IL-17 constrains natural killer cell activity by restraining IL-15–driven cell maturation via SOCS3

Significance IL-17A promotes tumorigenesis, metastasis, and viral infection. However, the underlying mechanisms remain elusive. By using diverse gene-deficient mice, antibody depletion, and animal models, we show that IL-17A promotes tumorigenesis, metastasis, and viral infection by constraining NK cell antitumor and antiviral activity via inhibition of NK cell maturation. The ablation of IL-17A signaling increases terminally mature CD27 − CD11b + NK cells, whereas constitutive IL-17A signaling reduces terminally mature NK cells. IL-17A suppresses IL-15–induced phosphorylation of STAT5 via up-regulation of SOCS3 in NK cells, leading to inhibition of NK cell terminal maturation. Therefore, IL-17A acts as the checkpoint during NK cell terminal maturation, which suggests potential interventions to defend against tumors and infections.