Laboratory of Mitochondrial Biology and Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Bioinformatics and Computational Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Nat Metab. 2021 Mar;3(3):318-326. doi: 10.1038/s42255-021-00356-0. Epub 2021 Mar 15.
Intermittent fasting blunts inflammation in asthma and rheumatoid arthritis, suggesting that fasting may be exploited as an immune-modulatory intervention. However, the mechanisms underpinning the anti-inflammatory effects of fasting are poorly characterized. Here, we show that fasting in humans is sufficient to blunt CD4 T helper cell responsiveness. RNA sequencing and flow cytometry immunophenotyping of peripheral blood mononuclear cells from volunteers subjected to overnight or 24-h fasting and 3 h of refeeding suggest that fasting blunts CD4 T helper cell activation and differentiation. Transcriptomic analysis reveals that longer fasting has a more robust effect on CD4 T-cell biology. Through bioinformatics analyses, we identify the transcription factor FOXO4 and its canonical target FK506-binding protein 5 (FKBP5) as a potential fasting-responsive regulatory axis. Genetic gain- or loss-of-function of FOXO4 and FKBP5 is sufficient to modulate T1 and T17 cytokine production. Moreover, we find that fasting-induced or genetic overexpression of FOXO4 and FKBP5 is sufficient to downregulate mammalian target of rapamycin complex 1 signalling and suppress signal transducer and activator of transcription 1/3 activation. Our results identify FOXO4-FKBP5 as a new fasting-induced, signal transducer and activator of transcription-mediated regulatory pathway to blunt human CD4 T helper cell responsiveness.
间歇性禁食可减轻哮喘和类风湿关节炎的炎症，表明禁食可能被用作免疫调节干预措施。然而，禁食的抗炎作用的机制还描述不清。在这里，我们表明禁食足以减弱 CD4 辅助性 T 细胞的反应性。对志愿者进行一夜或 24 小时禁食和 3 小时再进食后外周血单核细胞进行 RNA 测序和流式细胞术免疫表型分析表明，禁食会减弱 CD4 辅助性 T 细胞的激活和分化。转录组分析表明，较长时间的禁食对 CD4 T 细胞生物学有更强的影响。通过生物信息学分析，我们确定转录因子 FOXO4 及其典型靶标 FK506 结合蛋白 5（FKBP5）作为潜在的禁食反应调节轴。FOXO4 和 FKBP5 的遗传功能获得或丧失足以调节 T1 和 T17 细胞因子的产生。此外，我们发现，禁食诱导或遗传过表达 FOXO4 和 FKBP5 足以下调雷帕霉素复合物 1 信号和抑制信号转导子和转录激活子 1/3 的激活。我们的结果确定 FOXO4-FKBP5 作为一种新的禁食诱导的、信号转导子和转录激活子介导的调节途径，以减弱人类 CD4 辅助性 T 细胞的反应性。
