Modulation of mTOR signalling triggers the formation of stem cell-like memory T cells

Scholz, Godehard; Jandus, Camilla; Zhang, Lianjun; Grandclément, Camille; Lopez-Mejia, Isabel C; Soneson, Charlotte; Delorenzi, Mauro; Fajas, Lluis; Held, Werner; Dormond, Olivier; Romero, Pedro

doi:10.1016/j.ebiom.2016.01.019

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Title		Modulation of mTOR signalling triggers the formation of stem cell-like memory T cells
Authors		Scholz, Godehard Jandus, Camilla Zhang, Lianjun Grandclément, Camille Lopez-Mejia, Isabel C Soneson, Charlotte Delorenzi, Mauro Fajas, Lluis Held, Werner Dormond, Olivier Romero, Pedro show all authors [1 - 11]
Published in		EBioMedicine. 2016, vol. 4, p. 50-61
Abstract		Robust, long-lasting immune responses are elicited by memory T cells that possess properties of stem cells, enabling them to persist long-term and to permanently replenish the effector pools. Thus, stem cell-like memory T (TSCM) cells are of key therapeutic value and efforts are underway to characterize TSCM cells and to identify means for their targeted induction. Here, we show that inhibition of mechanistic/mammalian Target of Rapamycin (mTOR) complex 1 (mTORC1) by rapamycin or the Wnt-β-catenin signalling activator TWS119 in activated human naive T cells leads to the induction of TSCM cells. We show that these compounds switch T cell metabolism to fatty acid oxidation as favoured metabolic programme for TSCM cell generation. Of note, pharmacologically induced TSCM cells possess superior functional features as a long-term repopulation capacity after adoptive transfer. Furthermore, we provide insights into the transcriptome of TSCM cells. Our data identify a mechanism of pharmacological mTORC1 inhibitors, allowing us to confer stemness to human naive T cells which may be significantly relevant for the design of innovative T cell-based cancer immunotherapies.
Keywords		Animals — CD4-Positive T-Lymphocytes/cytology/immunology — Cells — Cultured — Female — Humans — Immunologic Memory — Lymphopoiesis — Mechanistic Target of Rapamycin Complex 1 — Mice — Multiprotein Complexes/antagonists & inhibitors/metabolism — Precursor Cells — T-Lymphoid/cytology/immunology — Pyrimidines/pharmacology — Pyrroles/pharmacology — Signal Transduction — TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
Identifiers		DOI: 10.1016/j.ebiom.2016.01.019 PMID: 26981571
Full text		Article (Published version) (2 MB) - Free access
Research group		Ciblage des lymphocytes sécrétant des cytokines (1015)
Citation (ISO format)		SCHOLZ, Godehard et al. Modulation of mTOR signalling triggers the formation of stem cell-like memory T cells. In: EBioMedicine, 2016, vol. 4, p. 50-61. doi: 10.1016/j.ebiom.2016.01.019 https://archive-ouverte.unige.ch/unige:132395