Mitochondrial complex III is essential for suppressive function of regulatory T cells

Samuel E. Weinberg, Benjamin Singer, Elizabeth M. Steinert, Carlos A. Martinez, Manan M. Mehta, Inmaculada Martínez-Reyes, Peng Gao, Kathryn A. Helmin, Hiam Abdala-Valencia, Laura A. Sena, Paul T Schumacker, Laurence A. Turka, Navdeep Chandel

Research output: Contribution to journalLetter

4 Citations (Scopus)

Abstract

Regulatory T cells (T reg cells), a distinct subset of CD4 + T cells, are necessary for the maintenance of immune self-tolerance and homeostasis 1,2 . Recent studies have demonstrated that T reg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4 + effector subsets 3,4 . Furthermore, the T reg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration 5,6 ; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of T reg cells. Here we report that T reg cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting T reg cell number. Mice that lack mitochondrial complex III specifically in T reg cells displayed a loss of T cell-suppression capacity without altering T reg cell proliferation and survival. T reg cells deficient in complex III showed decreased expression of genes associated with T reg function, whereas Foxp3 expression remained stable. Loss of complex III in T reg cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases 7 . Thus, T reg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.

Original languageEnglish (US)
Pages (from-to)495-499
Number of pages5
JournalNature
Volume565
Issue number7740
DOIs
StatePublished - Jan 24 2019

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Electron Transport Complex III
Regulatory T-Lymphocytes
Electron Transport
T-Lymphocytes
Self Tolerance
Gene Expression
Immune Tolerance
Metabolome
T-Lymphocyte Subsets
Succinic Acid
Cell Lineage
DNA Methylation
Regulator Genes
Cell Survival
Respiration
Homeostasis
Transcription Factors
Cell Count
Maintenance
Cell Proliferation

ASJC Scopus subject areas

  • General

Cite this

Weinberg, S. E., Singer, B., Steinert, E. M., Martinez, C. A., Mehta, M. M., Martínez-Reyes, I., ... Chandel, N. (2019). Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature, 565(7740), 495-499. https://doi.org/10.1038/s41586-018-0846-z
Weinberg, Samuel E. ; Singer, Benjamin ; Steinert, Elizabeth M. ; Martinez, Carlos A. ; Mehta, Manan M. ; Martínez-Reyes, Inmaculada ; Gao, Peng ; Helmin, Kathryn A. ; Abdala-Valencia, Hiam ; Sena, Laura A. ; Schumacker, Paul T ; Turka, Laurence A. ; Chandel, Navdeep. / Mitochondrial complex III is essential for suppressive function of regulatory T cells. In: Nature. 2019 ; Vol. 565, No. 7740. pp. 495-499.
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abstract = "Regulatory T cells (T reg cells), a distinct subset of CD4 + T cells, are necessary for the maintenance of immune self-tolerance and homeostasis 1,2 . Recent studies have demonstrated that T reg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4 + effector subsets 3,4 . Furthermore, the T reg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration 5,6 ; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of T reg cells. Here we report that T reg cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting T reg cell number. Mice that lack mitochondrial complex III specifically in T reg cells displayed a loss of T cell-suppression capacity without altering T reg cell proliferation and survival. T reg cells deficient in complex III showed decreased expression of genes associated with T reg function, whereas Foxp3 expression remained stable. Loss of complex III in T reg cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases 7 . Thus, T reg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.",
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Weinberg, SE, Singer, B, Steinert, EM, Martinez, CA, Mehta, MM, Martínez-Reyes, I, Gao, P, Helmin, KA, Abdala-Valencia, H, Sena, LA, Schumacker, PT, Turka, LA & Chandel, N 2019, 'Mitochondrial complex III is essential for suppressive function of regulatory T cells' Nature, vol. 565, no. 7740, pp. 495-499. https://doi.org/10.1038/s41586-018-0846-z

Mitochondrial complex III is essential for suppressive function of regulatory T cells. / Weinberg, Samuel E.; Singer, Benjamin; Steinert, Elizabeth M.; Martinez, Carlos A.; Mehta, Manan M.; Martínez-Reyes, Inmaculada; Gao, Peng; Helmin, Kathryn A.; Abdala-Valencia, Hiam; Sena, Laura A.; Schumacker, Paul T; Turka, Laurence A.; Chandel, Navdeep.

In: Nature, Vol. 565, No. 7740, 24.01.2019, p. 495-499.

Research output: Contribution to journalLetter

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T1 - Mitochondrial complex III is essential for suppressive function of regulatory T cells

AU - Weinberg, Samuel E.

AU - Singer, Benjamin

AU - Steinert, Elizabeth M.

AU - Martinez, Carlos A.

AU - Mehta, Manan M.

AU - Martínez-Reyes, Inmaculada

AU - Gao, Peng

AU - Helmin, Kathryn A.

AU - Abdala-Valencia, Hiam

AU - Sena, Laura A.

AU - Schumacker, Paul T

AU - Turka, Laurence A.

AU - Chandel, Navdeep

PY - 2019/1/24

Y1 - 2019/1/24

N2 - Regulatory T cells (T reg cells), a distinct subset of CD4 + T cells, are necessary for the maintenance of immune self-tolerance and homeostasis 1,2 . Recent studies have demonstrated that T reg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4 + effector subsets 3,4 . Furthermore, the T reg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration 5,6 ; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of T reg cells. Here we report that T reg cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting T reg cell number. Mice that lack mitochondrial complex III specifically in T reg cells displayed a loss of T cell-suppression capacity without altering T reg cell proliferation and survival. T reg cells deficient in complex III showed decreased expression of genes associated with T reg function, whereas Foxp3 expression remained stable. Loss of complex III in T reg cells increased DNA methylation as well as the metabolites 2-hydroxyglutarate (2-HG) and succinate that inhibit the ten-eleven translocation (TET) family of DNA demethylases 7 . Thus, T reg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.

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Weinberg SE, Singer B, Steinert EM, Martinez CA, Mehta MM, Martínez-Reyes I et al. Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature. 2019 Jan 24;565(7740):495-499. https://doi.org/10.1038/s41586-018-0846-z