Mitochondrial complex III is essential for suppressive function of regulatory T cells
Obstract
Recent studies have demonstrated that Treg cells exhibit a unique metabolic profile, characterized by an increase in mitochondrial metabolism relative to other CD4+ effector subsets. Furthermore, the Treg cell lineage-defining transcription factor, Foxp3, has been shown to promote respiration; 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 demethylases. Thus, Treg cells require mitochondrial complex III to maintain immune regulatory gene expression and suppressive function.
Result
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Figure 1
Loss of complex III in Treg cells results in a lethal inflammatory disorder and loss of Treg cell suppressive function
RISP是线粒体复合物Ⅲ重要subunit
ECAR和OCR都是细胞能量代谢检测，检测细胞氧化磷酸化和糖酵解能力
RISP KO mice had fewer CD25low Treg cells than wild-type mice, and CD25 expression was increased in CD25+Foxp3+ cells from RISP KO mice in comparison to in CD25+Foxp3+ cells from wild-type mice. Expression of the other hallmark Treg cell markers CTLA-4, GITR and EOS was also increased in RISP-deficient Treg cells relative to wild-type Treg cells, whereas HELIOS expression was unchanged
Treg cells deficient in RISP displayed increased surface expression of activation markers and similar rates of proliferation, as indicated by Ki-67 staining, relative to wild-type cells
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Figure2
Loss of complex III in Treg cells impairs suppressive function
QPC iKO (n = 4) mice three months after administration of three doses
without altering Foxp3 expression
QPC:complex III subunit
CD44 co-stimulation promotes expression of FoxP3, in part through production of IL-2. This promotion of IL-2 production was also resistant to Cyclosporine A treatment, suggesting that CD44 costimulation may promote IL-2 production through bypassing FoxP3-mediated suppression of NFAT. CD44 co-stimulation increased production of IL-10 in a partially Il-2 dependant manner and also promoted cell-surface TGF-β expression.
引用：CD44 co-stimulation promotes FoxP3+ regulatory T-cell persistence and function via production of IL-2, IL-10 and TGF-beta
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Figure3
Complex III deficiency in Treg cells results in a cell-autonomous impairment in expression of genes associated with Treg cell suppressive function, along with DNA hypermethylation
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Figure4
Inhibition of different electron transport chain complexes in regulatory T cells results in distinct alterations in metabolites and gene expression
individual mitochondrial respiratory chain inhibitors targeting either complex I (piercidin), complex II (3-nitropropionic acid (3-NPA)), or complex III (antimycin A)
These results suggest that inhibition at different complexes of the respiratory chain result in differential changes in metabolite concentrations, thereby causing distinct changes in gene expression. It will be informative to determine whether the conditional loss of different respiratory chain complexes within Treg cells causes distinct pathologies in mice
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