title: T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow.
abstract: Trail(+)DX5(-)Eomes(-) natural killer (NK) cells arise in the mouse fetal liver and persist in the adult liver. Their relationships with Trail(-)DX5(+) NK cells remain controversial. We generated a novel Eomes-GFP reporter murine model to address this question. We found that Eomes(-) NK cells are not precursors of classical Eomes(+) NK cells but rather constitute a distinct lineage of innate lymphoid cells. Eomes(-) NK cells are strictly dependent on both T-bet and IL-15, similarly to NKT cells. We observed that, in the liver, expression of T-bet in progenitors represses Eomes expression and the development of Eomes(+) NK cells. Reciprocally, the bone marrow (BM) microenvironment restricts T-bet expression in developing NK cells. Ectopic expression of T-bet forces the development of Eomes(-) NK cells, demonstrating that repression of T-bet is essential for the development of Eomes(+) NK cells. Gene profile analyses show that Eomes(-) NK cells share part of their transcriptional program with NKT cells, including genes involved in liver homing and NK cell receptors. Moreover, Eomes(-) NK cells produce a broad range of cytokines, including IL-2 and TNF in vitro and in vivo, during immune responses against vaccinia virus. Thus, mutually exclusive expression of T-bet and Eomes drives the development of different NK cell lineages with complementary functions.
authors: CIRI, International Center for Infectiology Research, Université de Lyon; 2 Institut National de la Santé et de la Recherche Médicale, U1111; 3 Ecole Normale Supérieure de Lyon; 4 Université Lyon 1, Centre International de Recherche en Infectiologie; and 5 Centre National de la Recherche Scientifique, UMR5308, 69007 Lyon, France.
authors: Cécile
authors: C
authors: Daussy
authors: Fabrice
authors: F
authors: Faure
authors: Katia
authors: K
authors: Mayol
authors: Sébastien
authors: S
authors: Viel
authors: Georg
authors: G
authors: Gasteiger
authors: Emily
authors: E
authors: Charrier
authors: Jacques
authors: J
authors: Bienvenu
authors: Thomas
authors: T
authors: Henry
authors: Emilie
authors: E
authors: Debien
authors: Uzma A
authors: UA
authors: Hasan
authors: Jacqueline
authors: J
authors: Marvel
authors: Keigyou
authors: K
authors: Yoh
authors: Satoru
authors: S
authors: Takahashi
authors: Immo
authors: I
authors: Prinz
authors: Simon
authors: S
authors: de Bernard
authors: Laurent
authors: L
authors: Buffat
authors: Thierry
authors: T
authors: Walzer
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis; D023421:Models, Animal; D060888:Real-Time Polymerase Chain Reaction; D055153:Stem Cell Niche / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D017931:DNA Primers; C491198:Eomes protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor