Identification of heme oxygenase-1–specific regulatory CD8+ T cells in cancer patients
Mads Hald Andersen, … , Jürgen C. Becker, Per thor Straten
Mads Hald Andersen, … , Jürgen C. Becker, Per thor Straten
Published July 6, 2009
Citation Information: J Clin Invest. 2009;119(8):2245-2256. https://doi.org/10.1172/JCI38739.
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Research Article

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

Abstract

Treg 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.

Authors

Mads Hald Andersen, Rikke Bæk Sørensen, Marie K. Brimnes, Inge Marie Svane, Jürgen C. Becker, Per thor Straten

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Figure 1

Detection of HO-1–reactive T cells ex vivo.

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Detection of HO-1–reactive T cells ex vivo. (A) Peptide binding to HLA-A...
(A) Peptide binding to HLA-A2 as examined by the assembly assay. The binding of HO212 (QLFEELQEL) was compared with that of the known HLA-A2–restricted epitope HIV-1 pol476–484 (ILKEPVHGV). (B) An example of HO212-specific PBMCs from an RCC patient visualized by flow cytometry staining using HLA-A2/HO212–PE pentamer and CD8-allophycocyanin (APC-A). As negative controls, PBMCs from the same patient were stained with CD8-allophycocyanin as well as the following pentamer complexes: HLA-A2/HIV-1 pol476–484–PE, HLA-A2/HIV-1 gag76–84–PE, and HLA-A2 MART-126–35–PE (non-MM patients). (C) PBMCs from healthy donors or from patients with BC, MM, or RCC were stained with the pentamer complex HLA-A2/HO212 and analyzed by flow cytometry ex vivo. Point represent patients, and horizontal bars represent median frequency of specific cells.