title: In vitro-generated MDSCs prevent murine GVHD by inducing type 2 T cells without disabling antitumor cytotoxicity.
abstract: Myeloid-derived suppressor cells (MDSCs) inhibit T-cell expansion and functions by versatile mechanisms such as nutrient depletion, nitrosylation, or apoptosis. Since graft-versus-host disease (GVHD) is characterized by the expansion of donor-derived T cells destroying recipient tissue, we analyzed whether MDSCs can be used for GVHD prevention in murine allogeneic bone marrow transplantation models. Transplantation of MDSCs, generated from bone marrow cells by granulocyte-macrophage colony-stimulating factor (GM-CSF)/G-CSF in vitro, inhibited GVHD-induced death and attenuated histologic GVHD, whereas antitumor cytotoxicity of alloantigen-specific T cells was maintained. MDSCs expanded in vivo and invaded lymphatic and GVHD target organs. Major histocompatibility complex class I expression on MDSCs was dispensable for their suppressive capacity. Inhibition of GVHD required the presence of MDSCs during T-cell priming, whereas allogeneic T-cell numbers and homing in lymphoid and GVHD target organs were not considerably affected in MDSC-treated mice. However, MDSCs skewed allogeneic T cells toward type 2 T cells upregulating T helper 2 (Th2)-specific cytokines. Type 2 T-cell induction was indispensable for GVHD prevention since MDSC treatment failed to prevent GVHD when allogeneic STAT6-deficient T cells, which are unable to differentiate into Th2 cells, were transplanted. MDSC-induced Th2 induction might be applicable for GVHD treatment in clinical settings.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm Ulm, Germany;
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Messmann
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm Ulm, Germany;
authors.forename: Tanja
authors.initials: T
authors.lastname: Reisser
authors.affiliation: Institute of Pathology, University of Ulm, Ulm, Germany; and.
authors.forename: Frank
authors.initials: F
authors.lastname: Leithäuser
authors.affiliation: Institute of Virology and Immunobiology, Julius-Maximillians University Würzburg, Würzburg, Germany.
authors.forename: Manfred B
authors.initials: MB
authors.lastname: Lutz
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm Ulm, Germany;
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm Ulm, Germany;
authors.forename: Gudrun
authors.initials: G
authors.lastname: Strauss
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000379:methods*; D018845:CD11 Antigens / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005805:Genes, MHC Class I; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D018845:CD11 Antigens; D016179:Granulocyte Colony-Stimulating Factor