CD1d-restricted T cells (or """"""""iNKT cells"""""""") have been reported to regulate an extremely diverse set of immunologic responses and diseases. Dysfunction including cytokine secretion by these T cells is clearly correlated with the development of autoimmunity, and in particular autoimmune type 1 diabetes. Despite the importance of CDId-restricted T cells in this disease, the question of how these T cells function normally and the exact nature of the disease-associated defects remains unclear. In this regard, potential regulatory functions that would be predicted to have significant impact on type 1 diabetes include recently described critical interactions of CDId-restricted T cells with dendritic cells (DC;the focus of Project 2) and the activation-induced secretion of regulatory cytokines. Recent work has demonstrated that in normal human volunteers, the CD4+ CDId-restricted subset preferentially secrete regulatory cytokines, whereas the CD4- (or """"""""DM"""""""") subset were strongly biased towards the secretion of Th1-related cytokines and expressed greater levels of proteins with cytotoxic function. We have observed that individuals at risk for type 1 diabetes have a significant bias towards the DN subset. Perhaps more importantly, CD4+ iNKT cells preferentially express FOXP3 (the focus of Project 3) and secrete an as of yet to be identified factor that induces myeloid DC differentiation. Interestingly, the expression of FOXP3 is dependent on IL-2 and CD25, both of which are candidate type 1 diabetes susceptibility alleles. Thus, CD4+ CD1 d-restricted T cells might serve to prevent progression to diabetes by controlling DC maturation and effector T cells while DN CDId-restricted T cells might promote pro-inflammatory responses. In this proposal, we plan to investigate with Projects 2 and 3, the mechanism by which CD4+ and DN iNKT cells interact and regulate T effector cells and APC. To that end, our proposal will specifically test the hypothesis that CD4+ iNKT cells are a unique class of regulatory T cells and may serve to prevent progression to autoimmune type 1 diabetes, while DN iNKT cells play a more pathogenic role. This hypothesis predicts that reduced activity of the CD4+ iNKT cell subset compared to that of the DN subset (which could result from a selective defect in CD4+ functions, or an alteration in DN vs. CD4+ proportion), could in some cases be associated with progression to type 1 diabetes. This hypothesis will be tested by performance of two specific aims involving: 1) Analyses of iNKT frequency and function, and 2) Characterization of DC differentiation factor(s) secreted by CD4+ iNKT cells. Together with Projects 2 and 3, the successful completion of these studies could lead to an improved understanding of the mechanisms underlying the autoimmune activity that that results in type 1 diabetes as well as the identification of novel factors important to immune regulation.
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