Granulocytic myeloid-derived suppressor cells to prevent and treat murine immune-mediated bone marrow failure.

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells which originate in the bone marrow (BM) and have immunoregulatory functions. MDSCs have been implicated in the pathogenesis of several autoimmune diseases but have not been investigated in immune aplastic anemia (AA). We examined the roles of granulocytic-MDSCs (G-MDSCs) in murine models of human AA and bone marrow failure (BMF). As both prophylaxis and therapy, BM-derived G-MDSCs improved pancytopenia and BM cellularity and suppressed BM T cell infiltration in major histocompatibility complex (MHC)-matched C.B10 BMF mice. These effects were not obtained in MHC-mismatched CByB6F1 AA model, likely due to MHC disparity between G-MDSCs and donor T cells. Single cell RNA sequencing demonstrated that G-MDSCs downregulated cell cycle related genes in BM infiltrated T cells, consistent with suppression of T cell proliferation by G-MDSCs through reactive oxygen species pathway. Clearance of G-MDSCs in MHC-mismatched CByB6F1 model using anti-Ly6G antibody facilitated T cell-mediated BM destruction, suggesting an intrinsic immunosuppressive property of G-MDSCs. However, the same anti-Ly6G antibody mildly mitigated marrow failure due to expansion of an intermediate Ly6G population in the BM of MHC-matched C.B10 AA model. Our results demonstrate that G-MDSC eradication and therapeutic efficacy are immune context-dependent.