In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8⁺ T cell inflammation

A current paradigm states that non-antigen-specific inflammatory cues attract noncognate, bystander T cell specificities to sites of infection and autoimmune inflammation. Here we show that cues emanating from a tissue undergoing spontaneous autoimmune inflammation cannot recruit naive or activated bystander T cell specificities in the absence of local expression of cognate antigen. We monitored the recruitment of CD8⁺ T cells specific for the prevalent diabetogenic epitope islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)₂₀₆₋₂₁₄ in gene-targeted nonobese diabetic (NOD) mice expressing a T cell "invisible" IGRP₂₀₆₋₂₁₄ sequence. These mice developed islet inflammation and diabetes with normal incidence and kinetics, but their inflammatory lesions could recruit neither naive (endogenous or exogenous) nor ex vivo-activated IGRP₂₀₆₋₂₁₄-reactive CD8⁺ T cells. Conversely, IGRP₂₀₆₋₂₁₄-reactive, but not nonautoreactive CD8⁺ T cells rapidly homed to and accumulated in the inflamed islets of wild-type NOD mice. Our results indicate that CD8⁺ T cell recruitment to a site of autoimmune inflammation results from an active process that is strictly dependent on local display of cognate pMHC and suggest that CD8⁺ T cells contained in extralymphoid autoimmune lesions are largely autoreactive.