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2.
J Immunol ; 193(12): 6152-60, 2014 Dec 15.
Article in English | MEDLINE | ID: mdl-25398328

ABSTRACT

Humoral immunity, including Ab switching and somatic hypermutation, is critically regulated by CD4(+) T cells. T follicular helper (Tfh) cells have been recently shown to be a distinct T cell subset important in germinal center reactions. The transcriptional regulation of Tfh cell development and function has not been well understood. In this study, we report that C/EBPα, a basic region/leucine zipper transcription factor, is highly expressed in Tfh cells. Cebpa-deficient CD4(+) T cells exhibit enhanced IFN-γ expression in vitro and in vivo. T cell-specific Cebpa knockout mice, although not defective in Tfh cell generation, produce significantly increased levels of IgG2a/b and IgG3 following immunization with a protein Ag. Moreover, C/EBPα binds to the Ifng gene and inhibits T-bet-driven Ifng transcription in a DNA binding-dependent manner. Our study thus demonstrates that C/EBPα restricts IFN-γ expression in T cells to allow proper class switching by B cells.


Subject(s)
CCAAT-Enhancer-Binding Protein-alpha/metabolism , Gene Expression Regulation , Interferon-gamma/genetics , T-Lymphocyte Subsets/metabolism , Animals , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , CCAAT-Enhancer-Binding Protein-alpha/deficiency , CCAAT-Enhancer-Binding Protein-alpha/genetics , Cell Differentiation/genetics , Cell Differentiation/immunology , Gene Expression Profiling , Immunity, Humoral , Immunoglobulin Class Switching , Immunoglobulin G/immunology , Interferon-gamma/metabolism , Mice , Mice, Knockout , T-Box Domain Proteins/metabolism , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolism , Transcription, Genetic
3.
Nature ; 507(7493): 513-8, 2014 Mar 27.
Article in English | MEDLINE | ID: mdl-24463518

ABSTRACT

In immune responses, activated T cells migrate to B-cell follicles and develop into follicular T-helper (TFH) cells, a recently identified subset of CD4(+) T cells specialized in providing help to B lymphocytes in the induction of germinal centres. Although Bcl6 has been shown to be essential in TFH-cell function, it may not regulate the initial migration of T cells or the induction of the TFH program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation. Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor--is selectively upregulated in TFH cells. Ectopic expression of Ascl2 upregulates CXCR5 but not Bcl6, and downregulates C-C chemokine receptor 7 (CCR7) expression in T cells in vitro, as well as accelerating T-cell migration to the follicles and TFH-cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates TFH-related genes whereas it inhibits expression of T-helper cell 1 (TH1) and TH17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in CD4(+) T cells, results in impaired TFH-cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances TFH-cell generation. Thus, Ascl2 directly initiates TFH-cell development.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Differentiation , Germinal Center/cytology , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Basic Helix-Loop-Helix Transcription Factors/deficiency , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Differentiation/genetics , Cell Movement , DNA-Binding Proteins/metabolism , Down-Regulation , Germinal Center/immunology , Humans , Inhibitor of Differentiation Proteins/genetics , Inhibitor of Differentiation Proteins/metabolism , Mice , Mutation/genetics , Proto-Oncogene Proteins c-bcl-6 , Receptors, CCR7/metabolism , Receptors, CXCR5/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Th17 Cells/cytology , Th17 Cells/immunology , Th17 Cells/metabolism , Transcription, Genetic/genetics , Up-Regulation
4.
Sci Signal ; 6(306): ra110, 2013 Dec 17.
Article in English | MEDLINE | ID: mdl-24345681

ABSTRACT

The proto-oncogene c-Maf is a transcription factor that plays a critical role in the differentiation of various T helper (T(H)) cell subsets. The amount of c-Maf increases after stimulation of the T cell receptor (TCR), which results in the production of multiple cytokines. We showed that two essential regulators of the transcription factor nuclear factor κB (NF-κB), the scaffold protein CARMA1 and the kinase IKKß [inhibitor of NF-κB (IκB) kinase ß], are also critical for the activation of c-Maf. Although CARMA1 deficiency did not affect the TCR-dependent increase in c-Maf abundance in T cells, CARMA1-dependent activation of the IKK complex was required for the nuclear translocation of c-Maf and its binding to the promoters of its target genes. Consistent with a role for c-Maf in the development of T follicular helper (T(FH)) cells, which provide help to B cells in the germinal centers of the spleen, CARMA1- or IKKß-deficient mice immunized with peptide antigen had defects in the generation of T(FH) cells, formation of germinal centers, and production of antigen-specific antibodies. Together, these data suggest a mechanism by which c-Maf is regulated during T cell activation and differentiation.


Subject(s)
CARD Signaling Adaptor Proteins/metabolism , Guanylate Cyclase/metabolism , I-kappa B Kinase/metabolism , Proto-Oncogene Proteins c-maf/metabolism , Signal Transduction , CD4-Positive T-Lymphocytes/enzymology , Humans , Interleukins/biosynthesis , Jurkat Cells , Ovalbumin/administration & dosage , Proto-Oncogene Mas
5.
Immunol Rev ; 252(1): 139-45, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23405901

ABSTRACT

T-follicular helper (Tfh) cells are a new subset of effector CD4(+) T cells that are specialized in helping B cells in the germinal center reaction. Tfh cells are distinct from other established CD4(+) T-cell lineages, Th1, Th2, Th17, and T-regulatory cells, in their gene expression profiles. Tfh cell differentiation results from a network of transcriptional regulation by a master transcriptional factor Bcl6 as well as IRF4, c-Maf, Batf, and STAT3/5. During Tfh cell ontogeny, increased CXCR5 expression directs activated T-cell migration to the follicles, and their interaction with B cells leads to Bcl6 upregulation, which helps establish effector and memory Tfh cell program. This review summarizes the recent progress in molecular mechanisms underlying Tfh differentiation and discusses the future perspectives for this important area of research.


Subject(s)
B-Lymphocytes/immunology , DNA-Binding Proteins/immunology , Germinal Center/immunology , T-Lymphocytes, Helper-Inducer/immunology , Transcription, Genetic , B-Lymphocytes/cytology , Basic-Leucine Zipper Transcription Factors/genetics , Basic-Leucine Zipper Transcription Factors/immunology , Cell Lineage/immunology , DNA-Binding Proteins/genetics , Gene Expression Regulation , Germinal Center/cytology , Humans , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/immunology , Proto-Oncogene Proteins c-bcl-6 , Proto-Oncogene Proteins c-maf/genetics , Proto-Oncogene Proteins c-maf/immunology , Receptors, CXCR5/genetics , Receptors, CXCR5/immunology , STAT Transcription Factors/genetics , STAT Transcription Factors/immunology , Signal Transduction , T-Lymphocytes, Helper-Inducer/cytology
6.
J Exp Med ; 209(10): 1841-52, S1-24, 2012 Sep 24.
Article in English | MEDLINE | ID: mdl-22987803

ABSTRACT

T follicular helper cells (Tfh cells) play a pivotal role in germinal center reactions, which require B cell lymphoma 6 (Bcl6) transcription factor. To analyze their relationships with other effector T cell lineages and their stability in vivo, we developed and analyzed a new Bcl6 reporter mouse alone or together with other lineage reporter systems. Assisted with genome-wide transcriptome analysis, we show substantial plasticity of T cell differentiation in the early phase of immune response. At this stage, CXCR5 appears to be expressed in a Bcl6-independent manner. Once Bcl6 is highly expressed, Tfh cells can persist in vivo and some of them develop into memory cells. Together, our results indicate Bcl6 as a bona fide marker for Tfh polarized program.


Subject(s)
DNA-Binding Proteins/genetics , T-Lymphocytes, Helper-Inducer/immunology , Animals , Antibody Formation/immunology , Cell Differentiation/immunology , Cluster Analysis , DNA-Binding Proteins/immunology , Gene Expression , Gene Expression Profiling , Gene Order , Gene Targeting , Genes, Reporter , Germinal Center/immunology , Immunologic Memory , Mice , Mice, Transgenic , Proto-Oncogene Proteins c-bcl-6 , Receptors, CXCR5/genetics , Receptors, CXCR5/metabolism , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/metabolism , Transcription, Genetic
7.
J Biol Chem ; 287(14): 11234-9, 2012 Mar 30.
Article in English | MEDLINE | ID: mdl-22318729

ABSTRACT

Recent work has identified a new subset of CD4(+) T cells named as Tfh cells that are localized in germinal centers and critical in germinal center formation. Tfh cell differentiation is regulated by IL-6 and IL-21, possibly via STAT3 factor, and B cell lymphoma 6 (Bcl6) is specifically expressed in Tfh cells and required for their lineage specification. In the current study, we characterized the role of STAT5 in Tfh cell development. We found that a constitutively active form of STAT5 effectively inhibited Tfh differentiation by suppressing the expression of Tfh-associated factors (CXC motif) receptor 5 (CXCR5), musculoaponeurotic fibrosarcoma (c-Maf), Bcl6, basic leucine zipper transcription factor ATF-like (Batf), and IL-21, and STAT5 deficiency greatly enhanced Tfh gene expression. Importantly, STAT5 regulated the expression of Tfh cell suppressor factor B lymphocyte-induced maturation protein 1 (Blimp-1); STAT5 deficiency impaired Blimp-1 expression and resulted in elevated expression of Tfh-specific genes. Similarly, inhibition of IL-2 potentiated Tfh generation, associated with dampened Blimp-1 expression; Blimp-1 overexpression inhibited Tfh gene expression in Stat5-deficient T cells, suggesting that the IL-2/STAT5 axis functions to regulate Blimp-1 expression. In vivo, deletion of STAT5 in CD4(+) T cells resulted in enhanced development of Tfh cells and germinal center B cells and led to an impairment of B cell tolerance in a well defined mouse tolerance model. Taken together, this study demonstrates that STAT5 controls Tfh differentiation.


Subject(s)
CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , Cell Differentiation , STAT5 Transcription Factor/metabolism , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Mice , Positive Regulatory Domain I-Binding Factor 1 , STAT5 Transcription Factor/deficiency , Transcription Factors/genetics , Up-Regulation
8.
Immunity ; 36(1): 23-31, 2012 Jan 27.
Article in English | MEDLINE | ID: mdl-22244845

ABSTRACT

T helper 17 (Th17) cells specifically transcribe the Il17 and Il17f genes, which are localized in the same chromosome region, but the underlying mechanism is unclear. Here, we report a cis element that we previously named conserved noncoding sequence 2 (CNS2) physically interacted with both Il17 and Il17f gene promoters and was sufficient for regulating their selective transcription in Th17 cells. Targeted deletion of CNS2 resulted in impaired retinoic acid-related orphan receptor gammat (RORγt)-driven IL-17 expression in vitro. CNS2-deficient T cells also produced substantially decreased amounts of IL-17F. These cytokine defects were associated with defective chromatin remodeling in the Il17-Il17f gene locus, possibly because of effects on CNS2-mediated recruitment of histone-modifying enzymes p300 and JmjC domain-containing protein 3 (JMJD3). CNS2-deficient animals were also shown to be resistant to experimental autoimmune encephalomyelitis (EAE). Our results thus suggest that CNS2 is sufficient and necessary for Il17 and optimal Il17f gene transcription in Th17 cells.


Subject(s)
Conserved Sequence , Gene Expression Regulation , Interleukin-17/genetics , Promoter Regions, Genetic , RNA, Small Untranslated , Animals , Encephalomyelitis, Autoimmune, Experimental/genetics , Interleukin-17/metabolism , Mice , Mice, Knockout , Real-Time Polymerase Chain Reaction , Regulatory Elements, Transcriptional
9.
Nat Med ; 17(8): 983-8, 2011 Jul 24.
Article in English | MEDLINE | ID: mdl-21785430

ABSTRACT

Foxp3(+) regulatory T (T(reg)) cells suppress different types of immune responses to help maintain homeostasis in the body. How T(reg) cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of T(reg) cells expressing CXCR5 and Bcl-6 that localize to the germinal centers in mice and humans. The expression of CXCR5 on T(reg) cells depends on Bcl-6. These CXCR5(+)Bcl-6(+) T(reg) cells are absent in the thymus but can be generated de novo from CXCR5(-)Foxp3(+) natural T(reg) precursors. A lack of CXCR5(+) T(reg) cells leads to greater germinal center reactions including germinal center B cells, affinity maturation of antibodies and the differentiation of plasma cells. These results unveil a Bcl-6-CXCR5 axis in T(reg) cells that drives the development of follicular regulatory T (T(FR)) cells that function to inhibit the germinal center reactions.


Subject(s)
Cell Differentiation/immunology , DNA-Binding Proteins/metabolism , Forkhead Transcription Factors/metabolism , Germinal Center/immunology , Self Tolerance/immunology , T-Lymphocytes, Regulatory/immunology , Adoptive Transfer , Animals , B-Lymphocytes/metabolism , DNA-Binding Proteins/genetics , Humans , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Knockout , Palatine Tonsil/immunology , Palatine Tonsil/metabolism , Proto-Oncogene Proteins c-bcl-6 , Receptors, CXCR5/metabolism , T-Lymphocytes, Regulatory/metabolism , T-Lymphocytes, Regulatory/physiology
10.
J Biol Chem ; 286(26): 22707-10, 2011 Jul 01.
Article in English | MEDLINE | ID: mdl-21566134

ABSTRACT

Th17 cells have recently emerged as a major player in inflammatory and autoimmune diseases via the production of pro-inflammatory cytokines IL-17, IL-17F, and IL-22. The differentiation of Th17 cells and the associated cytokine production is directly controlled by RORγt. Here we show that ursolic acid (UA), a small molecule present in herbal medicine, selectively and effectively inhibits the function of RORγt, resulting in greatly decreased IL-17 expression in both developing and differentiated Th17 cells. In addition, treatment with UA ameliorated experimental autoimmune encephalomyelitis. The results thus suggest UA as a valuable drug candidate or leading compound for developing treatments of Th17-mediated inflammatory diseases and cancer.


Subject(s)
Anti-Infective Agents/pharmacology , Interleukin-17/biosynthesis , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Th17 Cells/metabolism , Triterpenes/pharmacology , Animals , Cell Differentiation/drug effects , Cell Differentiation/immunology , Cell Line , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Humans , Interleukin-17/immunology , Mice , Neoplasms/drug therapy , Neoplasms/immunology , Neoplasms/metabolism , Th17 Cells/immunology , Ursolic Acid
11.
Immunol Rev ; 241(1): 133-44, 2011 May.
Article in English | MEDLINE | ID: mdl-21488895

ABSTRACT

CD4(+) T cells are the master regulators of adaptive immune responses, and many autoimmune diseases arise due to a breakdown of self-tolerance in CD4(+) T cells. Activation of CD4(+) T cells is regulated by not only the binding of peptide-major histocompatibility complexes to T-cell receptor but also costimulatory signals from antigen-presenting cells. Recently, there has been progress in understanding the extracellular and intracellular mechanisms that are required for implementation and maintenance of T-cell tolerance. Understanding of the molecular mechanisms underlying T-cell tolerance will lead to development of pharmacological approaches either to promote the tolerance state in terms of autoimmunity or to break tolerance in cancer.


Subject(s)
Antigen-Presenting Cells/immunology , Autoantigens/immunology , CD4-Positive T-Lymphocytes/immunology , Receptors, Antigen, T-Cell/immunology , Animals , Autoimmunity/genetics , CD4-Positive T-Lymphocytes/metabolism , Epigenesis, Genetic , Gene Expression Regulation/immunology , Humans , Immune Tolerance/genetics , Lymphocyte Activation/genetics , Receptor Cross-Talk/immunology
12.
Immunity ; 32(5): 692-702, 2010 May 28.
Article in English | MEDLINE | ID: mdl-20434372

ABSTRACT

Toll-like receptors (TLRs) have previously been shown to play critical roles in the activation of innate immunity. Here, we describe that T cell expression of TLR2 regulates T helper 17 (Th17) cell responses. Stimulation with TLR2 agonists promoted Th17 differentiation in vitro and led to more robust proliferation and Th17 cytokine production. Using the experimental autoimmune encephalomyelitis (EAE) model, we found that TLR2 regulated Th17 cell-mediated autoimmunity in vivo and that loss of TLR2 in CD4(+) T cells dramatically ameliorated EAE. This study thus reveals a critical role of a TLR in the direct regulation of adaptive immune response and pathogenesis of autoimmune diseases.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Interleukin-17/metabolism , Signal Transduction , T-Lymphocytes, Helper-Inducer/immunology , Toll-Like Receptor 2/physiology , Animals , CD4-Positive T-Lymphocytes/cytology , Cell Differentiation , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Gene Deletion , Mice , Mice, Inbred C57BL , Mice, Knockout , T-Lymphocytes, Helper-Inducer/cytology , Toll-Like Receptor 2/genetics
13.
Immunity ; 32(5): 670-80, 2010 May 28.
Article in English | MEDLINE | ID: mdl-20493730

ABSTRACT

T cell activation is tightly regulated to avoid autoimmunity. Gene related to anergy in lymphocytes (GRAIL, encoded by Rnf128) is an E3 ubiquitin ligase associated with T cell tolerance. Here, we generated and analyzed GRAIL-deficient mice and found they were resistant to immune tolerance induction and exhibited greater susceptibility to autoimmune diseases than wild-type mice. GRAIL-deficient naive T cells, after activation, exhibited increased proliferation and cytokine expression than controls and did not depend on costimulation for effector generation. Moreover, GRAIL-deficient regulatory T (Treg) cells displayed reduced suppressive function, associated with increased Th17 cell-related gene expression. GRAIL-deficient naive and Treg cells were less efficient in downregulating T cell receptor (TCR)-CD3 expression after activation and exhibited increased NFATc1 transcription factor expression; GRAIL expression promoted CD3 ubiquitinylation. Our results indicate that GRAIL, by mediating TCR-CD3 degradation, regulates naive T cell tolerance induction and Treg cell function.


Subject(s)
CD3 Complex/immunology , Immune Tolerance/immunology , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes, Regulatory/immunology , Ubiquitin-Protein Ligases/immunology , Animals , Gene Expression Regulation , Immunoblotting , Mice , Mice, Knockout , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , T-Lymphocytes, Regulatory/enzymology , Ubiquitin-Protein Ligases/genetics
14.
Cell Mol Immunol ; 7(3): 190-7, 2010 May.
Article in English | MEDLINE | ID: mdl-20383172

ABSTRACT

A fundamental function of T helper (Th) cells is to regulate B-cell proliferation and immunoglobulin class switching, especially in the germinal centers. Th1 and Th2 lineages of CD4(+) T cells have long been considered to play an essential role in helping B cells by promoting the production immunoglobulin G2a (IgG2a) and IgG1/IgE, respectively. Recently, it has become clear that a subset CD4(+) T cells, named T follicular helper (Tfh) cells, is critical to B-cell response induction. In this review, we summarize the latest advances in our understanding of the regulation of Tfh cell differentiation, the relationship of Tfh cells to other CD4(+) T-cell lineages, and the role of Tfh cells in health and disease.


Subject(s)
Cell Differentiation , Cell Lineage , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Autoimmune Diseases/immunology , B-Lymphocytes/immunology , Cell Communication , Humans
16.
J Biol Chem ; 284(45): 30815-24, 2009 Nov 06.
Article in English | MEDLINE | ID: mdl-19748894

ABSTRACT

MAPKs are evolutionarily conserved immune regulators. MAPK phosphatases (MKPs) that negatively regulate MAPK activities have recently emerged as critical players in both innate and adaptive immune responses. MKP-1, also known as DUSP1, was previously shown to negatively regulate innate immunity by inhibiting pro-inflammatory cytokine production. Here, we found that MKP-1 is necessary in T cell activation and function. MKP-1 deficiency in T cells impaired the activation, proliferation, and function of T cells in vitro, associated with enhanced activation of JNK and reduced NFATc1 translocation into the nucleus. Consistently, MKP-1(-/-) mice were defective in anti-influenza immunity in vivo and resistant to experimental autoimmune encephalomyelitis. Our results thus demonstrate that MKP-1 is a critical positive regulator of T cell activation and function and may be targeted in treatment of autoimmune diseases.


Subject(s)
Dual Specificity Phosphatase 1/immunology , Lymphocyte Activation , T-Lymphocytes/enzymology , T-Lymphocytes/immunology , Animals , Cell Proliferation , Cells, Cultured , Dual Specificity Phosphatase 1/genetics , Dual Specificity Phosphatase 1/metabolism , Influenza A virus/physiology , Mice , Mice, Knockout , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/virology , Protein Transport , T-Lymphocytes/cytology
17.
Science ; 325(5943): 1001-5, 2009 Aug 21.
Article in English | MEDLINE | ID: mdl-19628815

ABSTRACT

A fundamental function of CD4+ helper T (T(H)) cells is the regulation of B cell-mediated humoral immunity. Development of T follicular helper (T(FH)) cells that provide help to B cells is mediated by the cytokines interleukin-6 and interleukin-21 but is independent of TH1, TH2, and TH17 effector cell lineages. Here, we characterize the function of Bcl6, a transcription factor selectively expressed in T(FH) cells. Bcl6 expression is regulated by interleukin-6 and interleukin-21. Bcl6 overexpression induced T(FH)-related gene expression and inhibited other T(H) lineage cell differentiation in a DNA binding-dependent manner. Moreover, Bcl6 deficiency in T cells resulted in impaired T(FH) cell development and germinal center reactions, and altered production of other effector T cell subsets. Our data thus illustrate that Bcl6 is required for programming of T(FH) cell generation.


Subject(s)
DNA-Binding Proteins/metabolism , Germinal Center/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Helper-Inducer/immunology , Transcription Factors/metabolism , Animals , Antibody Formation , B-Lymphocytes/immunology , Cell Differentiation , Cell Lineage , Cytokines/immunology , Cytokines/metabolism , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Germinal Center/cytology , Immunoglobulins/biosynthesis , Interleukin-6/immunology , Interleukin-6/metabolism , Interleukins/immunology , Interleukins/metabolism , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation , Proto-Oncogene Proteins c-bcl-6 , RNA, Messenger/genetics , RNA, Messenger/metabolism , T-Lymphocyte Subsets/cytology , T-Lymphocytes, Helper-Inducer/cytology , Transcription Factors/genetics
18.
Immunol Rev ; 229(1): 88-100, 2009 May.
Article in English | MEDLINE | ID: mdl-19426216

ABSTRACT

SUMMARY: In addition to signals from the T-cell receptor complex, it has been recognized for many years that a 'second' signal, most notably from CD28, is also important in T-cell activation. In the recent years, many new members of CD28 family as well as the molecules that share structural homology to CD28 ligands CD80 and CD86 have been discovered. Interestingly, some of these proteins function to dampen T-cell activation and regulate the induction of T-cell tolerance. Therefore, positive and negative costimulation are the two sides of the coin to fine tune T-cell receptor signaling to determine the outcome of T-cell receptor engagement-tolerance versus function.


Subject(s)
CD28 Antigens/immunology , Immune Tolerance , Lymphocyte Activation , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology , Animals , Antibody Formation/immunology , Antigens, CD/immunology , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte , Apoptosis Regulatory Proteins/immunology , Apoptosis Regulatory Proteins/metabolism , Autoimmunity/immunology , B7 Antigens , B7-1 Antigen/immunology , B7-1 Antigen/metabolism , CD28 Antigens/metabolism , Humans , Inducible T-Cell Co-Stimulator Protein , Receptors, Antigen, T-Cell/metabolism , Receptors, Immunologic/immunology , Receptors, Immunologic/metabolism , Signal Transduction/immunology , T-Lymphocytes/metabolism
19.
J Immunol ; 182(8): 4516-20, 2009 Apr 15.
Article in English | MEDLINE | ID: mdl-19342624

ABSTRACT

T cell activation and tolerance are delicately regulated by costimulatory molecules. Although B and T lymphocyte attenuator (BTLA) has been shown as a negative regulator for T cell activation, its role in peripheral T cell tolerance induction in vivo has not been addressed. In this study, we generated a novel strain of BTLA-deficient mice and used three different models to characterize the function of BTLA in controlling T cell tolerance. In an oral tolerance model, BTLA-deficient mice were found resistant to the induction of T cell tolerance to an oral Ag. Moreover, compared with wild-type OT-II cells, BTLA(-/-) OT-II cells were less susceptible to tolerance induction by a high-dose OVA peptide administered i.v. Finally, BTLA(-/-) OT-I cells caused autoimmune diabetes in RIP-mOVA recipient mice. Our results thus demonstrate an important role for BTLA in the induction of peripheral tolerance of both CD4(+) and CD8(+) T cells in vivo.


Subject(s)
Immune Tolerance/immunology , Receptors, Immunologic/immunology , Receptors, Immunologic/metabolism , T-Lymphocytes/immunology , Animals , Autoimmune Diseases/immunology , Mice , Mice, Knockout , Receptors, Immunologic/deficiency , Receptors, Immunologic/genetics
20.
Ann N Y Acad Sci ; 1143: 188-211, 2008 Nov.
Article in English | MEDLINE | ID: mdl-19076351

ABSTRACT

Naïve CD4(+) helper T (TH) cells, upon activation by antigen-presenting cells (APC), differentiate into different types of effector cells that are characterized by their distinct cytokine production profiles and immune regulatory functions. In addition to TH1 and TH2 cells, a third subset of effector TH cells has recently been described and termed TH17. Since their identification, TH17 cells have emerged as crucial players in infectious, inflammatory, and autoimmune diseases, and cancer. In this review, we summarize the latest discoveries on the cytokine-mediated regulation and transcriptional programming of TH17 cells and their roles in different immune responses and diseases.


Subject(s)
Inflammation/immunology , Interleukin-17/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Cell Differentiation , Cell Lineage , Humans , Interleukin-17/genetics , Models, Biological , Nuclear Receptor Subfamily 1, Group F, Member 3 , Phenotype , Receptors, Retinoic Acid/immunology , Receptors, Retinoic Acid/metabolism , Receptors, Thyroid Hormone/immunology , Receptors, Thyroid Hormone/metabolism , STAT Transcription Factors/immunology , STAT Transcription Factors/metabolism , Transcription, Genetic
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