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

• DOI: 10.1073/pnas.1904125116
• Publication Date: 2019-08-13T00:25:31Z
• Authors: Xuefu Wang; Rui Sun; Xiaolei Hao; Zhe-Xiong Lian; Haiming Wei; Zhigang Tian
• Keywords: Cytotoxicity, Immunologic; Interleukin-15; Male; Mice, Knockout; 0303 health sciences; Interleukin-17; Melanoma, Experimental; Cell Differentiation; Lymphocyte Activation; 3. Good health; Killer Cells, Natural; Mice; 03 medical and health sciences; Suppressor of Cytokine Signaling 3 Protein; Animals; Signal Transduction

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.