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+ Ly6Chigh 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.
Highlights
CD11b+ Gr1+ myeloid-derived suppressor cells (MDSCs) are known to accumulate and play critical roles in various conditions like tumors, infections, autoimmune diseases and graft rejection[1,2,3]
Alloskin grafts promoted the accumulation of CD11b+ Gr1+ innate cells in the spleens and dLNs of recipient mice compared with the un-grafted mice (P < 0.001, Fig. 1A,B), as reported previously[3,14]
It is known that CD11b+ Gr1+ MDSCs consists of two major subsets of granulocytic CD11b+ Ly6Cmed and monocytic CD11b+ Ly6Chigh cells[26]
Summary
CD11b+ Gr1+ myeloid-derived suppressor cells (MDSCs) are known to accumulate and play critical roles in various conditions like tumors, infections, autoimmune diseases and graft rejection[1,2,3]. These cells are a highly heterogeneous cell population with hematopoietic cell precursors at various differentiation stages to mature macrophages, dendritic cells (DCs), and granulocytes[4]. Studies using mice with a myeloid-specific deletion of mTOR or mTORC2 essential component rictor demonstrate that mTORC1 but not mTORC2 intrinsically controls CD11b+ Ly6Chigh M-MDSC differentiation and immunosuppressive function through controlling cellular metabolism pathway. We believe the present study may have great potential impacts on the clinical usage of RPM, 2-DG and metformin to treat patients with allograft transplantation, autoimmune diseases and cancers
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
