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.
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