Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, the Chinese Academy of Sciences (CAS) Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 230027 Anhui, China.
Institute of Immunology, University of Science and Technology of China, Hefei, 230027 Anhui, China.
Proc Natl Acad Sci U S A. 2019 Aug 27;116(35):17409-17418. doi: 10.1073/pnas.1904125116. Epub 2019 Aug 12.
Increasing evidence demonstrates that IL-17A promotes tumorigenesis, metastasis, and viral infection. Natural killer (NK) cells are critical for defending against tumors and infections. However, the roles and mechanisms of IL-17A in regulating NK cell activity remain elusive. Herein, our study demonstrated that IL-17A constrained NK cell antitumor and antiviral activity by restraining NK cell maturation. It was observed that the development and metastasis of tumors were suppressed in IL-17A-deficient mice in the NK cell-dependent manner. In addition, the antiviral activity of NK cells was also improved in IL-17A-deficient mice. Mechanistically, ablation of IL-17A signaling promoted generation of terminally mature CD27CD11b NK cells, whereas constitutive IL-17A signaling reduced terminally mature NK cells. Parabiosis or mixed bone marrow chimeras from and wild-type (WT) mice could inhibit excessive generation of terminally mature NK cells induced by IL-17A deficiency. Furthermore, IL-17A desensitized NK cell responses to IL-15 and suppressed IL-15-induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) via up-regulation of SOCS3, leading to down-regulation of Blimp-1. Therefore, IL-17A acts as the checkpoint during NK cell terminal maturation, which highlights potential interventions to defend against tumors and viral infections.
越来越多的证据表明，IL-17A 促进肿瘤发生、转移和病毒感染。自然杀伤 (NK) 细胞对于抵御肿瘤和感染至关重要。然而，IL-17A 调节 NK 细胞活性的作用和机制仍不清楚。本研究表明，IL-17A 通过抑制 NK 细胞成熟来限制 NK 细胞的抗肿瘤和抗病毒活性。研究发现，在 NK 细胞依赖性方式下，缺乏 IL-17A 的小鼠中肿瘤的发展和转移受到抑制。此外，缺乏 IL-17A 的小鼠的 NK 细胞抗病毒活性也得到了提高。机制上，IL-17A 信号的缺失促进了终末成熟的 CD27^+CD11b^+ NK 细胞的产生，而组成性的 IL-17A 信号则减少了终末成熟的 NK 细胞。和野生型 (WT) 小鼠之间的联体或混合骨髓嵌合体可以抑制由 IL-17A 缺乏引起的终末成熟 NK 细胞的过度产生。此外，IL-17A 通过上调 SOCS3 使 NK 细胞对 IL-15 的反应脱敏，并抑制 IL-15 诱导的信号转导和转录激活因子 5 (STAT5) 的磷酸化，从而下调 Blimp-1。因此，IL-17A 作为 NK 细胞终末成熟的检查点，这突出了针对肿瘤和病毒感染的潜在干预措施。
