Fasting-induced FOXO4 blunts human CD4+ T helper cell responsiveness

Abstract Intermittent fasting blunts inflammation in asthma and rheumatoid arthritis, suggesting that may be exploited as an immune-modulatory intervention. However, mechanisms underpinning anti-inflammatory effects of remain poorly characterized. Here, we show humans is sufficient to blunt CD4+ T helper cell responsiveness. RNA-seq flow cytometric immunophenotyping peripheral blood mononuclear cells (PBMCs) from volunteers subjected overnight or 24-hour fasting, 3-hours refeeding implicate activation differentiation. Transcriptomic analysis reveal the longer fast-duration has a more robust effect on biology. Through bioinformatic analyses, identify transcription factor FOXO4 its canonical target FKBP5 potential fasting-responsive regulatory axis. Genetic gain- loss-of-function modulate Th1 Th17 cytokine production. Moreover, find fasting-induced genetic overexpression downregulate mTORC1 signaling suppress STAT1/3 activation. Our results FOXO4-FKBP5 novel fasting-induced, STAT-mediated, pathway human