Continuous activity of Foxo1 is required to prevent anergy and maintain the memory state of CD8+ T cells

J Exp Med. 2018 Feb 5;215(2):575-594. doi: 10.1084/jem.20170697. Epub 2017 Dec 27.


Upon infection with an intracellular pathogen, cytotoxic CD8+ T cells develop diverse differentiation states characterized by function, localization, longevity, and the capacity for self-renewal. The program of differentiation is determined, in part, by FOXO1, a transcription factor known to integrate extrinsic input in order to specify survival, DNA repair, self-renewal, and proliferation. At issue is whether the state of T cell differentiation is specified by initial conditions of activation or is actively maintained. To study the spectrum of T cell differentiation, we have analyzed an infection with mouse cytomegalovirus, a persistent-latent virus that elicits different cytotoxic T cell responses characterized as acute resolving or inflationary. Our results show that FOXO1 is continuously required for all the phenotypic characteristics of memory-effector T cells such that with acute inactivation of the gene encoding FOXO1, T cells revert to a short-lived effector phenotype, exhibit reduced viability, and manifest characteristics of anergy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, Viral
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / immunology
  • Cell Survival / immunology
  • Clonal Anergy*
  • Forkhead Box Protein O1 / deficiency
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / immunology*
  • Hepatocyte Nuclear Factor 1-alpha / immunology
  • Immunologic Memory*
  • Lectins, C-Type
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muromegalovirus / immunology
  • Receptors, Immunologic / immunology


  • Antigens, Viral
  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Klrg1 protein, mouse
  • Lectins, C-Type
  • Receptors, Immunologic