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

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.