近日，美国德克萨斯大学MD安德森癌症中心的孙少聪研究组，发现去泛素化酶Otub1通过IL-15通路参与调节CD8⁺T细胞和NK细胞的激活。2019年7月出版的《自然—免疫学》杂志发表了这一研究成果。

CD8⁺T细胞和自然杀伤（NK）细胞是免疫系统抵抗病原体和癌症的核心细胞组分，这两者均依赖于白介素（IL）-15进行稳态调控。

研究人员发现，IL-15同样介导了CD8⁺T细胞应对抗原活化时的稳态起始，这由去泛素化酶Otub1所调控。IL-15通过将Otub1招募至细胞膜来泛素化AKT，从而抑制其激活；而AKT作为激酶对于T细胞的活化和代谢是关键的。在小鼠模型中，Otub1的缺失使得CD8⁺T细胞对IL-15的反应异常，即使得初始CD8⁺T细胞对抗原刺激过度敏感，因此代谢重编程和效应功能增强。Otub1也调控NK细胞的成熟与活化。Otub1的缺失通过释放CD8⁺T细胞和NK细胞的活力极大地增强了抗肿瘤免疫。这些发现表明，Otub1通过作为IL-15通路的检查点来参与调控CD8⁺T细胞和NK细胞的活化。

附：英文原文

Title: The deubiquitinase Otub1 controls the activation of CD8 + T cells and NK cells by regulating IL-15-mediated priming

Author: Xiaofei Zhou, Jiayi Yu, Xuhong Cheng, Baoyu Zhao, Ganiraju C. Manyam, Li Zhang, Kimberly Schluns, Pingwei Li, Jing Wang, Shao-Cong Sun

Issue&Volume:Volume 20 Issue 7, July 2019

Abstract: CD8+ T cells and natural killer (NK) cells are central cellular components of immune responses against pathogens and cancer, which rely on interleukin (IL)-15 for homeostasis. Here we show that IL-15 also mediates homeostatic priming of CD8+ T cells for antigen-stimulated activation, which is controlled by a deubiquitinase, Otub1. IL-15 mediates membrane recruitment of Otub1, which inhibits ubiquitin-dependent activation of AKT, a kinase that is pivotal for T cell activation and metabolism. Otub1 deficiency in mice causes aberrant responses of CD8+ T cells to IL-15, rendering naive CD8+ T cells hypersensitive to antigen stimulation characterized by enhanced metabolic reprograming and effector functions. Otub1 also controls the maturation and activation of NK cells. Deletion of Otub1 profoundly enhances anticancer immunity by unleashing the activity of CD8+ T cells and NK cells. These findings suggest that Otub1 controls the activation of CD8+ T cells and NK cells by functioning as a checkpoint of IL-15-mediated priming.

DOI: 10.1038/s41590-019-0405-2

Source:https://www.nature.com/articles/s41590-019-0405-2