期刊
CELL REPORTS
卷 30, 期 6, 页码 1898-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.01.022
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资金
- National Institutes of Health (NIH) [R01 AI113007]
- O'Brien Center [P30 DK079337]
- American Heart Association [16PRE29650004]
- AMC21 Award from the UAB School of Medicine
- Blue Sky Award from the UAB School of Medicine
- NIH [P30 AI27667, P30 AR048311]
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.
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