A2AR limits IL-15-induced generation of CD39⁺ NK cells with high cytotoxicity

CD39-mediated inhibition of natural killer (NK) cell activity has been demonstrated, but the characteristics of CD39⁺ NK cells in humans are not known. We investigated the characteristics of human circulating CD39⁺ NK cells. In healthy donors, the proportion of circulating CD39⁺ NK cells in total NK cells was relatively low compared with that of CD39^- NK cells. Nonetheless, a higher proportion of CD39⁺ NK cells expressed CD107a. Similarly, a higher proportion of CD39⁺ NK cells expressed CD107a in patients with hepatitis B virus or patients with hepatocellular carcinoma. Stimulation with NK-sensitive K562 cells or interleukin (IL)-12/IL-18 activated CD39⁺ NK cells to express higher levels of CD107a, IFN-γ and TNF-α, relative to CD39^- NK cells. Importantly, IL-15 induced the generation of CD39⁺ NK cells. In contrast, A2A adenosine receptor (A2AR) ligation suppressed the generation of CD39⁺ NK cells by inhibiting IL-15 signaling. These data for the first time demonstrated that A2AR counteracts IL-15-induced generation of human CD39⁺ NK cells, which have a stronger cytotoxicity than CD39^- NK cells. IL-15-induced human CD39⁺ NK cells might be better choice for immunotherapy based on adoptive transfer of NK cells.