M-CSF induces a coordinated myeloid and NK cell differentiation program protecting against CMV after hematopoietic cell transplantation
Authors: Kandalla Prashanth K. , Subburayalu Julien , Cocita Clément , de Laval Bérengère , Tomasello Elena , Iacono Johanna , Nitsche Jessica , Canali Maria M. , Cathou Wilfried , Bessou Gilles , Mossadegh-Keller Noushine , Huber Caroline , Sarrazin Sandrine , Mouchiroud Guy , Bourette Roland , Grasset Marie-France , Dalod Marc , Sieweke Michael H. 
Published: February 2023

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.

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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.