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

Abstract

Mutually exclusive expression of T-bet and Eomes drives the development of distinct NK cell lineages with complementary functions.

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.