Thymic development of insulin reactive T cells (BA11P.128)

Abstract Type 1 Diabetes (T1D) is a T cell-mediated autoimmune disease that involves the destruction of insulin (Ins) producing β cells found within the pancreatic islets of Langerhans. While multiple studies have characterized the pathogenicity and diabetogenic potential of β-cell specific T cells, we have limited mechanistic insight into autoimmune T cell development and their escape from thymic selection. Utilizing the retrogenic mouse technology, we show that ectopic expression of InsB9-23 or insulin agonist mimetope (R22E) in the thymus influences the onset of diabetes. Our results demonstrate that increasing InsB9-23 expression in the thymus is insufficient to induce insulin reactive CD4+ T cell deletion, and upon escape from thymic selection, these insulin reactive T cells infiltrate the pancreas of NOD mice. Interestingly, these pancreatic-residing autoreactive CD4+ T cells are no longer able to induce spontaneous diabetes development. In contrast, when R22E mimetope is expressed, thymocyte development is halted at the double positive stage and insulin reactive T cells undergo negative selection. As a result, thymic expression of R22E completely prevents autoreactive thymocytes selection and diabetes development. Collectively, these results suggest that antigen dose or peptide:MHC complex stability of self-antigen presentation in the thymus can lead to multiple fates of insulin reactive CD4+T cell development and autoimmune outcome.