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.

Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation.

Cumulative T-cell receptor signal strength and ensuing T-cell responses are affected by both antigen affinity and antigen dose. Here we examined the distinct contributions of these parameters to CD4 T-cell differentiation during infection. We found that high antigen affinity positively correlates with T helper (Th)1 differentiation at both high and low doses of antigen. In contrast, follicular helper T cell (TFH) effectors are generated after priming with high, intermediate, and low affinity ligand. Unexpectedly, memory T cells generated after priming with very low affinity antigen remain impaired in their ability to generate secondary Th1 effectors, despite being recalled with high affinity antigen. These data challenge the view that only strongly stimulated CD4 T cells are capable of differentiating into the TFH and memory T-cell compartments and reveal that differential strength of stimulation during primary T-cell activation imprints unique and long lasting T-cell differentiation programs.