CD Id-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 diabetes. Despite the importance of CD Id-restricted T cells in this disease, 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 CD Id-restricted T cells with dendritic cells and the activation-induced secretion of Thl and Th2 cytokines. Th2 cytokine secretion by CD Id-restricted T cells has been associated with protection from autoimmune diabetes in murine models. Conversely, CD Id-restricted T cells cloned from patients with type 1 diabetes were found, amongst other defects, to have an extreme Thl cytokine bias. Recent work has demonstrated that in normal human volunteers, the CD4+ CD Id-restricted subset is responsible for Th2 cytokine production in vivo, whereas the CD4- (or """"""""DN"""""""") subset were strongly biased towards the secretion of Thl cytokines and expressed greater levels of proteins with cytotoxic function. Recently we found that people at risk for type 1 diabetes have a significant increase in the DN subset. Importantly, we have also identified factors secreted by CD4+ but not by DN iNKT cells that positively regulate DC differentiation. Defective maturation of myeloid DC is thought to be a significant cellular defect related to diabetes risk. Hence, CD4+ iNKT cells might serve to prevent progression to diabetes whilst DN iNKT cells might promote pro-inflammatory responses. To test the hypothesis of distinct effector function for these two subsets we propose to compare diabetes patients, at risk donors, and control donors in the following specific aims:
Aim 1. Analyses of CDld-restricted T frequency and function.
Aim 2. Characterization of dendritic cell differentiation factor(s) secreted by CD4+ iNKT cells Aim 3. Molecular analysis of the requirements for co-receptor function during APC-dependent activation and formation of the immunologic synapse.
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