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

Nat Metab. 2021 Mar;3(3):318-326. doi: 10.1038/s42255-021-00356-0. Epub 2021 Mar 15.


Intermittent fasting blunts inflammation in asthma1 and rheumatoid arthritis2, suggesting that fasting may be exploited as an immune-modulatory intervention. However, the mechanisms underpinning the anti-inflammatory effects of fasting are poorly characterized3-5. 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 TH1 and TH17 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.

Trial registration: NCT02719899 NCT01143454 NCT00001846.

Publication types

  • Letter
  • Research Support, N.I.H., Intramural

MeSH terms

  • Cell Cycle Proteins / biosynthesis*
  • Fasting*
  • Forkhead Transcription Factors / biosynthesis*
  • Gene Expression Regulation
  • Humans
  • Sequence Analysis, RNA
  • T-Lymphocytes, Helper-Inducer / immunology*


  • Cell Cycle Proteins
  • FOXO4 protein, human
  • Forkhead Transcription Factors

Associated data