Editors' ChoiceImmunology

Immune suppression with complex III

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Sci. Signal.  29 Jan 2019:
Vol. 12, Issue 566, eaaw7886
DOI: 10.1126/scisignal.aaw7886

Loss of mitochondrial complex III in regulatory T cells reduces their suppressive activity without affecting their survival.

Regulatory T cells (Treg cells) suppress the activity of effector T cells, thus preventing autoimmunity. Compared with other effector CD4+ T cell subsets, Treg cells depend more on mitochondrial respiration for their energy requirements. Weinberg et al. generated mice with a Treg cell–specific deletion of Rieske iron-sulfur protein (RISP), an essential component of mitochondrial complex III (RISP KO mice). Compared with control mice, the RISP KO mice showed decreased mitochondrial respiration and increased glycolytic metabolism and died within 4 weeks after birth due to systemic inflammation. Although the RISP KO mice had similar numbers of Treg cells to those of control mice, the RISP KO Treg cells had impaired suppressive activity in vivo and in vitro. Mice with a tamoxifen-inducible, Treg cell–specific deletion of the complex III subunit QPC (QPC iKO mice) also exhibited systemic inflammatory disease despite having normal numbers of Treg cells. Loss of QPC had no effect on the stability of the protein Foxp3, a critical transcriptional regulator of Treg cell identity. Whereas B16 melanoma cells formed tumors when injected into wild-type mice, they failed to do so in QPC iKO mice after tamoxifen treatment, indicating the importance of mitochondrial respiration to the suppressive function of Treg cells in vivo. DNA methylation and RNA sequencing analyses correlated increased DNA hypermethylation with decreased expression of genes associated with Treg cell function in cells lacking mitochondrial complex III; however, the expression of canonical Treg cell genes, including Foxp3, was unaffected. Together, these data suggest that Treg cells require mitochondrial complex III to maintain the expression of genes necessary for their suppressive function.

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