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

16 Scopus citations

Abstract

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 (US)
Pages (from-to)838-848
Number of pages11
JournalNature immunology
Volume19
Issue number8
DOIs
StatePublished - Aug 1 2018

Bibliographical note

Funding Information:
We thank M. Li (Memorial Sloan Kettering Cancer Center) for Foxo1AAA mice; F. Gounari (University of Chicago) for CD4Cre–ERT2 mice; M. Farrar (University of Minnesota) for a constitutively active STAT5b retroviral construct; Z. Herbert and K. Bi for assistance with transcriptome analysis; the MGH-CNY FACS core facility for cell sorting; and members of the laboratory of L.A.T. for discussions. This work was supported by the US National Institutes of Health (P01HL018646 to L.A.T.; R21AI126143 to L.A.T. and R.H.N.; R01AI124693 to D.J.C.; R01HL011879 and P01AI056299 to B.R.B.; AI101407 and CA176624 to H.C.), the Wellcome Trust (PRF 100262 to M.L.D.) and the European Research Council (ERC-2014-AdG_670930 to M.L.D. and E.B.C.).

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