Modulation of mTOR Signalling Triggers the Formation of Stem Cell-like Memory T Cells

EBioMedicine. 2016 Jan 16;4:50-61. doi: 10.1016/j.ebiom.2016.01.019. eCollection 2016 Feb.

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: Adoptive cell transfer therapy; Human T cells; Rapamycin; T cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology*
  • CD4-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • Female
  • Humans
  • Immunologic Memory*
  • Lymphopoiesis
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / metabolism*
  • Precursor Cells, T-Lymphoid / cytology*
  • Precursor Cells, T-Lymphoid / immunology
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Multiprotein Complexes
  • Pyrimidines
  • Pyrroles
  • TWS 119
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1