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

144 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Cell Differentiation
Transcription Factors
T-Lymphocytes
Phosphotransferases
Differentiation Antigens
Sirolimus
Interleukin-12
Transcriptional Activation
Homeostasis
Phosphorylation
mechanistic target of rapamycin complex 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

Cite this

Transcription Factor Foxo1 Represses T-bet-Mediated Effector Functions and Promotes Memory CD8 + T Cell Differentiation. / Rao, Rajesh R.; Li, Qingsheng; Bupp, Melanie R Gubbels; Shrikant, Protul A.

In: Immunity, Vol. 36, No. 3, 23.03.2012, p. 374-387.

Research output: Contribution to journalArticle

Rao, Rajesh R. ; Li, Qingsheng ; Bupp, Melanie R Gubbels ; Shrikant, Protul A. / Transcription Factor Foxo1 Represses T-bet-Mediated Effector Functions and Promotes Memory CD8 + T Cell Differentiation. In: Immunity. 2012 ; Vol. 36, No. 3. pp. 374-387.
@article{5bf72791047e43f390a1e117d8e68b65,
title = "Transcription Factor Foxo1 Represses T-bet-Mediated Effector Functions and Promotes Memory CD8 + T Cell Differentiation",
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.",
author = "Rao, {Rajesh R.} and Qingsheng Li and Bupp, {Melanie R Gubbels} and Shrikant, {Protul A.}",
year = "2012",
month = "3",
day = "23",
doi = "10.1016/j.immuni.2012.01.015",
language = "English (US)",
volume = "36",
pages = "374--387",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Transcription Factor Foxo1 Represses T-bet-Mediated Effector Functions and Promotes Memory CD8 + T Cell Differentiation

AU - Rao, Rajesh R.

AU - Li, Qingsheng

AU - Bupp, Melanie R Gubbels

AU - Shrikant, Protul A.

PY - 2012/3/23

Y1 - 2012/3/23

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84863344634&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863344634&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2012.01.015

DO - 10.1016/j.immuni.2012.01.015

M3 - Article

C2 - 22425248

AN - SCOPUS:84863344634

VL - 36

SP - 374

EP - 387

JO - Immunity

JF - Immunity

SN - 1074-7613

IS - 3

ER -