mTOR masters monocytic myeloid-derived suppressor cells in mice with allografts or tumors

Sci Rep. 2016 Feb 1;6:20250. doi: 10.1038/srep20250.

Abstract

CD11b(+) Gr1(+) myeloid-derived suppressor cells (MDSCs) play critical roles in controlling the processes of tumors, infections, autoimmunity and graft rejection. Immunosuppressive drug rapamycin (RPM), targeting on the key cellular metabolism molecule mTOR, is currently used in clinics to treat patients with allo-grafts, autoimmune diseases and tumors. However, the effect of RPM on MDSCs has not been studied. RPM significantly decreases the cell number and the immunosuppressive ability on T cells of CD11b(+) Ly6C(high) monocytic MDSCs (M-MDSCs) in both allo-grafts-transplanted and tumor-bearing mice respectively. Mice with a myeloid-specific deletion of mTOR have poor M-MDSCs after grafting with allo-skin tissue or a tumor. Grafting of allo-skin or tumors significantly activates glycolysis pathways in myeloid precursor cells in bone marrow, which is inhibited by RPM or mTOR deletion. 2-deoxyglucose (2-DG), an inhibitor of the glycolytic pathway, inhibits M-MDSC differentiation from precursors, while enhancing glycolysis by metformin significantly rescues the RPM-caused deficiency of M-MDSCs. Therefore, we offer evidence supporting that mTOR is an intrinsic factor essential for the differentiation and immunosuppressive function of M-MDSCs and that these metabolism-relevant medicines may impact MDSCs-mediated immunosuppression or immune tolerance induction, which is of considerable clinical importance in treating graft rejection, autoimmune diseases and cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts
  • Animals
  • Cell Count
  • Cell Differentiation / drug effects
  • Disease Models, Animal
  • Energy Metabolism / drug effects
  • Graft Rejection / genetics
  • Graft Rejection / immunology
  • Immunosuppression
  • Mice
  • Mice, Knockout
  • Myeloid-Derived Suppressor Cells / cytology
  • Myeloid-Derived Suppressor Cells / drug effects
  • Myeloid-Derived Suppressor Cells / metabolism*
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • Skin Transplantation
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • TOR Serine-Threonine Kinases / deficiency
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Nitric Oxide Synthase Type II
  • TOR Serine-Threonine Kinases
  • Sirolimus