Early autoimmune destruction of islet grafts is associated with a restricted repertoire of IGRP-specific CD8⁺ T cells in diabetic nonobese diabetic mice

β Cell replacement via islet or pancreas transplantation is currently the only approach to cure type 1 diabetic patients. Recurrent β cell autoimmunity is a critical factor contributing to graft rejection along with alloreactivity. However, the specificity and dynamics of recurrent β cell autoimmunity remain largely undefined. Accordingly, we compared the repertoire of CD8⁺ T cells infiltrating grafted and endogenous islets in diabetic nonobese diabetic mice. In endogenous islets, CD8⁺ T cells specific for an islet-specific glucose-6-phosphatase catalytic subunit-related protein derived peptide (IGRP_206-214) were the most prevalent T cells. Similar CD8⁺ T cells dominated the early graft infiltrate but were expanded 6-fold relative to endogenous islets. Single-cell analysis of the TCR α and β chains showed restricted variable gene usage by IGRP _206-214-specific CD8⁺ T cells that was shared between the graft and endogenous islets of individual mice. However, as islet graft infiltration progressed, the number of IGRP_206-214-specific CD8 ⁺ T cells decreased despite stable numbers of CD8⁺ T cells. These results demonstrate that recurrent β cell autoimmunity is characterized by recruitment to the grafts and expansion of already prevalent autoimmune T cell clonotypes residing in the endogenous islets. Furthermore, depletion of IGRP_206-214-specific CD8⁺ T cells by peptide administration delayed islet graft survival, suggesting IGRP_206-214- specific CD8⁺ T cells play a role early in islet graft rejection but are displaced with time by other specificities, perhaps by epitope spread.