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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]

The transcription factor IRF-4 is necessary for Th17 cell differentiation. In this issue of Immunity, show that IRF-4-binding protein is a critical negative regulator of IRF-4 function, regulating production of the cytokines IL-21 and IL-17. [Copyright &y& Elsevier]

Apart from T helper (Th)-2 cells, T follicular helper (Tfh) cells are a major class of IL-4 producing T cells, required for regulation of type 2 humoral immunity. Although the transcriptional control of IL-4 has been an area of extensive investigation, the precise regulation mechanism of IL-4 production in Tfh cells remains mainly unknown. In the current study, we found that the transcription factor Batf, a member of the AP-1/Jun family is essential for IL-4 expression in Tfh cells rather than in canonical Th2 cells. Functionally, Batf in cooperation with interferon regulatory factor (IRF)4 along with Stat3 and Stat6 trigger IL-4 production in Tfh cells by directly binding to and activation of the CNS2 region in the IL-4 locus. Additionally, Batf-to-c-Maf signaling is an important determinant of IL-4 expression in Tfh cells. We also found that in addition to IL-6/STAT3 signaling, IL-4-Stat6 axis could contribute to triggering Batf expression in Tfh cells. Importantly, IL-4-expressing Tfh cells could trigger an allergic inflammation, since deletion of Batf in Tfh cells leads to an IL-4 defect and protects mice from induction of allergic asthma. Our results thus indicate a novel and critical role of Batf in promoting the generation of pro-allergic IL-4 producing Tfh cells; Batf may be targeted in treating allergic inflammatory diseases. [ABSTRACT FROM AUTHOR]

In this study, we determined the role of IL-21R signaling in Mycobacterium tuberculosis infection, using IL-21R knockout (KO) mice. A total of 50% of M. tuberculosis H37Rv--infected IL-21R KO mice died in 6 mo compared with no deaths in infected wild type (WT) mice. M. tuberculosis--infected IL-21R KO mice had enhanced bacterial burden and reduced infiltration of Ag-specific T cells in lungs compared with M. tuberculosis--infected WT mice. Ag-specific T cells from the lungs of M. tuberculosis--infected IL-21R KO mice had increased expression of T cell inhibitory receptors, reduced expression of chemokine receptors, proliferated less, and produced less IFN-γ, compared with Ag-specific T cells from the lungs of M. tuberculosis--infected WT mice. T cells from M. tuberculosis--infected IL-21R KO mice were unable to induce optimal macrophage responses to M. tuberculosis. This may be due to a decrease in the Ag-specific T cell population. We also found that IL-21R signaling is associated with reduced expression of a transcriptional factor Eomesodermin and enhanced functional capacity of Ag-specific T cells of M. tuberculosis--infected mice. The sum of our findings suggests that IL-21R signaling is essential for the optimal control of M. tuberculosis infection. [ABSTRACT FROM AUTHOR]

Summary: 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. [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]