Expression of IRF-4 is upregulated in response to T cell activation and we, as well as others, have shown that IRF-4 can regulate IL-4 production and TH2 differentiation ( Hu et al., 2002 Rengarajan et al., 2002a). ![]() Interferon Regulatory Factor 4 (IRF-4) is a member of the IRF family of transcription factors whose absence leads to profound defects in the function and homeostasis of mature T and B cells ( Mittrucker et al., 1997). The regulatory pathways that prevent the inappropriate production of IL-17 and IL-21 have, however, not been fully elucidated. Given the potentially deleterious effects of the cytokines produced by TH17 cells, their production needs to be strictly controlled so that acquisition of these effector functions occurs only in response to the appropriate antigenic stimuli. Induction of IL-17 production depends on the presence of Stat3 and RORγt ( Ivanov et al., 2006 Laurence et al., 2007 Yang et al., 2007), while IL-21 expression requires the presence of Stat3 but not of RORγt ( Nurieva et al., 2007). TH17 cells develop via a pathway distinct from TH1 and TH2 cells. TH17 cells have also recently been shown to produce IL-21 ( Korn et al., 2007 Nurieva et al., 2007 Zhou et al., 2007), a cytokine that can amplify the differentiation of TH17 cells in an autocrine manner as well as control T-dependent humoral responses ( Leonard and Spolski, 2005 Mehta et al., 2004). The ability of the TH17 subset to produce IL-17 is critical to their role in RA pathogenesis, since IL-17 can induce the production of proinflammatory cytokines such as TNF-α and IL-1 as well as stimulate MMP activity, matrix catabolism, and bone resorption ( Koenders et al., 2006 Stamp et al., 2004). In particular, TH17 cells are believed to play a key role in rheumatoid arthritis (RA) ( McInnes and Schett, 2007 Toh and Miossec, 2007), a disease characterized by destructive inflammatory lesions affecting the synovial membranes of joints and by aberrant humoral responses that result in the production of autoantibodies like Rheumatoid Factor and anti-cyclic citrullinated peptide (CCP) antibodies. Recent studies have uncovered the existence of a novel TH effector subset, the TH17 lineage, whose deregulation has been implicated in the pathogenesis of autoimmunity ( Bettelli et al., 2007b Weaver et al., 2006). Taken together these studies suggest that IBP plays a key regulatory role in the prevention of T cell-mediated autoimmunity by ensuring that the production of IL-17 and IL-21 does not occur in response to self-antigens. Consistent with this finding, the enhanced ability of IBP deficient T cells to produce IL-17 and IL-21 is abolished by the concurrent lack of IRF-4. Furthermore, we demonstrate that the effect of IBP on cytokine production is due to its ability to sequester IRF-4 and prevent it from targeting the transcriptional regulatory regions of the IL-17 and IL-21 genes. The pathology observed in the absence of IBP is associated with an enhanced responsiveness of T cells to low-levels of stimulation and with the inappropriate synthesis of IL-17 and IL-21. Here we show that TCR transgenic IBP deficient mice rapidly develop rheumatoid arthritis-like joint disease and large-vessel vasculitis. Our studies previously demonstrated that IBP can act as an activator of Rho GTPases and that mice deficient in IBP develop a lupus-like syndrome upon aging. ![]() Our laboratory has isolated a protein, which interacts with IRF-4, that we have termed IBP (IRF-4 Binding Protein). IRF-4 is a transcription factor that has recently emerged as a key regulator of TH17 differentiation. The regulatory pathways that prevent the inappropriate development of TH17 cells have not been fully elucidated. Given the potentially deleterious effects of TH17 cells, their generation needs to be strictly controlled. The TH17 lineage is a novel CD4 + T cell effector subset that plays a key role in inflammatory and autoimmune responses, via its ability to produce IL-17 and IL-21.
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