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bioRxiv · 10.1101/2023.01.30.526105

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

Kandalla, P. K.·Subburayalu, J.·Cocita, C.·de Laval, B.·Tomasello, E.·Iacono, J.·Nitsche, J.·Canali, M. M.·Cathou, W.·Bessou, G.·Mossadegh-Keller, N.·Huber, C.·Sarrazin, S.·Mouchiroud, G.·Bourette, R.·Grasset, M.-F.·Dalod, M.·Sieweke, M. H.
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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-{gamma}. This NK cell response depended upon M-CSF-induced myelopoiesis leading to IL15R-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 IL15R 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 pointsO_LIM-CSF protects from lethal CMV viremia during leukopenia following hematopoietic cell transplantation, a vulnerable period of immunosuppression. C_LIO_LIEarly action of M-CSF on donor hematopoietic stem and progenitor cells rapidly reconstitutes antiviral immune responses. C_LIO_LIM-CSF stimulates a coordinated myeloid-NK cell-differentiation program resulting in increased NK cell numbers and activity. C_LIO_LIIncreased NK cell differentiation and activity depends on M-CSF-induced myelopoiesis generating IL-15-producing monocytes and I-IFN-producing pDCs. C_LIO_LIM-CSF also stimulates monopoiesis, IL15Ra expression in monocytes and functional NK cell differentiation in G-CSF-mobilized human PBMC. C_LIO_LINo impaired HCT engraftment or proclivity to graft-versus-host-disease by M-CSF. C_LIO_LIM-CSF could provide a single cytokine therapy addressing a major medical need, supporting current antiviral therapies during leukopenia following HCT. C_LI Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/526105v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1b1398eorg.highwire.dtl.DTLVardef@39a9e3org.highwire.dtl.DTLVardef@1c08cc3org.highwire.dtl.DTLVardef@5996b4_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryM-CSF drives myeloid reconstitution to support CMV-directed natural killer cell competence via IL-15/I-IFN after hematopoietic cell transplantation.

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Kandalla, P. K., Subburayalu, J., Cocita, C., de Laval, B., Tomasello, E., Iacono, J., Nitsche, J., Canali, M. M., Cathou, W., Bessou, G., Mossadegh-Keller, N., Huber, C., Sarrazin, S., Mouchiroud, G., Bourette, R., Grasset, M.-F., Dalod, M., Sieweke, M. H.. 2023-02-01. M-CSF induces a coordinated myeloid and NK cell differentiation program protecting against CMV after hematopoietic cell transplantation. https://doi.org/10.1101/2023.01.30.526105

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