NKp46 Calibrates Tumoricidal Potential of Type 1 Innate Lymphocytes by Regulating TRAIL Expression

NK cells are a subset of group 1 innate lymphocytes that recognize and eliminate virus-infected and transformed cells. During the course of their development, NK cells acquire a repertoire of activating and inhibitory receptors, which ultimately define their reactivity against target cells. The array of receptors and their specificity during early developmental stages will control and imprint functional properties of NK cells, a process known as "NK cell education." Innate lymphoid cells (ILCs) are a diverse group of lymphocytes, which, like NK cells, do not rely on somatically rearranged Ag receptors for recognition. Among ILC subsets, ILC1s are most like NK cells functionally. Prototypic ILC1s reside in the liver, and a large part of their function is attributed to the expression of TRAIL, a TNF superfamily member with a well-documented antitumor activity. In this article, we show that TRAIL expression on mouse ILC1s is controlled by an activating receptor NKp46, which has been previously shown to control NK cell education. In the absence of NKp46, ILC1s fail to express normal levels of TRAIL on the surface, which results in diminished cytotoxicity toward TRAIL receptor-positive targets. To our knowledge, these findings provide the first evidence of a role of NKp46 in ILC1s that calibrates their antitumor response.