title: Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner.
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.
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland. Electronic address: lianjun.zhang@unil.ch.
authors.forename: Lianjun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Benjamin O
authors.initials: BO
authors.lastname: Tschumi
authors.affiliation: Department of Physiology, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Isabel C
authors.initials: IC
authors.lastname: Lopez-Mejia
authors.affiliation: Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland.
authors.forename: Susanne G
authors.initials: SG
authors.lastname: Oberle
authors.affiliation: German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Marten
authors.initials: M
authors.lastname: Meyer
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Guerric
authors.initials: G
authors.lastname: Samson
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.affiliation: Department of Physiology, University of Lausanne, 1011 Lausanne, Switzerland.
authors.forename: Lluis
authors.initials: L
authors.lastname: Fajas
authors.affiliation: Swiss Vaccine Research Institute, 1066 Epalinges, Switzerland.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Zehn
authors.affiliation: Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Mach
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland.
authors.forename: Alena
authors.initials: A
authors.lastname: Donda
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, 1066 Epalinges, Switzerland. Electronic address: pedro.romero@unil.ch.
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007156:Immunologic Memory / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis; D000076225:Mechanistic Target of Rapamycin Complex 2; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D020825:T-Box Domain Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor
chemical_list: D002352:Carrier Proteins; C491198:Eomes protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007376:Interleukin-2; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C525637:rictor protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: CD8 T cell; Foxo1; Rictor; infection; mTORC2