mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation

Hu Zeng, Sivan Cohen, Cliff Guy, Sharad Shrestha, Geoffrey Neale, Scott A. Brown, Caryn Cloer, Rigel J. Kishton, Xia Gao, Ben Youngblood, Mytrang Do, Ming O. Li, Jason W. Locasale, Jeffrey C. Rathmell, Hongbo Chi

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

Follicular helper T (Tfh) cells are crucial for germinal center (GC) formation and humoral adaptive immunity. Mechanisms underlying Tfh cell differentiation in peripheral and mucosal lymphoid organs are incompletely understood. We report here that mTOR kinase complexes 1 and 2 (mTORC1 and mTORC2) are essential for Tfh cell differentiation and GC reaction under steady state and after antigen immunization and viral infection. Loss of mTORC1 and mTORC2 in T cells exerted distinct effects on Tfh cell signature gene expression, whereas increased mTOR activity promoted Tfh responses. Deficiency of mTORC2 impaired CD4+ T cell accumulation and immunoglobulin A production and aberrantly induced the transcription factor Foxo1. Mechanistically, the costimulatory molecule ICOS activated mTORC1 and mTORC2 to drive glycolysis and lipogenesis, and glucose transporter 1-mediated glucose metabolism promoted Tfh cell responses. Altogether, mTOR acts as a central node in Tfh cells by linking immune signals to anabolic metabolism and transcriptional activity.

Original languageEnglish (US)
Pages (from-to)540-554
Number of pages15
JournalImmunity
Volume45
Issue number3
DOIs
StatePublished - Sep 20 2016
Externally publishedYes

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Helper-Inducer T-Lymphocytes
Cell Differentiation
Phosphotransferases
Glucose
Germinal Center
Lipogenesis
Facilitative Glucose Transport Proteins
Adaptive Immunity
Glycolysis
Virus Diseases
Humoral Immunity
Transcriptome
Immunoglobulin A
Immunization
Transcription Factors
Antigens
TOR complex 2
mechanistic target of rapamycin complex 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation. / Zeng, Hu; Cohen, Sivan; Guy, Cliff; Shrestha, Sharad; Neale, Geoffrey; Brown, Scott A.; Cloer, Caryn; Kishton, Rigel J.; Gao, Xia; Youngblood, Ben; Do, Mytrang; Li, Ming O.; Locasale, Jason W.; Rathmell, Jeffrey C.; Chi, Hongbo.

In: Immunity, Vol. 45, No. 3, 20.09.2016, p. 540-554.

Research output: Contribution to journalArticle

Zeng, H, Cohen, S, Guy, C, Shrestha, S, Neale, G, Brown, SA, Cloer, C, Kishton, RJ, Gao, X, Youngblood, B, Do, M, Li, MO, Locasale, JW, Rathmell, JC & Chi, H 2016, 'mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation', Immunity, vol. 45, no. 3, pp. 540-554. https://doi.org/10.1016/j.immuni.2016.08.017
Zeng, Hu ; Cohen, Sivan ; Guy, Cliff ; Shrestha, Sharad ; Neale, Geoffrey ; Brown, Scott A. ; Cloer, Caryn ; Kishton, Rigel J. ; Gao, Xia ; Youngblood, Ben ; Do, Mytrang ; Li, Ming O. ; Locasale, Jason W. ; Rathmell, Jeffrey C. ; Chi, Hongbo. / mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation. In: Immunity. 2016 ; Vol. 45, No. 3. pp. 540-554.
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