Transcription Factor Foxo1 Represses T-bet-Mediated Effector Functions and Promotes Memory CD8 + T Cell Differentiation

Rajesh R. Rao, Qingsheng Li, Melanie R.Gubbels Bupp, Protul A. Shrikant

Research output: Contribution to journalArticle

154 Scopus citations

Abstract

The evolutionary conserved Foxo transcription factors are important regulators of quiescence and longevity. Although, Foxo1 is known to be important in regulating CD8 + T cell trafficking and homeostasis, its role in functional differentiation of antigen-stimulated CD8 + T cells is unclear. Herein, we demonstrate that inactivation of Foxo1 was essential for instructing T-bet transcription factor-mediated effector differentiation of CD8 + T cells. The Foxo1 inactivation was dependent on mTORC1 kinase, given that blockade of mTORC1 abrogated mTORC2-mediated Akt (Ser473) kinase phosphorylation, resulting in Foxo1-dependent switch from T-bet to Eomesodermin transcription factor activation and increase in memory precursors. Silencing Foxo1 ablated interleukin-12- and rapamycin-enhanced CD8 + T cell memory responses and restored T-bet-mediated effector functions. These results demonstrate an essential role of Foxo1 in actively repressing effector or terminal differentiation processes to promote memory CD8 + T cell development and identify the functionally diverse mechanisms utilized by Foxo1 to promote quiescence and longevity.

Original languageEnglish (US)
Pages (from-to)374-387
Number of pages14
JournalImmunity
Volume36
Issue number3
DOIs
StatePublished - Mar 23 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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