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Nat Immunol. 2018 Aug;19(8):838-848. doi: 10.1038/s41590-018-0157-4. Epub 2018 Jul 9.

Maintenance of CD4 T cell fitness through regulation of Foxo1.

Author information

1
Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
2
Celsius Therapeutics, Cambridge, MA, USA.
3
Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
4
Department of Immunology, University of Washington, Seattle and Immunology Program, Benaroya Research Institute, Seattle, WA, USA.
5
Division of Pediatric Hematology and Oncology, Children's Hospital, Boston, MA, USA.
6
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
7
Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
8
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
9
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.
10
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
11
Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. lturka@rheosrx.com.
12
Rheos Medicines, Cambridge, MA, USA. lturka@rheosrx.com.

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.

PMID:
29988091
DOI:
10.1038/s41590-018-0157-4

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