The Transcription Factors T-bet and Eomes Control Key Checkpoints of Natural Killer Cell Maturation

• Published in: Immunity (Cambridge, Mass.) Vol. 36; no. 1; pp. 55 - 67
• Main Authors: Gordon, Scott M., Chaix, Julie, Rupp, Levi J., Wu, Junmin, Madera, Sharline, Sun, Joseph C., Lindsten, Tullia, Reiner, Steven L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.01.2012; Elsevier Limited
• Subjects: Animals; Antigens; Blood; Cell Cycle - genetics; Cell Differentiation; Cell Lineage; Development; Fetuses; Flow Cytometry; Gene Deletion; Gene expression; Hemopoiesis; Immune system; Integrins; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Liver; Ly-49 antigen; Lymphatic system; Lymphocytes; Mice; Mice, Knockout; Models, Immunological; Natural killer cells; Pathogens; Real-Time Polymerase Chain Reaction; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; TRAIL protein; Transcription factors; Tumors; Women
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2011.11.016

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. [Display omitted] ► NK cells are absent in mice lacking both T-bet and Eomes ► T-bet is essential to stabilize immature, TRAIL + NK cells ► Eomes is required to develop and partially maintain mature, DX5 + NK cells ► NK cells lose NK antigens after deletion of T-bet and Eomes