Type 1 diabetes (T1D) is an autoimmune disease characterized by the highly specific destruction of the pancreatic pcells. Numerous studies have demonstrated that the primary mediators of p cell destruction are CD4+ and CD8+ T cells. Aberrant thymic selection and failing peripheral tolerance are believed to contribute to the development of pathogenic T cells, however, the precise mechanisms that over-ride self-tolerance still require elucidation. We have been studying the role of professional antigen presenting cells (ARC) such as macrophages (Me) and dendritic cells (DC) in the initiation and establishment of T1D. Recently, we have found that the progression of p cell autoimmunity is profoundly altered in nonobese diabetic (NOD) mice deficient in MerTK expression (NOD.mertk ). MerTK is a receptor tyrosine kinase expressed by Me and DC among other cell types. NOD.mertkKD mice remain diabetes-free and preliminary data suggest that protection correlates with enhanced negative selection in the thymus. In marked contrast, p cell autoimmunity is exacerbated in NOD.mertk mice transgenic for the pcell-specific BDC2.5 clonotypic T cell receptor. Here, """"""""enhanced"""""""" T1D is associated with events ongoing in the periphery. Notably, MerTK has been reported to serve various functions including apoptotic body uptake, and maintaining homeostasis of ARC activation. Strikingly, the gene encoding MerTK is located in the NOD insulin-dependent diabetes (Idd) 13 (Idd13) susceptibility locus and is conserved in the human IDDM13 locus. Based on our findings with NOD.mertk mice, MerTK may in fact have a key role in contributing to T1D. Accordingly, the current application will focus on determining the role(s) of MerTK in regulating the development and expansion of pcell-specific T cells in the context of thymic selection and peripheral tolerance. In this way, the cellular and molecular contribution of MerTK in regulating ARC activation and effector function, and how these events shape p cell-specific T cell reactivity will be ascertained.
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