Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner.

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State: Public
Version: Final published version
Serval ID
serval:BIB_CB0706D22A19
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner.
Journal
Cell Reports
Author(s)
Zhang L., Tschumi B.O., Lopez-Mejia I.C., Oberle S.G., Meyer M., Samson G., Rüegg M.A., Hall M.N., Fajas L., Zehn D., Mach J.P., Donda A., Romero P.
ISSN
2211-1247 (Electronic)
Publication state
Published
Issued date
2016
Peer-reviewed
Oui
Volume
14
Number
5
Pages
1206-1217
Language
english
Abstract
Upon infection, antigen-specific naive CD8 T cells are activated and differentiate into short-lived effector cells (SLECs) and memory precursor cells (MPECs). The underlying signaling pathways remain largely unresolved. We show that Rictor, the core component of mammalian target of rapamycin complex 2 (mTORC2), regulates SLEC and MPEC commitment. Rictor deficiency favors memory formation and increases IL-2 secretion capacity without dampening effector functions. Moreover, mTORC2-deficient memory T cells mount more potent recall responses. Enhanced memory formation in the absence of mTORC2 was associated with Eomes and Tcf-1 upregulation, repression of T-bet, enhanced mitochondrial spare respiratory capacity, and fatty acid oxidation. This transcriptional and metabolic reprogramming is mainly driven by nuclear stabilization of Foxo1. Silencing of Foxo1 reversed the increased MPEC differentiation and IL-2 production and led to an impaired recall response of Rictor KO memory T cells. Therefore, mTORC2 is a critical regulator of CD8 T cell differentiation and may be an important target for immunotherapy interventions.

Keywords
Animals, CD8-Positive T-Lymphocytes/cytology, CD8-Positive T-Lymphocytes/immunology, Carrier Proteins/metabolism, Cell Differentiation/genetics, Cell Nucleus/metabolism, Forkhead Transcription Factors/metabolism, Immunologic Memory/genetics, Interleukin-2/biosynthesis, Mice, Inbred C57BL, Mice, Knockout, Multiprotein Complexes/metabolism, T-Box Domain Proteins/metabolism, TOR Serine-Threonine Kinases/metabolism, Transcription, Genetic
Pubmed
Web of science
Open Access
Yes
Create date
04/03/2016 7:33
Last modification date
20/08/2019 15:45
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