Purinergic Receptor P2Y₆ Is a Negative Regulator of NK Cell Maturation and Function

NK cells are critical innate immune cells that target the tumor cells and cancer-initiating cells and clear viruses by producing cytokines and cytotoxic granules. However, the role of the purinergic receptor P2Y₆ in the NK cells remains largely unknown. In this study, we discovered that the expression of P2Y₆ was decreased upon the activation of the NK cells. Moreover, in the P2Y₆-deficient mice, we found that the deficiency of P2Y₆ promoted the development of the NK precursor cells into immature NK and mature NK cells. We also found that the P2Y₆ deficiency increased, but the P2Y₆ receptor agonist UDP or UDP analog 5-OMe-UDP decreased the production of IFN-γ in the activated NK cells. Furthermore, we demonstrated that the P2Y₆-deficient NK cells exhibited stronger cytotoxicity in vitro and antimetastatic effects in vivo. Mechanistically, P2Y₆ deletion promoted the expression of T-bet (encoded by Tbx21), with or without the stimulation of IL-15. In the absence of P2Y₆, the levels of phospho-serine/threonine kinase and pS6 in the NK cells were significantly increased upon the stimulation of IL-15. Collectively, we demonstrated that the P2Y₆ receptor acted as a negative regulator of the NK cell function and inhibited the maturation and antitumor activities of the NK cells. Therefore, inhibition of the P2Y₆ receptor increases the antitumor activities of the NK cells, which may aid in the design of innovative strategies to improve NK cell-based cancer therapy.