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

2014; Rockefeller University Press; Volume: 211; Issue: 3 Linguagem: Inglês

10.1084/jem.20131560

1540-9538

Cécile Daussy, Fabrice Faure, Katia Mayol, Sébastien Viel, Georg Gasteiger, Emily Charrier, Jacques Bienvenu, Thomas Henry, Emilie Debien, Uzma Hasan, Jacqueline Marvel, Keigyou Yoh, Satoru Takahashi, Immo Prinz, Simon de Bernard, Laurent Buffat, Thierry Walzer,

Reproductive System and Pregnancy

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.