PROJECT SUMMARY T cells responding to persistent antigen during cancer and chronic infection develop a hyporesponsive phenotype, while T cells responding to self-antigen during type 1 diabetes (T1D) maintain function and eliminate pancreatic beta cells. My co-mentor previously identified a transcriptional program induced by persistent stimulation that was shared by mouse and human T cells responding to chronic viral infections and tumors. This program was linked to the Nuclear Factor of Activated T cells (NFAT) and Nuclear Receptor Subfamily 4 Group A (NR4A) families of transcription factors (TFs), which are potently induced during chronic stimulation. This transcriptional program elicited a characteristic pattern of inhibitory receptor expression and also directly reduced expression of genes encoding effector proteins. In new preliminary studies, I found that only a subset of T cells specific for self-antigen in the pancreas of NOD mice induced this exhaustion associated transcriptional program. Cells with increased levels of exhaustion associated TFs had lower expression of genes encoding effector proteins. These data indicate that the canonical exhaustion program is weakly induced in the autoreactive T cell pool during diabetes and is a potential target to lessen effects of T cells during autoimmune disease. Based on these data, my central hypothesis is that expression and activity of the exhaustion program determines the function of self- antigen specific CD8+ T cells during type 1 diabetes. I predict that 1) the exhaustion associated program can be activated to limit autoreactive T cell function and 2) the induction of this program is determined by TCR affinity for self-antigen. I propose two aims to test these predictions during T1D using NOD mice and human T cells. The expected results of this study will address unanswered questions about the fundamental mechanisms controlling T cell activity during autoimmune disease and determine the potential to limit autoimmune disease by controlling exhaustion associated transcriptional programs.