Here we find that CD8⁺ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49⁺CD8⁺ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8⁺ T cells efficiently eliminated pathogenic gliadin-specific CD4⁺ T cells from celiac disease patients’ leukocytes in vitro. We also find elevated levels of KIR⁺CD8⁺ T cells, but not CD4⁺ regulatory T cells, in COVID-19 patients, which correlated with disease severity and vasculitis. Selective ablation of Ly49⁺CD8⁺ T cells in virus-infected mice led to autoimmunity post infection. Our results indicate that in both species, these regulatory CD8⁺ T cells act uniquely to suppress pathogenic T cells in autoimmune and infectious diseases.