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


Autoria(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.
Data(s)

2016

Resumo

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.

Identificador

https://serval.unil.ch/notice/serval:BIB_CB0706D22A19

info:pmid:26804903

https://serval.unil.ch/resource/serval:BIB_CB0706D22A19.P001/REF

http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_CB0706D22A194

urn:nbn:ch:serval-BIB_CB0706D22A194

Idioma(s)

eng

Fonte

Cell Reports1451206-1217

Tipo

info:eu-repo/semantics/article

article

Formato

application/pdf

Direitos

info:eu-repo/semantics/openAccess

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Palavras-Chave #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