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 5

HO212-reactive T cells inhibit effector T cells and protect target cells.

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HO212-reactive T cells inhibit effector T cells and protect target cells...
(A) 4 × 105 CD8+ cells from an MM patient were assayed in ELISPOT for reactivity against the MART-127–35 epitope after culture alone (left ELISPOT well) or after culture with 100 autologous HLA-A2/HO212 pentamer+ T cells (right ELISPOT well) (B) 189 isolated HO212-reactive T cells were added to 3 × 105 cells from a specific T cell bulk culture generated from the same patient that harbored cells that recognized an HLA-A3–restricted TAA, i.e., RhoC (RAGLQVRKNK); after a 5-day incubation, the RhoC-specific T cells were analyzed in a conventional 51Cr-release assay using peptide-pulsed T2-A3 cells as target cells (white bars) or unpulsed T2-A3 cells (black bars). The same T cell bulk culture without the addition of HO-1–reactive T cells was used as control. The effector/target ratio was 60:1. (C) 241 isolated HO212-reactive T cells were added to 1.5 × 104 cells from a specific T cell clone generated from the same patient that harbored cells that recognized an HLA-A3 restricted TAA, i.e., RhoC (RAGLQVRKNK); after a 5-day incubation, the RhoC-specific T cells were analyzed in a conventional 51Cr-release assay using peptide-pulsed T2-A3 cells as target cells (white bars) or unpulsed T2-A3 cells (black bars). The same T cell clone without the addition of HO-1–reactive T cells was used as control. The effector/target ratio was 3:1. (D) FM3 MM cells either cultured with 433 HO-1–specific T cells or CD8+ T cells were used as target cells in a conventional 51Cr-release assay. Effector cells were an autologous MART-1–specific T cell clone. All measurements were made in duplicate. Error bars indicate SD.