This is a proposal to continue studies on the mechanism of tolerance of CD8+ T cells specific for a peripheral antigen expressed in the beta cells of the pancreatic islets. The antigen under examination is the influenza hemagglutinin (HA) that is expressed under the control of the insulin promoter in Ins-HA mice. Tolerance is studied by following the fate of CD8 T cells derived from Clone 4 TCR transgenic mice, which express a TCR specific for a Kd restricted epitope of HA. Tolerance in this model occurs as a result of abortive activation and deletion of naive T cells that encounter cross-presented antigen on dendritic cells in the pancreatic lymph nodes. In the course of examining the conditions that can override the induction of tolerance in this model we have identified stimulatory conditions that result in activation and survival of CD8 cells that do not exhibit effector function. A major goal in this application is to examine how differences in the conditions of initial activation determine the functional properties and survival of the resultant clonally expanded CD8 effector and memory cells. CD4 helper and regulatory T cells are prime candidates for directing the fate of the CD8 cell, as are molecules that instruct dendritic cells maturation. Also included in these studies is an examination of the fate of CD8 T cells specific for HA antigen in NOD mice with the goal of determining how a genetic predisposition towards autoimmunity disrupts CD8 tolerance in the InsHA model. These studies also take advantage of Clone 4 TCR-NOD mice and InsHA-NOD mice as well as congenic strains of NOD that do not develop diabetes. Preliminarydata suggest that deletional tolerance of Clone 4 cells in this NOD InsHA-NOD is incomplete as the mice retain a repertoire of HA specific CD8 cells of high avidity. ? ?
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