Regulatory T cells (Treg cells), a distinct subset of CD4+ T cells, are necessary for the maintenance of immune self-tolerance and homeostasis1,2. Recent studies have demonstrated that Treg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets3,4. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration5,6; however, it remains unknown whether the mitochondrial respiratory chain is required for the T cell-suppression capacity, stability and survival of Treg cells. Here we report that Treg cell-specific ablation of mitochondrial respiratory chain complex III in mice results in the development of fatal inflammatory disease early in life, without affecting Treg cell number. Mice that lack mitochondrial complex III specifically in Treg cells displayed a loss of T cell-suppression capacity without altering Treg cell proliferation and survival. Treg cells deficient in complex III showed decreased expression of genes associated with Treg function, whereas Foxp3 expression remained stable. Loss of complex III in Treg 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 demethylases7. Thus, Treg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.
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All RNA-seq and DNA methylation data have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE120452. All other data from the manuscript are available from the corresponding author on request.
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We thank Robert H. Lurie Cancer Center Flow Cytometry facility and Metabolomics Core, and the High Throughput RNA-Seq Center, within the Division of Pulmonary and Critical Care and the Mouse Histology and Phenotyping Laboratory at Northwestern University. We thank K. Nam for processing of RNA sequencing samples. This research was supported in part through the computational resources and staff contributions provided by Quest high performance computing cluster. This work was supported by the NIH (R35CA197532, 5P01AG049665, 5P01HL071643) to N.S.C., and NIH (T32 T32HL076139) to S.E.W. B.D.S was supported by NIH K08HL128867 and the Francis Family Foundation’s Parker B. Francis Research Opportunity Award. E.M.S is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute.
Nature thanks R. Johnson and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Seminars in Immunopathology (2019)