4A)

4A). regions of the IL-17 and IL-21 genes. 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 Amprolium HCl IRF-4. 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 Amprolium HCl and IL-21 does not occur in response to self-antigens. == INTRODUCTION == 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). 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. 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- and IL-1 as well as stimulate MMP activity, matrix catabolism, and bone resorption (Koenders et al., 2006;Stamp et al., 2004). 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). TH17 cells develop via a pathway distinct from TH1 and TH2 cells. Induction of IL-17 production depends on the presence of Stat3 and RORt (Ivanov et al., 2006;Laurence et al., 2007;Yang et al., 2007), while IL-21 expression requires the presence of Stat3 but not of RORt (Nurieva et al., 2007). 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. The regulatory Amprolium HCl pathways that prevent the inappropriate production of IL-17 and IL-21 have, however, not been fully elucidated. 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). Expression of IRF-4 is upregulated in response to T cell activation and we, as well as others, have Amprolium HCl shown that IRF-4 can regulate IL-4 production and Amprolium HCl TH2 differentiation (Hu et al., 2002;Rengarajan et al., 2002a). Interestingly, recent studies have demonstrated that IRF-4 is also a crucial regulator of TH17 differentiation (Brustle et al., 2007). During a yeast two-hybrid screen aimed at identifying proteins interacting with IRF-4, our laboratory isolated a human cDNA encoding a novel protein that we termed IBP (IRF-4 Binding Protein) (Gupta et Rabbit polyclonal to SLC7A5 al., 2003b). IBP shares significant homology with SWAP-70, a novel type of Rac activator. In contrast to SWAP-70 that is expressed mostly in B cells and mast cells, IBP is highly expressed in T cells. In unstimulated T cells, IBP is present in a dormant conformation due to an inhibitory interaction between its N- and C-termini. TCR engagement leads to the tyrosine phosphorylation of the N-terminus of IBP, disrupting the autoinhibitory interaction and enabling IBP to be recruited to the immunological synapse (IS) where IBP activates Rac and Cdc42 (Gupta et al., 2003a). Our previous studies in mice deficient for IBP (IBPtrap/trapmice) have revealed that lack of IBP, with age, leads to the development of a lupus-like syndrome,.