Peripheral T cell tolerance mechanisms, unlike those operational in the thymus, target mature self reactive T cells. By virtue of acting on mature T cells, such mechanisms involved a tenuous balance between antigen mediated activation leading to effector function and deletion/anergy of mature autoreactive T cells. An important mechanism for the elimination of mature antigen reactive T cells involves a process of activation induced clonal deletion. The overall hypothesis tested in this proposal is that an imbalance in the homeostasis governing activation versus activation- induced clonal deletion of mature T cells contributes to autoimmunity. Using the NOD mouse as a paradigm of spontaneous T cell mediated autoimmune disease, our studies have demonstrated that mature NOD CD4+ T cells are characterized by a profound inertia in activation and resistance to activation induced death. Thus, in the present proposal we will first determine whether peripheral NOD CD4+ T cell activation is a stringent process requiring a higher threshold stimulus for triggering as compared to activation of non-autoimmune CD4+ T cells. We will then determine if in vivo activated aberrant activation properties of peripheral NOD CD4+ T cells result from intrinsic T cell characteristics or stem from unique properties of NOD APCs. An understanding of the mechanisms by which diabetogenic T cells abnormally persist in NOD mice can provide the basis for the design of novel strategies for the prevention of IDDM.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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University of Pennsylvania
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