Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner
| Autor: | Jean-Pierre Mach, Guerric Samson, Marten Meyer, Pedro Romero, Lianjun Zhang, Michael N. Hall, Isabel C. Lopez-Mejia, Markus A. Rüegg, Benjamin O. Tschumi, Susanne Oberle, Dietmar Zehn, Lluis Fajas, Alena Donda |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Interleukin 2 Transcription Genetic Cellular differentiation Regulator Mechanistic Target of Rapamycin Complex 2 CD8-Positive T-Lymphocytes Biology mTORC2 General Biochemistry Genetics and Molecular Biology Rictor 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Foxo1 medicine Animals Cytotoxic T cell lcsh:QH301-705.5 Cell Nucleus Mice Knockout Forkhead Box Protein O1 Effector TOR Serine-Threonine Kinases Cell Differentiation Forkhead Transcription Factors infection Cell biology Mice Inbred C57BL Rapamycin-Insensitive Companion of mTOR Protein 030104 developmental biology lcsh:Biology (General) Multiprotein Complexes 030220 oncology & carcinogenesis 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 Multiprotein Complexes/metabolism T-Box Domain Proteins/metabolism TOR Serine-Threonine Kinases/metabolism Cancer research Interleukin-2 Signal transduction Carrier Proteins T-Box Domain Proteins Immunologic Memory CD8 T cell medicine.drug |
| Zdroj: | Cell Reports, vol. 14, no. 5, pp. 1206-1217 Cell reports Cell Reports, Vol 14, Iss 5, Pp 1206-1217 (2016) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2015.12.095 |
| Popis: | Summary: 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. : Zhang et al. demonstrate that mTORC2 deficiency favors CD8 T cell memory differentiation during the primary antigen-specific T cell response to Listeria infection. The effects result from higher Foxo1 transcriptional activity without dampening effector functions. They also show enhanced recall responses by mTORC2-deficient memory CD8 T cells. Keywords: Rictor, mTORC2, Foxo1, CD8 T cell, infection |
| Databáze: | OpenAIRE |
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