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

  • Author(s): Delpoux, Arnaud
  • Michelini, Rodrigo Hess
  • Verma, Shilpi
  • Lai, Chen-Yen
  • Omilusik, Kyla D
  • Utzschneider, Daniel T
  • Redwood, Alec J
  • Goldrath, Ananda W
  • Benedict, Chris A
  • Hedrick, Stephen M
  • et al.
Abstract

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.

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