Autoantigen Recognition Is Required for Recruitment of IGRP206-214-Autoreactive CD8+ T Cells but Is Dispensable for Tolerance

The progression of autoimmune responses is associated with an avidity maturation process driven by preferential expansion of high avidity clonotypes at the expense of their low avidity counterparts. Central and peripheral tolerance hinder the contribution of high-avidity clonotypes targeting residues 206-214 of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP(206-214)) during the earliest stages of autoimmune diabetes. In this study, we probe the molecular determinants and biochemical consequences of IGRP(206-214)/K-d recognition by high-, intermediate-, and low-avidity autoreactive CD8(+) T cells, and we investigate the effects of genetic IGRP(206-214) silencing on their developmental biology. We find that differences in avidity for IGRP(206-214)/K-d map to CDR1 alpha and are associated with quantitative differences in CD3 epsilon proline-rich sequence exposure and Nck recruitment. Unexpectedly, we find that tolerance of high-avidity CD8(+) T cells, unlike their activation and recruitment into the pancreas, is dissociated from recognition of IGRP(206-214), particularly in adult mice. This finding challenges the view that tolerance of pathogenic autoreactive T cells is invariably triggered by recognition of the peptide-MHC complex that drives their activation in the periphery, indicating the existence of mechanisms of tolerance that are capable of sensing the avidity, hence pathogenicity of autoreactive T cells without the need to rely on local autoantigen availability. The Journal of Immunology, 2012, 189: 2975-2984.