In vitro-generated MDSCs prevent murine GVHD by inducing type 2 T cells without disabling antitumor cytotoxicity

Abstract

Key Points• MDSC treatment prevents GVHD by skewing T cells toward type 2 T cells.• MDSCs proliferate in vivo, suppress independent of major histocompatibility complex class I expression, and do not impair allogeneic T-cell homing and the graft-versustumor effect.Myeloid-derived suppressor cells (MDSCs) inhibit T-cell expansion and functions by versatile mechanisms such as nutrient depletion, nitrosylation, or apoptosis. Since graftversus-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. (Blood. 2015;126(9):1138-1148

Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease

“…Compared with the infusion of BM + T cells alone, there was no significant improvement in median survival for mice receiving BM, T cells, and Il13 . We analyzed donor myeloid cells for expression of CD45, CD11b, Gr-1, Ly-6C, and Ly-6G, a phenotype that is consistent with MDSCs, which have been shown to suppress aGVHD ( Figure 5A) (12,27). We found a significant increase in donor MDSCs in the LP of colon and small bowel in ILC2-treated recipient mice ( Figure 5B).…”

Novel approaches for preventing acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

“…Several mouse experiments have reported that adding functional MDSCs in donor graft could alleviate aGVHD. [47,48] These observations, however, remain to be confirmed in clinical trials.…”

TLR/MyD88-mediated Innate Immunity in Intestinal Graft-versus-Host Disease

“…The phenotypes CD11b + LyG6 + Ly6C low and CD11b + LyG6 low Ly6C high are used to identify the respective populations in mice. MDSCs expand robustly in various pathological conditions, such as cancers (52), autoimmune diseases (53), inflammation (54), infectious diseases (55565758), and GVHD (49515960). Most MDSC biology has been studied in tumor microenvironments, and preclinical and clinical tumor therapies have been tested for their ability to block MDSC expansion and function.…”