Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells.
- Dimeloe S Immunobiology Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland. s.k.dimeloe@bham.ac.uk chess@uhbs.ch ch818@cam.ac.uk.
- Gubser P Immunobiology Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
- Loeliger J Immunobiology Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
- Frick C Immunobiology Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
- Develioglu L Immunobiology Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
- Fischer M Immunobiology Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
- Marquardsen F Immunodeficiency Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
- Bantug GR Immunobiology Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
- Thommen D Cancer Immunology Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
- Lecoultre Y Immunobiology Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
- Zippelius A Cancer Immunology Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
- Langenkamp A Roche Innovation Center Basel, 4070 Basel, Switzerland.
- Hess C Immunobiology Laboratory, Department of Biomedicine, University of Basel, 4031 Basel, Switzerland. s.k.dimeloe@bham.ac.uk chess@uhbs.ch ch818@cam.ac.uk.
- 2019-09-19
Published in:
- Science signaling. - 2019
Adenosine Triphosphate
Animals
CD4-Positive T-Lymphocytes
Humans
Interferon-gamma
Mitochondria
Mitochondrial Proton-Translocating ATPases
Neoplasms
Oxygen Consumption
Phosphorylation
Signal Transduction
Smad Proteins
Transforming Growth Factor beta
Tumor Microenvironment
English
Transforming growth factor-β (TGF-β) is produced by tumors, and increased amounts of this cytokine in the tumor microenvironment and serum are associated with poor patient survival. TGF-β-mediated suppression of antitumor T cell responses contributes to tumor growth and survival. However, TGF-β also has tumor-suppressive activity; thus, dissecting cell type-specific molecular effects may inform therapeutic strategies targeting this cytokine. Here, using human peripheral and tumor-associated lymphocytes, we investigated how tumor-derived TGF-β suppresses a key antitumor function of CD4+ T cells, interferon-γ (IFN-γ) production. Suppression required the expression and phosphorylation of Smad proteins in the TGF-β signaling pathway, but not their nuclear translocation, and depended on oxygen availability, suggesting a metabolic basis for these effects. Smad proteins were detected in the mitochondria of CD4+ T cells, where they were phosphorylated upon treatment with TGF-β. Phosphorylated Smad proteins were also detected in the mitochondria of isolated tumor-associated lymphocytes. TGF-β substantially impaired the ATP-coupled respiration of CD4+ T cells and specifically inhibited mitochondrial complex V (ATP synthase) activity. Last, inhibition of ATP synthase alone was sufficient to impair IFN-γ production by CD4+ T cells. These results, which have implications for human antitumor immunity, suggest that TGF-β targets T cell metabolism directly, thus diminishing T cell function through metabolic paralysis.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1126/scisignal.aav3334
- PMID 31530731
- Persistent URL
- https://sonar.ch/global/documents/92657
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