Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46

Natural killer (NIK) cells contribute to a variety of innate immune responses to viruses, tumors and allogeneic cells. However, our understanding of NIK cell biology is severely limited by the lack of consensus phenotypic definition of these cells across species, by the lack of specific markerto visualize them in situ, and by the lack of a genetic model where INK cells may be selectively ablated. NKp46/CD335 is an Ig-like superfamily cell surface receptor involved in human NK cell activation. In addition to human, we show here that NIKp46 is expressed by INK cells in all mouse strains analyzed, as well as in three common monkey species, prompting a unifying phenotypic definition of INK cells across species based on NKp46 cell surface expression. Mouse NKp46 triggers NK cell effector f unction and allows the detection of INK cells in situ. NKp46 expression parallels cell engagement into NK differentiation programs because it is detected on all NK cells from the immature CD122(+)NK1.1(+)DX5(-) stage and on a minute fraction of INK-like T cells, but not on CD1d-restricted NKT cells. Moreover, human NKp46 promoter drives NK cell selective expression both in vitro and in vivo. Using NKp46 promoter, we generated transgenic mice expressing EGIFP and the diphtheria toxin (DT) receptor in INK cells. DT injection in these mice leads to a complete and selective INK cell ablation. This model paves a way for the in vivo characterization and preclinical assessment of INK cell biological function.