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T reg deficiencies are associated with autoimmunity. Conversely, CD4⁺ and CD8⁺ Tregs accumulate in the tumor microenvironment and are associated with prevention of antitumor immunity and anticancer immunotherapy. Recently, CD4⁺ Tregs have been much studied, but little is known about CD8⁺ Tregs and the antigens they recognize. Here, we describe what we believe to be the first natural target for CD8⁺ Tregs. Naturally occurring HLA-A2–restricted CD8⁺ T cells specific for the antiinflammatory molecule heme oxygenase-1 (HO-1) were able to suppress cellular immune responses with outstanding efficacy. HO-1–specific CD8⁺ T cells were detected ex vivo and in situ among T cells from cancer patients. HO-1–specific T cells isolated from the peripheral blood of cancer patients inhibited cytokine release, proliferation, and cytotoxicity of other immune cells. Notably, the inhibitory effect of HO-1–specific T cells was far more pronounced than that of conventional CD4⁺CD25⁺CD127^– Tregs. The inhibitory activity of HO-1–specific T cells seemed at least partly to be mediated by soluble factors. Our data link the cellular stress response to the regulation of adaptive immunity, expand the role of HO-1 in T cell–mediated immunoregulation, and establish a role for peptide-specific CD8⁺ T cells in regulating cellular immune responses. Identification of potent antigen-specific CD8⁺ Tregs may open new avenues for therapeutic interventions in both autoimmune diseases and cancer.