Mitochondrial Oxidative Phosphorylation Regulates the Fate Decision between Pathogenic Th17 and Regulatory T Cells

Understanding metabolic pathways that regulate Th17 development is important to broaden therapeutic options for Th17-mediated autoimmunity. Here, we report a pivotal role of mitochondrial oxidative phosphorylation (OXPHOS) for lineage specification toward pathogenic Th17 differentiation. Th17 cells rapidly increase mitochondrial respiration during development, and this is necessary for metabolic reprogramming following T cell activation. Surprisingly, specific inhibition of mitochondrial ATP synthase ablates Th17 pathogenicity in a mouse model of autoimmunity by preventing Th17 pathogenic signature gene expression. Notably, cells activated under OXPHOS-inhibited Th17 conditions preferentially express Foxp3, rather than Th17 genes, and become suppressive Treg cells. Mechanistically, OXPHOS promotes the Th17 pioneer transcription factor, BATF, and facilitates T cell receptor (TCR) and mTOR signaling. Correspondingly, overexpression of BATF rescues Th17 development when ATP synthase activity is restricted. Together, our data reveal a regulatory role of mitochondrial OXPHOS in dictating the fate decision between Th17 and Treg cells by supporting early molecular events necessary for Th17 commitment. [Display omitted] •CD4 T cells rapidly increase mitochondrial respiration during Th17 differentiation•OXPHOS is essential for Th17 cell pathogenicity in a mouse model of MS•Mitochondrial respiration shapes the Th17 and Treg cell fate decision•OXPHOS facilitates TCR and mTOR signaling, which in turn support BATF induction Shin et al. report that ATP-linked mitochondrial respiration controls the Th17 and Treg cell fate decision by supporting TCR signaling and Th17-associated molecular events. Inhibition of mitochondrial OXPHOS ablates Th17 pathogenicity in a mouse model of MS and results in generation of functionally suppressive Treg cells under Th17 conditions.