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In immune responses, activated T cells migrate to B-cell follicles and develop into follicular T-helper ([T.sub.FH]) cells, a recently identified subset of [CD4.sup.+] T cells specialized in providing help to B lymphocytes in the induction of germinal centres (1,2). Although Bcl6 has been shown to be essential in [T.sub.FH]-cell function, it may not regulate the initial migration of T cells (3) or the induction of the [T.sub.FH] program, as exemplified by C-X-C chemokine receptor type 5 (CXCR5) upregulation (4). Here we show that expression of achaete-scute homologue 2 (Ascl2)--a basic helix-loop-helix (bHLH) transcription factor (5)--is selectively upregulated in [T.sub.FH] 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 [T.sub.FH]-cell development in vivo in mice. Genome-wide analysis indicates that Ascl2 directly regulates [T.sub.FH]-related genes whereas it inhibits expression of T-helper cell 1 ([T.sub.H]1) and [T.sub.H]17 signature genes. Acute deletion of Ascl2, as well as blockade of its function with the Id3 protein in [CD4.sup.+] T cells, results in impaired [T.sub.FH]-cell development and germinal centre response. Conversely, mutation of Id3, known to cause antibody-mediated autoimmunity, greatly enhances [T.sub.FH]-cell generation. Thus, Ascl2 directly initiates [T.sub.FH]-cell development., The development of [T.sub.FH] cells is initiated by and dependent on their movement out of the T-cell zone and into the B-cell follicle. This migration process is regulated by upregulation [...]

[Foxp3.sup.+] regulatory T ([T.sub.reg]) cells suppress different types of immune responses to help maintain homeostasis in the body. How [T.sub.reg] cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of [T.sub.reg] cells expressing CXCR5 and Bcl-6 that localize to the germinal centers in mice and humans. The expression of CXCR5 on [T.sub.reg] cells depends on Bcl-6. These [CXCR5.sup.+][Bcl-6.sup.+] [T.sub.reg] cells are absent in the thymus but can be generated de novo from CXCR5-[Foxp3.sup.+] natural [T.sub.reg] precursors. A lack of CXCR5+ [T.sub.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.sub.reg] cells that drives the development of follicular regulatory T ([T.sub.FR]) cells that function to inhibit the germinal center reactions., The vertebrate immune system contains a unique subset of T cells expressing Foxp3 that prevent autoimmunity against self antigens and exaggerated immune responses. Deficiency of Foxp3 in humans results in [...]

Foxp3+ regulatory T (Treg) cells suppress different types of immune responses to help maintain homeostasis in the body. How Treg cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of Treg cells expressing CXCR5 and Bcl-6 that localize to the germinal centers in mice and humans. The expression of CXCR5 on Treg cells depends on Bcl-6. These CXCR5+Bcl-6+ Treg cells are absent in the thymus but can be generated de novo from CXCR5?Foxp3+ natural Treg precursors. A lack of CXCR5+ Treg 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 Treg cells that drives the development of follicular regulatory T (TFR) cells that function to inhibit the germinal center reactions. [ABSTRACT FROM AUTHOR]

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. [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]

Dual specificity phosphatases (DUSPs) have been shown to play a critical role in regulation of various cellular processes and aberrations in their expression patterns are associated with pathogenesis of wide range of diseases. The atypical dual-specificity phosphatase DUSP11 was previously demonstrated to bind to ribonucleic acid–ribonucleoprotein (RNA–RNP) complexes and RNA-splicing factors and is a p53 target gene. Recent in vitro studies highlighted the importance of this molecule in cell proliferation, cancer suppression and chronic inflammation. Our in vitro studies showed that DUSP11 expression is induced in dendritic cells upon stimulation by TLR ligands and in T cells upon CD3/CD28 activation suggesting the prominence of DUSP11 in immune responses. To examine the function of DUSP11 in regulating immune responses, we generated and analyzed DUSP11 deficient mice. We found that DUSP11 KO antigen presenting cells produce decreased levels of proinflammatory cytokines during innate immune responses and CD4 T cells have enhanced IL-2 production and proliferation in response to TCR activation compared to the wild type cells but no apparent defect in in vitro T cell differentiation. However, our in vivo experiments demonstrated that DUSP11 deficient mice are defective in antigen-specific T cell responses and that they are more susceptible to Listeria monocytogenes infection. Using dendritic cell (DC) and T cell co-culture experiments we established that the DUSP11 signalling in DCs eventually regulates CD4 T cell activation. Together, these results demonstrate that DUSP11 is critical for innate immune responses and that the defects in innate responses ultimately affect the adaptive immune responses. This supports the growing body of evidence that intrinsic pathways in innate immune cells can modulate T cell lineage differentiation. Currently our efforts are dedicated to understanding the molecular mechanisms regulated by DUSP11. [ABSTRACT FROM AUTHOR]

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.