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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. [ABSTRACT FROM AUTHOR]

Summary: 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

After activation, CD4+ helper T (TH) cells differentiate into distinct effector subsets that are characterized by their unique cytokine expression and immunoregulatory function. During this differentiation, TH1 and TH2 cells produce interferon-γ and interleukin (IL)-4, respectively, as autocrine factors necessary for selective lineage commitment. A distinct TH subset, termed THIL-17, TH17 or inflammatory TH (THi), has been recently identified as a distinct TH lineage mediating tissue inflammation. TH17 differentiation is initiated by transforming growth factor-β and IL-6 (refs 5–7) and reinforced by IL-23 (ref. 8), in which signal transduction and activators of transcription (STAT)3 and retinoic acid receptor-related orphan receptor (ROR)-γ mediate the lineage specification. TH17 cells produce IL-17, IL-17F and IL-22, all of which regulate inflammatory responses by tissue cells but have no importance in TH17 differentiation. Here we show that IL-21 is another cytokine highly expressed by mouse TH17 cells. IL-21 is induced by IL-6 in activated T cells, a process that is dependent on STAT3 but not ROR-γ. IL-21 potently induces TH17 differentiation and suppresses Foxp3 expression, which requires STAT3 and ROR-γ, which is encoded by Rorc. IL-21 deficiency impairs the generation of TH17 cells and results in protection against experimental autoimmune encephalomyelitis. IL-21 is therefore an autocrine cytokine that is sufficient and necessary for TH17 differentiation, and serves as a target for treating inflammatory diseases. [ABSTRACT FROM AUTHOR]

Summary: 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. [Copyright &y& Elsevier]

MAPKs are evolutionarily conserved immune regulators. MAPI( 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 antiinfluenza 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. [ABSTRACT FROM AUTHOR]