Zhu Siyu, Zhang Chen, Sun Qian, Wang Yang, Yu Wenwen, Wei Feng, Ren Xiubao
Department of Immunology and Biotherapy, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
Department of Minimally Invasive Esophageal Surgery, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
J Oncol. 2022 Jun 23;2022:8724933. doi: 10.1155/2022/8724933. eCollection 2022.
CD+CD+ natural killer T (NKT)-like cells have an immune function of T cells and NK cells, which play an important role in antitumor and antiviral immune responses. This study aims to establish a CD+CD+ NKT-like cell model by simulating the memory NK effect induced by cytokines IL-12, IL-15, and IL-18 (IL-12/15/18) and explore the formation mechanism. Our study found that the IL-12/15/18 preactivated CD+CD+ NKT-like cells exhibited enhanced IFN- production in response to restimulation with IL-12/15/18 for 6h on day 7. The intrinsic potential of these trained cells was significantly improved, showing an increase in IFN-, TNF-, and cell proliferation potential. The IFN- release, granzyme B level, and proliferation ability significantly increased when stimulated by NK-cell-sensitive K562 tumor cells. Among these cytokines, the combination of IL-12/15/18 was particularly effective. After the preactivation of IL-12/15/18, some cell surface proteins related to function and differentiation, such as CD11b, CD62 L, NKp46, NKG2A, and CD127, showed an evident and consistent change trend. The CDK4/6 inhibitor can effectively weaken this effect, and the expression of cyclin D1, Rb protein phosphorylation, and E2F-1 decreased significantly. Our work revealed that cytokine IL-12/15/18 can induce CD+CD+ NKT-like cells to obtain enhanced training immunity, which was a memory-like phenomenon.
CD+CD+自然杀伤T（NKT）样细胞具有T细胞和NK细胞的免疫功能，在抗肿瘤和抗病毒免疫反应中发挥重要作用。本研究旨在通过模拟细胞因子IL-12、IL-15和IL-18（IL-12/15/18）诱导的记忆NK效应建立CD+CD+ NKT样细胞模型，并探索其形成机制。我们的研究发现，IL-12/15/18预激活的CD+CD+ NKT样细胞在第7天用IL-12/15/18再次刺激6小时后，IFN-产生增强。这些受过训练的细胞的内在潜能显著提高，表现为IFN-、TNF-和细胞增殖潜能增加。当受到NK细胞敏感的K562肿瘤细胞刺激时，IFN-释放、颗粒酶B水平和增殖能力显著增加。在这些细胞因子中，IL-12/15/18的组合特别有效。IL-12/15/18预激活后，一些与功能和分化相关的细胞表面蛋白，如CD11b、CD62L、NKp46、NKG2A和CD127，呈现出明显且一致的变化趋势。CDK4/6抑制剂可有效减弱这种效应，细胞周期蛋白D1、Rb蛋白磷酸化和E2F-1的表达显著降低。我们的工作表明，细胞因子IL-12/15/18可诱导CD+CD+ NKT样细胞获得增强的训练免疫，这是一种记忆样现象。
