Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells

Research output: Contribution to journalArticle

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Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells. / Dimeloe, Sarah; Gubser, P; Loeliger, J; Frick, C; Develioglu, Leyla; Fischer, M; Marquardsen, F; Bantug, Glenn R; Thommen, Daniela S; Lecoultre, Y; Zippelius, Alfred; Langenkamp, A; Hess, Christoph.

In: Science signaling, Vol. 12, No. 599, eaav3334, 17.09.2019.

Research output: Contribution to journalArticle

Harvard

Dimeloe, S, Gubser, P, Loeliger, J, Frick, C, Develioglu, L, Fischer, M, Marquardsen, F, Bantug, GR, Thommen, DS, Lecoultre, Y, Zippelius, A, Langenkamp, A & Hess, C 2019, 'Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells', Science signaling, vol. 12, no. 599, eaav3334. https://doi.org/10.1126/scisignal.aav3334

APA

Dimeloe, S., Gubser, P., Loeliger, J., Frick, C., Develioglu, L., Fischer, M., Marquardsen, F., Bantug, G. R., Thommen, D. S., Lecoultre, Y., Zippelius, A., Langenkamp, A., & Hess, C. (2019). Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells. Science signaling, 12(599), [eaav3334]. https://doi.org/10.1126/scisignal.aav3334

Vancouver

Author

Dimeloe, Sarah ; Gubser, P ; Loeliger, J ; Frick, C ; Develioglu, Leyla ; Fischer, M ; Marquardsen, F ; Bantug, Glenn R ; Thommen, Daniela S ; Lecoultre, Y ; Zippelius, Alfred ; Langenkamp, A ; Hess, Christoph. / Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells. In: Science signaling. 2019 ; Vol. 12, No. 599.

Bibtex

@article{6935165dec2a43c7a0db2ae7ca825548,
title = "Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells",
abstract = "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.",
author = "Sarah Dimeloe and P Gubser and J Loeliger and C Frick and Leyla Develioglu and M Fischer and F Marquardsen and Bantug, {Glenn R} and Thommen, {Daniela S} and Y Lecoultre and Alfred Zippelius and A Langenkamp and Christoph Hess",
year = "2019",
month = sep
day = "17",
doi = "10.1126/scisignal.aav3334",
language = "English",
volume = "12",
journal = "Science signaling",
issn = "1945-0877",
publisher = "American Association for the Advancement of Science",
number = "599",

}

RIS

TY - JOUR

T1 - Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells

AU - Dimeloe, Sarah

AU - Gubser, P

AU - Loeliger, J

AU - Frick, C

AU - Develioglu, Leyla

AU - Fischer, M

AU - Marquardsen, F

AU - Bantug, Glenn R

AU - Thommen, Daniela S

AU - Lecoultre, Y

AU - Zippelius, Alfred

AU - Langenkamp, A

AU - Hess, Christoph

PY - 2019/9/17

Y1 - 2019/9/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85072296209&partnerID=8YFLogxK

U2 - 10.1126/scisignal.aav3334

DO - 10.1126/scisignal.aav3334

M3 - Article

C2 - 31530731

VL - 12

JO - Science signaling

JF - Science signaling

SN - 1945-0877

IS - 599

M1 - eaav3334

ER -