Purinergic Receptor P2Y <sub>6</sub> Inhibits the Maturation and Function of NK Cells by Suppressing mTOR Signaling Pathway

Abstract

Natural killer (NK) cells are a critical immune cells of innate immunity that can kill tumor cells, cancer-initiating cells and clear virus infections by producing cytokines and cytotoxic granules. However, there are few reports that elucidate the role of purinergic receptor in regulating NK cells. In this study, we discovered the expression of purinergic receptor P2Y6 was decreased after the activation of NK cells. In P2Y6-deficient mice, we found that P2Y6 deficiency promoted the development of NKp cells into iNK cells and the maturation of NK cells. We also found P2Y6 deficiency increased the production of IFN-γ in NK cells after stimulated with Poly (I:C), IL-15, the combination of IL-12 and IL-15 or PMA. P2Y6 receptor agonist UDP or UDP analogue 5-OMe-UDP inhibited the production of IFN-γ in NK cells after stimulation. In addition, we demonstrated P2Y6 deficiency increased the cytotoxicty function of NK cells in vitro and anti-metastatic activity in vivo. Mechanistically, we found P2Y6 deletion increased the expression of T-bet with or without IL-15 stimulation. Additionally, P2Y6 deficiency increased the level of p-AKT and pS6 after IL-15 stimulation, respectively. Collectively, we identify P2Y6 receptor, as a negative regulation of of NK cells function, inhibits the expression of T-bet by suppressing mTOR signaling pathway activation, eventually prevents NK cells maturation and effector function.