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

Scholz, Godehard
Zhang, Lianjun
Grandclément, Camille
Lopez-Mejia, Isabel C
Soneson, Charlotte
Delorenzi, Mauro
Fajas, Lluis
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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 AnimalsCD4-Positive T-Lymphocytes/cytology/immunologyCellsCulturedFemaleHumansImmunologic MemoryLymphopoiesisMechanistic Target of Rapamycin Complex 1MiceMultiprotein Complexes/antagonists & inhibitors/metabolismPrecursor CellsT-Lymphoid/cytology/immunologyPyrimidines/pharmacologyPyrroles/pharmacologySignal TransductionTOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
PMID: 26981571
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Research group Ciblage des lymphocytes sécrétant des cytokines (1015)
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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

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Deposited on : 2020-03-17

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