Ontogeny of T cell tolerance to peripherally expressed antigens

Transgenic expression of the influenza virus hemagglutinin (IIA) in the pan creatic islet beta cells of InsHA mice leads to peripheral tolerance of HA- specific T cells. To examine the onset of tolerance, InsHA mice were immuni zed with influenza virus A/PR/8 at different ages, and the presence of nont olerant T cells was determined by the induction of autoimmune diabetes, The data revealed a neonatal period wherein T cells were not tolerant and infl uenza virus infection led to HA-specific beta cell destruction and autoimmu ne diabetes, The ability to induce autoimmunity gradually waned, such that adult mice were profoundly tolerant to viral HA and were protected from dia betes. Because cross presentation of islet antigens by professional antigen -presenting cells had been reported to induce peripheral tolerance, the tem poral relationship between tolerance induction and activation of HA-specifi c T cells in the lymph nodes draining the pancreas was examined, In toleran t adult mice, but not in 1-week-old neonates, activation and proliferation of HA-specific CD8(+) T cells occurred in the pancreatic lymph nodes. Thus, lack of tolerance in the perinatal period correlated with lack of activati on of antigen-specific CD8(+) T cells. This work provides evidence for the developmental regulation of peripheral tolerance induction.