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

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 T reg cell suppressive capacity, stability, and survival. Here we report that T reg cell-specific ablation of mitochondrial respiratory chain complex III results in the development of a fatal inflammatory disease early in life, without impacting T reg cell number. Mice lacking mitochondrial complex III specifically in T reg cells displayed a loss of T reg cell suppressive capacity without altering T reg cell proliferation and survival. T reg cells deficient in complex III had decreased expression of genes associated with T reg function while maintaining stable Foxp3 expression. 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.

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

“…However, it is also known that some facets of immunosurveillance (and in particular T cell expansion) may rely on OXPHOS . Interestingly, inhibition of complex III (by conditional knockout of Uqcrsf1 gene which encodes the Rieske iron–sulfur protein driven by a Cre recombinase placed under the control of the Foxp3 promoter), interferes with the function of regulatory T cells . Whether this effect simply resides in a reduction of regulatory T fitness rather than a specific effect that differentiates regulatory T from positive immune effectors has not been determined.…”

“…64 Interestingly, inhibition of complex III (by conditional knockout of Uqcrsf1 gene which encodes the Rieske iron-sulfur protein driven by a Cre recombinase placed under the control of the Foxp3 promoter), interferes with the function of regulatory T cells. 65 Whether this effect simply resides in a reduction of regulatory T fitness rather than a specific effect that differentiates regulatory T from positive immune effectors has not been determined. Thus, the question remains open, whether systemic inhibition of distinct respiratory chain complexes may have "specific" immunostimulatory effects via the suppression of regulatory T function.…”

MitoRACE: evaluating mitochondrial function in vivo and in single cells with subcellular resolution using multiphoton NADH autofluorescence

“…; Weinberg et al . ), and in vivo assessments of high energy phosphates (Younkin et al . ), oxygen saturation (Grassi et al .…”

“…As a result, assessment of mitochondrial function has been a major area of interest across much of biomedical research for decades (Picard et al 2016). Classical in vitro measures of oxygen consumption rates in mitochondria removed from the cellular environment or cells in culture have provided a wide variety of metabolic insights (Pesta & Gnaiger, 2012;Hebert-Chatelain et al 2016;Weinberg et al 2019), and in vivo assessments of high energy phosphates (Younkin et al 1984), oxygen saturation Ryan et al 2013), and carbon labelling (Befroy et al 2007) have provided integrative, non-invasive measures of oxidative metabolic rates in humans. However, each of the above techniques only provide a single bulk assessment of generally many thousands of cells.…”

Metabolic determinants of lupus pathogenesis

“…223 Succinate builds up in Treg cells in which mt complex III has been deleted and contributes to their dysfunction. 224 In addition, a novel CXCR5 -CXCR3 + PD1 hi CD4 + T cell population provides help to B cells in the blood and the tubular interstitium of SLE patients in the form of succinate, along with IL-10, rather than IL-21. 225 Succinate accumulates in these helper T cells as a result of stimulation by oxidized mtDNA, high levels of ROS production and reverse electron transport, and it stabilizes HIF1α and increases glycolysis.…”