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NF-κB诱导激酶在抗肿瘤免疫中维持T细胞的代谢适应性
作者:小柯机器人 发布时间:2021/1/6 17:22:09

近日,美国德克萨斯大学MD安德森癌症中心孙少聪及其研究组发现,NF-κB诱导激酶在抗肿瘤免疫中维持T细胞的代谢适应性。相关论文于2021年1月4日在线发表在《自然—免疫学》杂志上。

研究人员表明缺乏NF-κB诱导激酶(NIK)损害了糖酵解诱导,从而使CD8+效应T细胞在肿瘤微环境中功能低下。相反,NIK的异位表达促进CD8+T细胞代谢和效应子功能,从而显著地增强了抗肿瘤免疫力并提高了T细胞过继治疗的疗效。NIK通过不依赖于NF-κB的机制来调节T细胞代谢,该机制涉及稳定己糖激酶2(HK2,一种糖酵解途径的限速酶)。NIK通过控制细胞中活性氧的含量来防止HK2的自噬降解,这反过来又涉及调节葡萄糖6磷酸脱氢酶(G6PD),该酶介导抗氧化剂NADPH的产生。

研究人员显示,G6PD–NADPH氧化还原系统对于HK2稳定性和活化T细胞中的新陈代谢非常重要。这些发现将NIK确立为T细胞代谢的关键调节因子,并突出了代谢调节的翻译后机制。

据介绍,朝向有氧糖酵解的代谢重编程是塑造免疫应答的关键机制。

附:英文原文

Title: NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity

Author: Meidi Gu, Xiaofei Zhou, Jee Hyung Sohn, Lele Zhu, Zuliang Jie, Jin-Young Yang, Xiaofeng Zheng, Xiaoping Xie, Jie Yang, Yaoyao Shi, Hans D. Brightbill, Jae Bum Kim, Jing Wang, Xuhong Cheng, Shao-Cong Sun

Issue&Volume: 2021-01-04

Abstract: Metabolic reprograming toward aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show that deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8+ effector T cells hypofunctional in the tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8+ T cell metabolism and effector function, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. NIK regulates T cell metabolism via a NF-κB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK prevents autophagic degradation of HK2 through controlling cellular reactive oxygen species levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that mediates production of the antioxidant NADPH. We show that the G6PD–NADPH redox system is important for HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a post-translational mechanism of metabolic regulation.

DOI: 10.1038/s41590-020-00829-6

Source: https://www.nature.com/articles/s41590-020-00829-6

期刊信息

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex