GSE125204
Calcium signaling controls pathogenic Th17 cell-mediated inflammation by regulating mitochondrial metabolism
Pathogenic Th17 cells play an important role in many autoimmune and inflammatory  diseases. Their function is dependent on signaling through the T cell receptor (TCR)  and cytokines that activate the transcription factor signal transducer and activator of  transcription 3 (STAT3). TCR engagement activates stromal interaction molecule 1  (STIM1) and calcium (Ca2+) influx through the Ca2+ release-activated Ca2+ (CRAC)  channel. We here show that deletion of STIM1 and Ca2+ influx in T cells expressing a  hyperactive form of STAT3 (STAT3C) attenuates pathogenic Th17 cell function and  multiorgan inflammation associated with STAT3C expression. Deletion of STIM1 in  pathogenic Th17 cells impairs the expression of nuclear encoded mitochondrial  electron transport chain genes and oxidative phosphorylation (OXPHOS) but enhances  reactive oxygen species (ROS) production. Deletion of STIM1 or inhibition of OXPHOS  is associated with impaired Th17 cell function and a non-pathogenic Th17 gene  expression signature. Our findings establish STIM1 and Ca2+ signals as a critical  regulator of OXPHOS and oxidative stress in pathogenic Th17 cells and multiorgan  inflammation. Overall design: Comparing the transcriptome of in vitro differentiated pathogenic Th17 cells from Stat3CSTOPf/flCD4Cre and Stim1fl/flStat3CSTOPfl/flCD4Cre mice