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

Abstract

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-b. This NK cell response depended upon M-CSF-induced myelopoiesis leading to IL15Ra-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 IL15Ra 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 episodes of leukopenia.

Macrophage colony-stimulating factor and its role in the tumor microenvironment: novel therapeutic avenues and mechanistic insights

“…It has been implicated in dendritic cell differentiation and development, and it can also affect T-cell activation (18). Furthermore, M-CSF regulates the survival and proliferation of NK, T, and B cells and neutrophils, further expanding its role in immune responses (25,26).…”