Identification of heme oxygenase-1--specific regulatory [CD8.sup.+] T cells in cancer patients

Treg deficiencies are associated with autoimmunity. Conversely, [CD4.sup.+] and [CD8.sup.+] Tregs accumulate in the tumor microenvironment and are associated with prevention of antitumor immunity and anticancer immunotherapy. Recently, [CD4.sup.+] Tregs have been much studied, but little is known about [CD8.sup.+] Tregs and the antigens they recognize. Here, we describe what we believe to be the first natural target for [CD8.sup.+] Tregs. Naturally occurring HLA-A2-restricted [CD8.sup.+] 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.sup.+] 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.sup.+][CD25.sup.+][CD127.sup.-] 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.sup.+] T cells in regulating cellular immune responses. Identification of potent antigen-specific [CD8.sup.+] Tregs may open new avenues for therapeutic interventions in both autoimmune diseases and cancer.
Introduction The immune system responds vigorously to invading pathogens nonself) while remaining unresponsive (tolerant) to the body's own components and circulating constituents (self). This tolerance to self components is the [...]