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

Samuel E. Weinberg, Benjamin D. 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 S. Chandel*

*Corresponding author for this work

Research output: Contribution to journalLetter

44 Scopus citations

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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Cite this

Weinberg, S. E., Singer, B. D., Steinert, E. M., Martinez, C. A., Mehta, M. M., Martínez-Reyes, I., Gao, P., Helmin, K. A., Abdala-Valencia, H., Sena, L. A., Schumacker, P. T., Turka, L. A., & Chandel, N. S. (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