Identification of heme oxygenase-1-specific regulatory CD8+ T cells in cancer patients

Treg deficiencies are associated with autoimmunity. Conversely, CD4(+) and CD8(+) Tregs accumulate in the tumor microenviromnent 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.