title: IRF8 acts in lineage-committed rather than oligopotent progenitors to control neutrophil vs monocyte production.
abstract: Interferon regulatory factor 8 (IRF8) is a key regulator of myelopoiesis in mice and humans. IRF8-deficient mice exhibit increased neutrophil numbers but defective monocyte and dendritic cell (DC) production. It has therefore been hypothesized that IRF8 regulates granulocyte vs monocyte/DC lineage commitment by oligopotent progenitors. Alternatively, IRF8 could control the differentiation of lineage-committed progenitors. In this study, we defined the role of IRF8 in lineage commitment and neutrophil vs monocyte differentiation using a novel sorting strategy that for the first time allows us to separate oligopotent granulocyte-monocyte progenitors (GMPs) and their lineage-committed progeny: granulocyte progenitors (GPs) and monocyte progenitors (MPs). We show that IRF8 is highly expressed by both GPs and MPs, but not GMPs, and is not required for GP or MP production by GMPs. In fact, IRF8-deficient mice have more GPs and MPs. This is not due to IRF8-mediated suppression of GP and MP production by GMPs, but rather to selective effects in GPs and MPs. We identify roles for IRF8 in regulating progenitor survival and differentiation and preventing leukemic cell accumulation. Thus, IRF8 does not regulate granulocytic vs monocytic fate in GMPs, but instead acts downstream of lineage commitment to selectively control neutrophil and monocyte production.
authors.affiliation: Board of Governors Regenerative Medicine Institute and Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA; and.
authors.forename: Alberto
authors.identifier: http://orcid.org/0000-0002-7719-1963
authors.initials: A
authors.lastname: Yáñez
authors.affiliation: Board of Governors Regenerative Medicine Institute and Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA; and.
authors.forename: Madelena Y
authors.initials: MY
authors.lastname: Ng
authors.affiliation: Board of Governors Regenerative Medicine Institute and Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA; and.
authors.forename: Nargess
authors.initials: N
authors.lastname: Hassanzadeh-Kiabi
authors.affiliation: Board of Governors Regenerative Medicine Institute and Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA; and David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Helen S
authors.initials: HS
authors.lastname: Goodridge
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D042381:Granulocyte Precursor Cells / Q000166:cytology* / Q000378:metabolism; D006098:Granulocytes / Q000166:cytology* / Q000378:metabolism; D006410:Hematopoiesis / Q000502:physiology*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8