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The inflammatory lesion at the pancreatic islet in type 1 diabetes (T1D) contains a heterogeneous infiltrate of T cells. In human and mouse studies, a large majority (98 to 99%) of the cytotoxic CD8+ T cells (CTLs) within islets are not specific to any islet antigen and are thought to passively add to tissue damage. We show by intravital confocal microscopy the opposite, immune-regulatory function of this cohort of CTLs. Diabetes did not develop in mice with islets showing high levels of infiltration of non–islet-specific CTLs not recognizing local antigens. Accumulation of such CTLs resulted in lower activation and proliferation of islet-specific CTLs, leading them to enter a state of unresponsiveness due to limited access to antigens at the inflammatory lesion. This nonspecific suppression by nonautoreactive CTLs was recapitulated in a model of viral meningitis, may explain viral interference in autoimmunity, and provides insight into the regulation of organ-specific autoimmune responses.