor induce exhaustion of effector T cells and infiltration of immune-suppressive regulatory T cells (Tregs). Therefore, much effort has been made to generate agonistic Abs targeting members of the TNFR superfamily, such as OX40, 4- 1BB, and GITR, expressed on effector T cells and Tregs, to reinvigorate T cell effector function and block Treg-suppressive function. In this article, we describe the development of a panel of anti-human OX40 agonistic mouse mAbs that could promote effector CD4+ and CD8+ T cell proliferation, inhibit the induction of CD4+ IL-10 -producing type 1 regulatory T cells, inhibit the expansion of ICOS+IL-10+ Tregs, inhibit TGF-b–induced FOXP3 expression on naive CD4+ T cells, and block natural Treg–suppressive function. We humanized two anti–human OX40 mAb clones, and they retained the potency of their parental clones. These Abs should provide broad opportunities for potential combination therapy to treat a wide realm of cancers and preventative vaccines against infectious diseases. PMID:24014877

Voo, Kui S.; Bover, Laura; Harline, Megan L.; Vien, Long T.; Facchinetti, Valeria; Arima, Kazuhiko; Kwak, Larry W.; Liu, Yong J.

2013-01-01

346

Islet-specific T-cell clones from nonobese diabetic mice express heterogeneous T-cell receptors.  

PubMed Central

Nonobese diabetic (NOD) mice spontaneously develop a T-cell-mediated autoimmune disease that is similar in many respects to insulin-dependent diabetes mellitus in humans. T-cell clones that specifically recognize pancreatic islet cell antigens can be derived from NOD mice, and most of these have been diabetogenic upon transfer to healthy recipients. We report herein the sequences of the T-cell receptor alpha and beta chains from four NOD-derived, islet-specific clones. The sequences are quite heterogeneous--in the junctional regions, specifically--so there seems to be little hope for treating this disease with specific anti-T-cell receptor reagents. This result contrasts with the strikingly restricted junctional region sequences reported for the receptors on clones derived from mice with experimental allergic encephalomyelitis, another T-cell-mediated autoimmune disease. We discuss possible explanations for this difference. PMID:2068098

Candeias, S; Katz, J; Benoist, C; Mathis, D; Haskins, K

1991-01-01

347

Control of Experimental Autoimmune Encephalomyelitis by T Cells Responding to Activated T Cells  

NASA Astrophysics Data System (ADS)

T cell vaccination against experimental autoimmune disease is herein shown to be mediated in part by anti-ergotypic T cells, T cells that recognize and respond to the state of activation of other T cells. The anti-ergotypic response thus combines with the previously shown anti-idiotypic T cell response to regulate autoimmunity.

Lohse, Ansgar W.; Mor, Felix; Karin, Nathan; Cohen, Irun R.

1989-05-01

348

Loss of T cell precursors after spaceflight and exposure to vector-averaged gravity  

NASA Technical Reports Server (NTRS)

Using fetal thymus organ culture (FTOC), we examined the effects of spaceflight and vector-averaged gravity on T cell development. Under both conditions, the development of T cells was significantly attenuated. Exposure to spaceflight for 16 days resulted in a loss of precursors for CD4+, CD8+, and CD4+CD8+ T cells in a rat/mouse xenogeneic co-culture. A significant decrease in the same precursor cells, as well as a decrease in CD4-CD8- T cell precursors, was also observed in a murine C57BL/6 FTOC after rotation in a clinostat to produce a vector-averaged microgravity-like environment. The block in T cell development appeared to occur between the pre-T cell and CD4+CD8+ T cell stage. These data indicate that gravity plays a decisive role in the development of T cells.

Woods, Chris C.; Banks, Krista E.; Gruener, Raphael; DeLuca, Dominick

2003-01-01

349

Thymic Deletion and Regulatory T Cells Prevent Antimyeloperoxidase GN  

PubMed Central

Loss of tolerance to neutrophil myeloperoxidase (MPO) underlies the development of ANCA-associated vasculitis and GN, but the mechanisms underlying this loss of tolerance are poorly understood. Here, we assessed the role of the thymus in deletion of autoreactive anti-MPO T cells and the importance of peripheral regulatory T cells in maintaining tolerance to MPO and protecting from GN. Thymic expression of MPO mRNA predominantly localized to medullary thymic epithelial cells. To assess the role of MPO in forming the T cell repertoire and the role of the autoimmune regulator Aire in thymic MPO expression, we compared the effects of immunizing Mpo?/? mice, Aire?/? mice, and control littermates with MPO. Immunized Mpo?/? and Aire?/? mice developed significantly more proinflammatory cytokine-producing anti-MPO T cells and higher ANCA titers than control mice. When we triggered GN with a subnephritogenic dose of anti-glomerular basement membrane antibody, Aire?/? mice had more severe renal disease than Aire+/+ mice, consistent with a role for Aire-dependent central deletion in establishing tolerance to MPO. Furthermore, depleting peripheral regulatory T cells in wild-type mice also led to more anti-MPO T cells, higher ANCA titers, and more severe GN after immunization with MPO. Taken together, these results suggest that Aire-dependent central deletion and regulatory T cell–mediated peripheral tolerance both play major roles in establishing and maintaining tolerance to MPO, thereby protecting against the development of anti-MPO GN. PMID:23393320

Tan, Diana S.Y.; Gan, Poh Y.; O'Sullivan, Kim M.; Hammett, Maree V.; Summers, Shaun A.; Ooi, Joshua D.; Lundgren, Brita A.; Boyd, Richard L.; Scott, Hamish S.; Kitching, A. Richard; Chidgey, Ann P.

2013-01-01

350

Stable Expression of the tax Gene of Type I Human T-Cell Leukemia Virus in Human T Cells Activates Specific Cellular Genes Involved in Growth  

Microsoft Academic Search

Stable expression of the 40-kDa transactivator protein (Tax) from the type I human T-cell leukemia virus (HTLV-I) in Jurkat T cells leads to the activation and sustained expression of certain cellular genes that are transiently induced during normal T-cell growth. Cellular genes induced by Tax include those encoding the alpha subunit of the high-affinity interleukin 2 receptor (Tac), interleukin 2,

Yuji Wano; Mark Feinberg; Jane B. Hosking; Hal Bogerd; Warner C. Greene

1988-01-01

351

Human Herpesvirus Replication and Abnormal CD8+ T Cell Activation and Low CD4+ T Cell Counts in Antiretroviral-Suppressed HIV-Infected Patients  

Microsoft Academic Search

BackgroundMost HIV-infected patients receiving virologically suppressive antiretroviral therapy continue to have abnormal, generalized T cell activation. We explored whether the degree of ongoing cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV) replication was associated with higher virus-specific T cell activation and the failure to achieve normal absolute CD4+ T cell counts in the face of long-term suppressive antiretroviral

Mark A. Jacobson; Dirk P. Ditmer; Elizabeth Sinclair; Jeffrey N. Martin; Steven G. Deeks; Peter Hunt; Edward S. Mocarski; Caroline Shiboski; Derya Unutmaz

2009-01-01

352

The cancer stem cell: Evidence for its origin as an injured autoreactive T Cell  

Microsoft Academic Search

This review explores similarities between lymphocytes and cancer cells, and proposes a new model for the genesis of human cancer. We suggest that the development of cancer requires infection(s) during which antigenic determinants from pathogens mimicking self-antigens are co-presented to the immune system, leading to breaking T cell tolerance. Some level of autoimmunity is normal and necessary for effective pathogen

Peter Grandics

2006-01-01

353

Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells  

Microsoft Academic Search

VIRUSES that are non- or poorly cytopathic have developed various strategies to avoid elimination by the immune system and to persist in the host1-3. Acute infection of adult mice with the noncytopathic lymphocytic choriomeningitis virus (LCMV) normally induces a protective cytotoxic T-cell response that also causes immunopathology4-7. But some LCMV strains (such as DOCILE8 (LCMV-D) or Cl-13 Armstrong (Cl-13) 9)

Demetrius Moskophidis; Franziska Lechner; Hanspeter Pircher; Rolf M. Zinkernagel

1993-01-01

354

Regulatory T Cells Are Resistant to Apoptosis via TCR but Not P2X7 1  

Microsoft Academic Search

Regulatory T cells (Tregs) are relatively autoreactive yet, paradoxically, have been found to display normal sensitivity to thymic deletion. The relationship between self-avidity, apoptosis, and the selection of Tregs therefore remains unclear. We show that thymic Tregs develop efficiently, even at low self-avidity, and are moderately resistant to apoptosis in comparison to conventional thymocytes. Consistent with this, although conventional self-reactive

Simon R. J. Taylor; Denis R. Alexander; Joanne C. Cooper; Christopher F. Higgins; James I. Elliott

355

Cytotoxic T cells in AIDS colonic cryptosporidiosis  

PubMed Central

Background/Aims—It is not known how enteric cryptosporidiosis induces severe intestinal impairment despite minimal invasion by the parasite. The aim of this study was to analyse the histological features and locally implicated immune cells in colonic biopsies of AIDS related cryptosporidiosis. Patients/Methods—Colonic biopsies from patients with AIDS related cryptosporidiosis (n = 10, group I), patients with AIDS but without intestinal infection (n = 9, group II), and human seronegative controls (n = 9, group III) were studied. Using immunohistochemistry the infiltrating mononuclear cells were analysed in both the epithelium and lamina propria for the expression of CD3, CD8, TiA1, granzyme B, and CD68 and for glandular expression of human major histocompatibility complex DR antigen (HLA-DR). Results—Severe histological changes, resulting in abundant crypt epithelial apoptosis and inflammatory infiltrate in the lamina propria, were seen in all biopsies from group I. A significant increase of CD8+, TiA1+, and granzyme B+ T cells in the lamina propria and HLA-DR glandular expression was noted in group I compared with groups II and III. However, the number of intraepithelial lymphocytes, lamina propria CD3+ T cells, and macrophages was not significantly increased in cryptosporidiosis specimens compared with controls. Conclusion—Epithelial apoptosis mediated by granzyme B+ cytotoxic host T cells might play a major role in the development of colonic lesions in AIDS related cryptosporidiosis. Key Words: cryptosporidiosis • acquired immunodeficiency syndrome • colon • apoptosis • cytotoxicity • immunochemistry PMID:11304847

Reijasse, D; de Serre, N P.-M.; Canioni, D; Huerre, M; Haddad, E; Leborgne, M; Blanche, S; Brousse, N

2001-01-01

356

T Cells in Allergic Disease  

Microsoft Academic Search

The type I (CD4 + Th1, CD8 + Tc1) and type II (CD4 + Th2, CD8 + Tc2) paradigm of cytokine-secreting T cell subsets has advanced\\u000a considerably in recent years. CD4 + Th2 cells have been closely associated with initiation and maintenance of allergic inflammation\\u000a and new signals, such as OX40, TSLP and IL-25 that promote this lineage in disease

Catherine M. Hawrylowicz; Christopher Corrigan; Alex Faith

357

Reduced response to Epstein-Barr virus antigens by T-cells in systemic lupus erythematosus patients  

PubMed Central

Objective Epstein–Barr virus (EBV) has for long been associated with systemic lupus erythematosus (SLE). In this study, we investigated the levels of latent and lytic antigen EBV-specific T-cells and antibodies in SLE patients. Methods T cells were analyzed by flow cytometry and antibodies were analyzed by enzyme-linked immunosorbent assay. Results SLE patients showed a significantly reduced number of activated (CD69) T-cells upon ex vivo stimulation with EBV nuclear antigen (EBNA) 1 or EBV early antigen diffuse (EBV-EA/D) in whole blood samples compared with healthy controls. Also, a reduced number of T-cells from SLE patients were found to produce interferon-? upon stimulation with these antigens. Importantly, responses to a superantigen were normal in SLE patients. Compared with healthy controls, SLE patients had fewer EBV-specific T-cells but higher titres of antibodies against EBV. Furthermore, an inverse correlation was revealed between the number of lytic antigen EBV-specific T-cells and disease activity of the SLE patients, with high-activity SLE patients having fewer T-cells than low-activity SLE patients. Conclusions These results indicate a limited or a defective EBV-specific T-cell response in SLE patients, which may suggest poor control of EBV infection in SLE with an immune reaction shift towards a humoral response in an attempt to control viral reactivation. A role for decreased control of EBV as a contributing agent in the development or exacerbation of SLE is proposed.

Draborg, Anette Holck; Jacobsen, S?ren; Westergaard, Marie; Mortensen, Shila; Larsen, Janni Lisander; Houen, Gunnar; Duus, Karen

2014-01-01

358

Multi-scale models of T cell activation  

E-print Network

The overarching theme of this thesis is to develop and apply multi-scale computational techniques adopted from physical sciences to study a key phenomenon underlying the adaptive immune response: the activation of T cells. ...

Zheng, Huan, Ph.D. Massachusetts Institute of Technology

2010-01-01

359

Rapid Isolation of Central Memory T Cells for Adoptive Immunotherapy  

Cancer.gov

The National Cancer Institute (NCI), Surgery Branch is seeking parties interested in collaborative research to further co-develop a methodology for the isolation of memory T cells for adoptive immunotherapy.

360

Antigen/major histocompatibility complex-specific activation of murine T cells transfected with functionally rearranged T-cell receptor genes.  

PubMed Central

The genes encoding the alpha and beta chains of the T-cell antigen receptor isolated from a cytochrome c-specific, major histocompatibility complex (MHC)-restricted murine T-cell hybridoma were introduced into a mouse T-cell line of helper lineage by electroporation. In order to examine the contributions of those gene products to antigen and/or MHC specificity, the resultant transfectants were tested for functional antigen and/or MHC recognition. Only those transfectants that express both the introduced genes (alpha and beta) contributed by the normal T cell can respond specifically to the appropriate antigen/MHC pair. None of the transfectants that express only one of the introduced genes (alpha or beta) of the normal T cell, or paired hybrid genes (i.e., one gene from the normal T cell and the other from the fusion partner), can respond to the same combination of antigen and MHC product recognized by the donor T cell. However, one clone expressing the transfected genes that encode the alpha and beta chains of the fusion partner shows reactivity to the antigen-presenting cells even in the absence of the antigens. These data suggest that the alpha beta heterodimer of the T-cell receptor is required to define the fine specificity of a T cell. Images PMID:2823268

Kuo, C L; Hood, L

1987-01-01

361

Overexpression of X-Linked Genes in T Cells From Women With Lupus  

PubMed Central

Women develop lupus more frequently than men and the reason remains incompletely understood. Evidence that men with Klinefelter’s Syndrome (XXY) develop lupus at approximately the same rate as women suggests that a second X chromosome contributes. However, since the second X is normally inactivated, how it predisposes to lupus is unclear. DNA methylation contributes to the silencing of one X chromosome in women, and CD4+ T cell DNA demethylation contributes to the development of lupus-like autoimmunity. This suggests that demethylation of genes on the inactive X may predispose women to lupus, and this hypothesis is supported by a report that CD40LG, an immune gene encoded on the X chromosome, demethylates and is overexpressed in T cells from women but not men with lupus. Overexpression of other immune genes on the inactive X may also predispose women to this disease. We therefore compared mRNA and miRNA expression profiles in experimentally demethylated T cells from women and men as well as in T cells from women and men with lupus. T cells from healthy men and women were treated with the DNA methyltransferase inhibitor 5-azacytidine, then X-linked mRNAs were surveyed with oligonucleotide arrays, and X-linked miRNA’s surveyed with PCR arrays. CD40LG, CXCR3, OGT, miR-98, let-7f-2*, miR 188-3p, miR-421 and miR-503 were among the genes overexpressed in women relative to men. MiRNA target prediction analyses identified CBL, which downregulates T cell receptor signaling and is decreased in lupus T cells, as a gene targeted by miR-188-3p and miR-98. Transfection with miR-98 and miR-188-3p suppressed CBL expression. The same mRNA and miRNA transcripts were also demethylated and overexpressed in CD4+ T cells from women relative to men with active lupus. Together these results further support a role for X chromosome demethylation in the female predisposition to lupus. PMID:23434382

Hewagama, Anura; Gorelik, Gabriela; Patel, Dipak; Liyanarachchi, Punsisi; McCune, W. Joseph; Somers, Emily; Gonzalez-Rivera, Tania; Strickland, Faith; Richardson, Bruce

2013-01-01

362

Synthetic Niches for Stem Cell Differentiation into T cells  

Microsoft Academic Search

\\u000a T cell development from hematopoietic stem cells takes place in the thymus under precisely controlled intercellular signaling\\u000a between the stem cells and thymic stromal and epithelial cells. In vitro or ex vivo development of mature T cells from stem\\u000a cells faces two primary hurdles; one being the inability of culture conditions to provide a three dimensional thymic niche\\u000a with lineage-specific

Ankur Singh; Krishnendu Roy

363

Sustained Signaling Leading to T Cell Activation Results from Prolonged T Cell Receptor Occupancy. Role of T Cell Actin Cytoskeleton  

Microsoft Academic Search

Summary Using antigen-specific T cell clones and peptide-pulsed antigen-presenting cells (APCs) we investigated the mechanisms that lead to sustained signaling, known to be required for activation of effector function. Four lines of evidence indicate that the T cell actin cytoskeleton plays a crucial role in T cell activation by antigen-pulsed APCs, but is not required when T cell receptor (TCR)

Salvatore Valitutti; Mark Dessing; Klaus Aktories; Harald Gallati; Antonio Lanzavecchia

364

A role for intrathymic B cells in the generation of natural regulatory T cells.  

PubMed

B cells inhabit the normal human thymus, suggesting a role in T cell selection. In this study, we report that B cells can modulate thymic production of CD4+ Foxp3+ T cells (regulatory T cells [Tregs]). Mice with transgenic expression of BAFF (BAFF-Tg) harbor increased numbers of Helios+ Foxp3+ thymic Tregs and, similar to some human autoimmune conditions, also exhibit increased numbers of B cells colonizing the thymus. Distinct intrathymic B cell subpopulations were identified, namely B220+, IgM+, CD23(hi), CD21(int) cells; B220+, IgM+, CD23(lo), CD21(lo) cells; and a population of B220+, IgM+, CD23(lo), CD21(hi) cells. Anatomically, CD19+ B cells accumulated in the thymic medulla region juxtaposed to Foxp3+ T cells. These intrathymic B cells engender Tregs. Indeed, thymic Treg development was diminished in both B cell-deficient BAFF-Tg chimeras, but also B cell-deficient wild-type chimeras. B cell Ag capture and presentation are critical in vivo events for Treg development. In the absence of B cell surface MHC class II expression, thymic expansion of BAFF-Tg Tregs was lost. Further to this, expansion of Tregs did not occur in BAFF-Tg/Ig hen egg lysozyme BCR chimeras, demonstrating a requirement for Ag specificity. Thus, we present a mechanism whereby intrathymic B cells, through the provision of cognate help, contribute to the shaping of the Treg repertoire. PMID:24872190

Walters, Stacey N; Webster, Kylie E; Daley, Stephen; Grey, Shane T

2014-07-01

365

Antigen-presenting effects of effector memory V?9V?2 T cells in rheumatoid arthritis  

PubMed Central

Rheumatoid arthritis is an autoimmune disease that primarily affects the limbs, but the pathogenic mechanism remains unclear. ?? T cells, a T-cell subpopulation, are characterized by multiple biological functions and associated with a variety of diseases. This study investigated the antigen-presenting effects of ?? T cells and their relationship with rheumatoid arthritis development. We found that V?9V?2 T cells (the predominant subtype of ?? T cells in peripheral blood) were activated by isopentenyl pyrophosphate to continuously proliferate and differentiate into effector memory cells. The effector memory V?9V?2 T cells exhibited phenotypic characteristics of specific antigen-presenting cells, including high HLA-DR and CD80/86 expression. These V?9V?2 T cells could present soluble antigens and synthetic peptides to CD4+ T cells. V?9V?2 T cells with different phenotypes showed different cytokine secretion patterns. Effector memory V?9V?2 T cells simultaneously secreted not only interferon (IFN)-? but also IL-17. The peripheral blood and joint synovial fluid from RA patients contained numerous heterogeneous ?? T cells that were predominantly effector memory V?9V?2 T cells with the ability to secrete inflammatory factors. We also found that ?? T cells had a similar antigen-presenting capability to B cells. These results suggest that during the development of rheumatoid arthritis, ?? T cells can aggravate immune dysfunction and produce abnormal immune damage by secreting cytokines and inducing inflammatory cells to participate in synergistic inflammatory responses. Furthermore, ?? T cells can behave similarly to B cells to present viral peptides and autoantigen peptides to CD4+ T cells, thus sustaining CD4+ T-cell activation. PMID:22139198

Hu, Chaoying; Qian, Liu; Miao, Yi; Huang, Qiuyu; Miao, Ping; Wang, Ping; Yu, Qiwen; Nie, Hong; Zhang, Jiying; He, Dongyi; Xu, Rong; Chen, Xuehua; Liu, Bingya; Zhang, Dongqing

2012-01-01

366

Comparison of T cell receptor alpha, beta, and gamma gene rearrangement and expression in T cell acute lymphoblastic leukemia.  

E-print Network

We have analyzed the configuration of the T cell receptor (TCR) alpha gene using newly developed genomic joining region (J alpha) probes, which cover approximately 80 kb of the J alpha region upstream from the constant ...

Hara, Junichi; Benedict, Stephen H.; Champagne, Eric; Mak, Tak W.; Minden, Mark; Gelfand, Erwin W.