Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming

Hao Wu; Xiufeng Zhao; Sophia M. Hochrein; Miriam Eckstein; Gabriela F. Gubert; Konrad Knöpper; Ana Maria Mansilla; Arman Öner; Remi Doucet-Ladevèze; Werner Schmitz; Bart Ghesquière; Sebastian Theurich; Jan Dudek; Georg Gasteiger; Alma Zernecke; Sebastian Kobold; Wolfgang Kastenmüller; Martin Vaeth

doi:10.1038/s41467-023-42634-3

Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming

Hao Wu, Xiufeng Zhao, Sophia M. Hochrein, Miriam Eckstein, Gabriela F. Gubert, Konrad Knöpper, Ana Maria Mansilla, Arman Öner, Remi Doucet-Ladevèze, Werner Schmitz, Bart Ghesquière, Sebastian Theurich, Jan Dudek, Georg Gasteiger, Alma Zernecke, Sebastian Kobold, Wolfgang Kastenmüller, Martin Vaeth^*

^*Corresponding author for this work

Clinic of Dermatology, Allergology and Venerology

196 Citations (Scopus)

Abstract

T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.

Original language	English
Article number	6858
Journal	Nature Communications
Volume	14
Issue number	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-023-42634-3
Publication status	Published - 12.2023

Funding

We thank Jeffery D. Molkentin (Cincinnati Children’s Hospital Medical Center, OH, USA), Anjana Rao (La Jolla Institute for Immunology, CA, USA) and Tobias Bald (University Hospital Bonn, Germany) for providing Slc25a3 mice, CAR constructs and MC38 cells, respectively. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) SFB-TR 124/3 (“FungiNet”), project number 210879364, SFB 1526/1 (“PANTAU”), project number 454193335, SFB 1583/1 (“DECIDE”), project number 492620490 and individual grants VA882/2-1 and VA882/3-2 (to M.V.). Further funding was provided by the SFB 1525/1 (“Cardio-Immune-Interfaces”), project number 453989101 (to M.V., A.Z., W.K., G.G. and J.D.) and SFB-TR 338/1 (“LETSimmun”), project number 452881907 (to. M.V. G.G., W.K., S.T. and S.K.). Our study was supported by the Interdisciplinary Center for Clinical Research (supporting the Core Units FACS and SysMed) and by the Bavarian ministry of economic affairs, Regional Development and energy within the project “Single Cell Analysis in personalized medicine” at the Helmholtz-Institute for RNA-based Infection Research (HIRI). We would like to thank Camila Takeno Cologna, Wesley Vermaelen, Anton Willems (VIB Metabolomics Expertise Center), Thorsten Bischler (IZKF Würzburg), and Fabian Imdahl (HIRI) for excellent technical assistance. fl/fl We thank Jeffery D. Molkentin (Cincinnati Children’s Hospital Medical Center, OH, USA), Anjana Rao (La Jolla Institute for Immunology, CA, USA) and Tobias Bald (University Hospital Bonn, Germany) for providing Slc25a3fl/flmice, CAR constructs and MC38 cells, respectively. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) SFB-TR 124/3 (“FungiNet”), project number 210879364, SFB 1526/1 (“PANTAU”), project number 454193335, SFB 1583/1 (“DECIDE”), project number 492620490 and individual grants VA882/2-1 and VA882/3-2 (to M.V.). Further funding was provided by the SFB 1525/1 (“Cardio-Immune-Interfaces”), project number 453989101 (to M.V., A.Z., W.K., G.G. and J.D.) and SFB-TR 338/1 (“LETSimmun”), project number 452881907 (to. M.V. G.G., W.K., S.T. and S.K.). Our study was supported by the Interdisciplinary Center for Clinical Research (supporting the Core Units FACS and SysMed) and by the Bavarian ministry of economic affairs, Regional Development and energy within the project “Single Cell Analysis in personalized medicine” at the Helmholtz-Institute for RNA-based Infection Research (HIRI). We would like to thank Camila Takeno Cologna, Wesley Vermaelen, Anton Willems (VIB Metabolomics Expertise Center), Thorsten Bischler (IZKF Würzburg), and Fabian Imdahl (HIRI) for excellent technical assistance.

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)
Centers: Center for Research on Inflammation of the Skin (CRIS)

DFG Research Classification Scheme

2.22-19 Dermatology
2.21-05 Immunology

Access to Document

10.1038/s41467-023-42634-3

Cite this

Wu, H., Zhao, X., Hochrein, S. M., Eckstein, M., Gubert, G. F., Knöpper, K., Mansilla, A. M., Öner, A., Doucet-Ladevèze, R., Schmitz, W., Ghesquière, B., Theurich, S., Dudek, J., Gasteiger, G., Zernecke, A., Kobold, S., Kastenmüller, W., & Vaeth, M. (2023). Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming. Nature Communications, 14(1), Article 6858. https://doi.org/10.1038/s41467-023-42634-3

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abstract = "T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.",

author = "Hao Wu and Xiufeng Zhao and Hochrein, \{Sophia M.\} and Miriam Eckstein and Gubert, \{Gabriela F.\} and Konrad Kn{\"o}pper and Mansilla, \{Ana Maria\} and Arman {\"O}ner and Remi Doucet-Ladev{\`e}ze and Werner Schmitz and Bart Ghesqui{\`e}re and Sebastian Theurich and Jan Dudek and Georg Gasteiger and Alma Zernecke and Sebastian Kobold and Wolfgang Kastenm{\"u}ller and Martin Vaeth",

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Wu, H, Zhao, X, Hochrein, SM, Eckstein, M, Gubert, GF, Knöpper, K, Mansilla, AM, Öner, A, Doucet-Ladevèze, R, Schmitz, W, Ghesquière, B, Theurich, S, Dudek, J, Gasteiger, G, Zernecke, A, Kobold, S, Kastenmüller, W & Vaeth, M 2023, 'Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming', Nature Communications, vol. 14, no. 1, 6858. https://doi.org/10.1038/s41467-023-42634-3

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T1 - Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming

AU - Wu, Hao

AU - Zhao, Xiufeng

AU - Hochrein, Sophia M.

AU - Eckstein, Miriam

AU - Gubert, Gabriela F.

AU - Knöpper, Konrad

AU - Mansilla, Ana Maria

AU - Öner, Arman

AU - Doucet-Ladevèze, Remi

AU - Schmitz, Werner

AU - Ghesquière, Bart

AU - Theurich, Sebastian

AU - Dudek, Jan

AU - Gasteiger, Georg

AU - Zernecke, Alma

AU - Kobold, Sebastian

AU - Kastenmüller, Wolfgang

AU - Vaeth, Martin

PY - 2023/12

Y1 - 2023/12

N2 - T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.

AB - T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress, which inhibits the proteasomal degradation of hypoxia-inducible factor 1α (HIF-1α) and promotes the transcriptional and metabolic reprogramming of Tpex cells into terminally exhausted T cells. Our findings also bear clinical significance, as metabolic engineering of chimeric antigen receptor (CAR) T cells is a promising strategy to enhance the stemness and functionality of Tpex cells for cancer immunotherapy.

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Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

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CRC 1526, PANTAU: Pathomechanisms of Antibody-mediated Autoimmunity

Cite this

Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

Access to Document

Other files and links

Fingerprint

Projects

CRC 1526, PANTAU: Pathomechanisms of Antibody-mediated Autoimmunity

Cite this