Maintenance of CD4 T cell fitness through regulation of Foxo1

Ryan H. Newton, Sharad Shrestha, Jenna M. Sullivan, Kathleen B. Yates, Ewoud B. Compeer, Noga Ron-Harel, Bruce R. Blazar, Steven J. Bensinger, W. Nicholas Haining, Michael L. Dustin, Daniel J. Campbell, Hongbo Chi, Laurence A. Turka

Research output: Contribution to journalArticlepeer-review


Foxo transcription factors play an essential role in regulating specialized lymphocyte functions and in maintaining T cell quiescence. Here, we used a system in which Foxo1 transcription-factor activity, which is normally terminated upon cell activation, cannot be silenced, and we show that enforcing Foxo1 activity disrupts homeostasis of CD4 conventional and regulatory T cells. Despite limiting cell metabolism, continued Foxo1 activity is associated with increased activation of the kinase Akt and a cell-intrinsic proliferative advantage; however, survival and cell division are decreased in a competitive setting or growth-factor-limiting conditions. Via control of expression of the transcription factor Myc and the IL-2 receptor β-chain, termination of Foxo1 signaling couples the increase in cellular cholesterol to biomass accumulation after activation, thereby facilitating immunological synapse formation and mTORC1 activity. These data reveal that Foxo1 regulates the integration of metabolic and mitogenic signals essential for T cell competitive fitness and the coordination of cell growth with cell division.

Original languageEnglish
Pages (from-to)838-848
Number of pages11
JournalNature Immunology
Issue number8
StatePublished - 1 Aug 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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