title: The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation.
abstract: Natural killer (NK) cells play critical roles defending against tumors and pathogens. We show that mice lacking both transcription factors Eomesodermin (Eomes) and T-bet failed to develop NK cells. Developmental stability of immature NK cells constitutively expressing the death ligand TRAIL depended on T-bet. Conversely, maturation characterized by loss of constitutive TRAIL expression and induction of Ly49 receptor diversity and integrin CD49b (DX5(+)) required Eomes. Mature NK cells from which Eomes was deleted reverted to phenotypic immaturity if T-bet was present or downregulated NK lineage antigens if T-bet was absent, despite retaining expression of Ly49 receptors. Fetal and adult hepatic hematopoiesis restricted Eomes expression and limited NK development to the T-bet-dependent, immature stage, whereas medullary hematopoiesis permitted Eomes-dependent NK maturation in adult mice. These findings reveal two sequential, genetically separable checkpoints of NK cell maturation, the progression of which is metered largely by the anatomic localization of hematopoiesis.
authors.affiliation: Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Gordon
authors.forename: Julie
authors.initials: J
authors.lastname: Chaix
authors.forename: Levi J
authors.initials: LJ
authors.lastname: Rupp
authors.forename: Junmin
authors.initials: J
authors.lastname: Wu
authors.forename: Sharline
authors.initials: S
authors.lastname: Madera
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Sun
authors.forename: Tullia
authors.initials: T
authors.lastname: Lindsten
authors.forename: Steven L
authors.initials: SL
authors.lastname: Reiner
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation; D019070:Cell Lineage; D005434:Flow Cytometry; D017353:Gene Deletion; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D060888:Real-Time Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: C491198:Eomes protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor