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

beta cell replacement via islet or pancreas transplantation is currently the only approach to cure type 1 diabetic patients. Recurrent beta cell autoimmunity is a critical factor contributing to graft rejection along with alloreactivity. However, the specificity and dynamics of recurrent beta 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 alpha and beta 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 beta 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.