Early Autoimmune Destruction of Islet Grafts Is Associated with a Restricted Repertoire of IGRP-Specific CD8+ T Cells in Diabetic Nonobese Diabetic Mice

Abstract

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 (IGRP206–214) 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 IGRP206–214-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 IGRP206–214-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 IGRP206–214-specific CD8+ T cells by peptide administration delayed islet graft survival, suggesting IGRP206–214-specific CD8+ T cells play a role early in islet graft rejection but are displaced with time by other specificities, perhaps by epitope spread.