Role of Ikaros in IL-2 gene expression and T cell anergy

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DESCRIPTION (provided by applicant): T cell anergy is an important mechanism of peripheral tolerance that controls the development of immunopathology in experimental models of autoimmunity and alloimmunity. Anergy involves the functional inactivation of inappropriate T cell responses and is thought to be largely the result of active silencing of effector gene transcription. Perhaps the most relevant gene affected by this phenomenon encodes the T cell growth factor IL-2, but the means by which this and other genes are silenced during this mode of tolerance induction is poorly understood. We find that the IL-2 promoter contains two putative binding motifs for Ikaros, a lymphoid-specific zinc-finger DNA binding protein required for normal T lymphocyte development. Interestingly, Ikaros acts primarily as a transcriptional repressor by recruiting histone deacetylases and chromatin remodeling complexes to gene promoters and enhancers. Our preliminary data suggest that Ikaros associates with the endogenous IL-2 promoter in primary T cells, and therefore could potentially contribute to active silencing of the IL-2 gene. The specific goal of the proposed studies outlined in this grant application is to determine whether Ikaros regulates IL-2 gene expression in naive T cells in response to signals from antigen and costimulatory receptors, and whether chromatin remodeling mediated by this factor contributes to silencing of the IL-2 gene during the induction of T cell anergy. Our hypothesis that Ikaros and/or chromatin remodeling may the influence IL-2 gene expression, and the induction of immune tolerance is novel, and represents an innovative approach to studying the molecular basis of immune tolerance. Therefore, the studies proposed are consistent with the exploratory nature of the R21 mechanism.