Low affinity CD8+ T cells in diabetes

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Thymic and peripheral deletion represent important safeguards to eliminate potentially autoreactive T cells. However, in the interest of maximizing diversity in the T cell repertoire, deletion is a mechanisms used sparingly and reserved for those T cells expressing TCRs with relatively high affinity for self-epitopes. As a result of this rather conservative approach, many T cells with specificity for self-epitopes persist. The main hypothesis of this proposal is that these otherwise innocuous T cells become important effector cells in autoimmune diabetes. Our goal is to test this hypothesis using a transgenic model in which the influenza hemagglutinin (HA), is expressed uniquely in the pancreatic islets (Ins-HA) and a TCR transgenic murine line expressing a TCR from a HA specific CD8+ T cell clone. (Clone 1 TCR). Importantly, this clone was derived from an Ins-HA mouse that demonstrates tolerance to HA and the TCR demonstrates relatively low affinity for HA as compared with TCRs from HA specific CTL from conventional mice. Some of the experimental parameters that may prove autoimmunity by the Clone 1 T cells that will be evaluated in this study include conditions that promote an inflammatory environment locally in the islets, such as occurs in NOD mice, or by creating an inflammatory environment in non- diabetes prone mice using HA specific, activated CD4+ T cells, or Coxsackie virus. Also to be evaluated is the hypothesis that eliminating such potentially autoimmune CD8+ T cells from the repertoire, by the use of a DNA vaccine expressing the target antigen, may prevent autoimmunity in NOD mice. Two different antigens will be evaluated in this context, an endogenous beta cell antigen, GAD65, and the HA transgene product.