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

Intermittent fasting blunts inflammation in asthma(1) and rheumatoid arthritis(2), suggesting that fasting may be exploited as an immune-modulatory intervention. However, mechanisms underpinning anti-inflammatory effects of fasting remain poorly characterized(3, 4, 5). Here, we show that fasting in humans is sufficient to blunt CD4(+) T helper cell responsiveness. RNA-seq and flow cytometric immunophenotyping of peripheral blood mononuclear cells (PBMCs) from volunteers subjected to overnight or 24-hour fasting, and 3-hours of refeeding implicate that fasting blunts CD4(+) T helper cell activation and differentiation. Transcriptomic analysis reveal that the longer fast-duration has a more robust effect on CD4(+) T cell biology. Through bioinformatic analyses, we identify the transcription factor FOXO4 and its canonical target FKBP5 as a potential fasting-responsive regulatory axis. Genetic gain- or loss-of-function of FOXO4 and FKBP5 is sufficient to modulate Th1 and Th17 cytokine production. Moreover, we find that fasting-induced or genetic overexpression of FOXO4 and FKBP5 is sufficient to downregulate mTORC1 signaling and suppress STAT1/3 activation. Our results identify FOXO4-FKBP5 as a novel fasting-induced, STAT-mediated, regulatory pathway to blunt human CD4(+) T helper cell responsiveness.