M-CSF induces a coordinated myeloid and NK cell differentiation program protecting against CMV after hematopoietic cell transplantation

Immunosuppressed patients are highly susceptible to viral infections. Therapies reconstituting autologous antiviral immunocompetence could therefore represent an important prophylaxis and treatment. Herpesviridae including cytomegalovirus (CMV) are a major cause of morbidity and mortality in patients after hematopoietic cell transplantation (HCT). Here, we show in a mouse model of HCT that macrophage colony-stimulating factor (M-CSF/CSF-1), a key cytokine for myeloid and monocytic differentiation, promoted rapid antiviral activity and protection from viremia caused by murine CMV. Mechanistically, M-CSF stimulated a coordinated myeloid and natural killer (NK) cell differentiation program culminating in increased NK cell numbers and production of granzyme B and interferon-γ. This NK cell response depended upon M-CSF-induced myelopoiesis leading to IL15Rα-mediated presentation of IL-15 on monocytes. Furthermore, M-CSF also induced differentiation of plasmacytoid dendritic cells producing type I interferons, which supported IL-15-mediated protection. In the context of human HCT, M-CSF induced monopoiesis, increased IL15Rα expression on monocytes and elevated numbers of functionally competent NK cells in G-CSF-mobilized human hematopoietic stem and progenitor cells. Together, our data show that M-CSF induces an integrated multistep differentiation program that culminates in increased NK cell numbers and activation, thereby protecting graft recipients from CMV infection. Thus, our results identify a mechanism by which M-CSF-induced myelopoiesis can rapidly reconstitute antiviral activity during leukopenia following HCT. Key points M-CSF protects from lethal CMV viremia during leukopenia following hematopoietic cell transplantation, a vulnerable period of immunosuppression. Early action of M-CSF on donor hematopoietic stem and progenitor cells rapidly reconstitutes antiviral immune responses. M-CSF stimulates a coordinated myeloid-NK cell-differentiation program resulting in increased NK cell numbers and activity. Increased NK cell differentiation and activity depends on M-CSF-induced myelopoiesis generating IL-15-producing monocytes and I-IFN-producing pDCs. M-CSF also stimulates monopoiesis, IL15Ra expression in monocytes and functional NK cell differentiation in G-CSF-mobilized human PBMC. No impaired HCT engraftment or proclivity to graft-versus-host-disease by M-CSF. M-CSF could provide a single cytokine therapy addressing a major medical need, supporting current antiviral therapies during leukopenia following HCT. Visual abstract One Sentence Summary M-CSF drives myeloid reconstitution to support CMV-directed natural killer cell competence via IL-15/I-IFN after hematopoietic cell transplantation.