title: Identification of the earliest natural killer cell-committed progenitor in murine bone marrow.
abstract: Natural killer (NK) cells develop in the bone marrow and are known to gradually acquire the ability to eliminate infected and malignant cells, yet the cellular stages of NK lineage commitment and maturation are incompletely understood. Using 12-color flow cytometry, we identified a novel NK-committed progenitor (pre-NKP) that is a developmental intermediate between the upstream common lymphoid progenitor and the downstream NKP, previously assumed to represent the first stage of NK lineage commitment. Our analysis also refined the purity of NKPs (rNKP) by 6-fold such that 50% of both pre-NKP and rNKP cells gave rise to NKp46+ NK cells at the single-cell level. On transplantation into unconditioned Rag2-/-Il2rγc-/- recipients, both pre-NKPs and rNKPs generated mature NK cells expressing a repertoire of Ly49 family members that degranulated on stimulation ex vivo. Intrathymic injection of these progenitors, however, yielded no NK cells, suggesting a separate origin of thymic NK cells. Unlike the rNKP, the pre-NKP does not express IL-2Rβ (CD122), yet it is lineage committed toward the NK cell fate, adding support to the theory that IL-15 signaling is not required for NK commitment. Taken together, our data provide a high-resolution in vivo analysis of the earliest steps of NK cell commitment and maturation.
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. jfathman@stanford.edu
authors.forename: John W
authors.initials: JW
authors.lastname: Fathman
authors.forename: Deepta
authors.initials: D
authors.lastname: Bhattacharya
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Inlay
authors.forename: Jun
authors.initials: J
authors.lastname: Seita
authors.forename: Holger
authors.initials: H
authors.lastname: Karsunky
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
mesh_terms: D000818:Animals; D015415:Biomarkers; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology*; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D005434:Flow Cytometry / Q000379:methods; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000166:cytology*; D054503:Lymphoid Progenitor Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D060168:Thymocytes / Q000166:cytology*
chemical_list: D015415:Biomarkers