Human NK cells and subsets of T cells or NKT cells express the orphan C-type lectin receptor CD161 (NKR-P1A) of unknown function. In contrast to rodents that possess several NKR-P1 genes coding for either activating or inhibitory receptors, the nature of signals delivered by the single human NKR-P1A receptor is still to be clarified. In this article, we show that the lectin-like transcript 1 (LLT1) molecule is a ligand for the CD161 receptor. Engagement of CD161 on NK cells with LLT1 expressed on target cells inhibited NK cell-mediated cytotoxicity and IFN-γ secretion. Conversely, LLT1/CD161 interaction in the presence of a TCR signal enhanced IFN-γ production by T cells. These findings identify a novel ligand/receptor pair that differentially regulate NK and T cell functions.

Background: CD161 expressed by NK cells and T cells interacts with LLT1.Results: LLT1 expression profile reveals LLT1 is induced by pathogens and IFN-␥ and LLT1/CD161 interaction inhibits NK cell functions whereas it costimulates T cells. Conclusion:The link between LLT1 expression and pathogen stimulation points toward a role in modulating immune responses to pathogens Significance: LLT1/CD161 interaction is relevant in immunity to infection.

The ability of NK cells to rapidly produce IFN-γ is an important innate mechanism of resistance to many pathogens including Leishmania major. Molecular and cellular components involved in NK cell activation in vivo are still poorly defined, although a central role for dendritic cells has been described. In this study, we demonstrate that Ag-specific CD4+ T cells are required to initiate NK cell activation early on in draining lymph nodes of L. major-infected mice. We show that early IFN-γ secretion by NK cells is controlled by IL-2 and IL-12 and is dependent on CD40/CD40L interaction. These findings suggest that newly primed Ag-specific CD4+ T cells could directly activate NK cells through the secretion of IL-2 but also indirectly through the regulation of IL-12 secretion by dendritic cells. Our results reveal an unappreciated role for Ag-specific CD4+ T cells in the initiation of NK cell activation in vivo upon L. major infection and demonstrate bidirectional regulations between innate and adaptive immunity.