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J Exp Med. 2014 Mar 10;211(3):563-77. doi: 10.1084/jem.20131560. Epub 2014 Feb 10.

T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow.

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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.


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.

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