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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 Article has an altmetric score of 7

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

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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 6

Direct comparison of inhibitory capacity of HO212-reactive CD8+ T cells and conventional Tregs.

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Direct comparison of inhibitory capacity of HO212-reactive CD8+ T cells ...
Fifty-thousand PKH26-labeled autologous PBMCs were cocultured with CD4+CD25hiCD127– Tregs, CD4+CD25–CD127+ T cells, HO212-reactive CD8+ T cells, or CMV-specific CD8+ T cells for 6 days (cell numbers are indicated in the figure). Cells were stained with anti-CD4 and anti-CD8 antibodies and proliferation was determined by dilution of PKH26. All measurements were made in duplicate. (A) Proliferation of CD8+ T cells either without stimulation or after CD3 stimulation alone or in cocultures with conventional Tregs, HO212-reactive CD8+ T cells, or relevant controls. Data depict triplicates (CD4+CD25hiCD127– Tregs or CD4+CD25–CD127+ T cells) and single experiment (HO212-reactive CD8+ T or CMV-specific CD8+ T cells). Shown are representative results of 2 independent experiments. (B) Percentage inhibition of CD8+ T cell proliferation induced by conventional Tregs or HO212-reactive CD8+ T cells. (C) Proliferation of CD4+ T cells either without stimulation or after CD3 stimulation alone or i cocultures with conventional Tregs, HO212-reactive CD8+ T cells, or relevant control cells. Error bars indicate SD. (D) Percentage inhibition of CD4+ T cell proliferation induced by conventional Tregs or HO212-reactive CD8+ T cells. (E) Sorting strategy for CD4+CD25hiCD127– Tregs and CD4+CD25–CD127+ T cells.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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