2023年8月30日，《自然》杂志在线发表了美国科学家的一项最新研究成果。来自美国加州大学圣迭戈分校的Ananda W. Goldrath研究小组发现，T细胞组织驻留的代谢程序增强肿瘤免疫力。

为了系统地确定支持组织常驻记忆CD8⁺ T（T_RM）细胞分化、存活和功能的代谢重编程的基础，研究人员利用了体内功能基因组学、非靶向代谢组学和病毒特异性记忆CD8⁺ T细胞群的转录组学。研究人员发现，记忆CD8⁺ T细胞对组织驻留进行了一系列适应性调整，包括在转录因子SREBP2活性增强的驱动下，依赖于甲羟戊酸胆固醇途径的非甾体产物，如辅酶Q。这种新陈代谢适应在小肠中最为明显，T_RM细胞在小肠中与膳食胆固醇接触，并保持高度活化状态，小鼠和人类不同类型肿瘤中的功能性肿瘤浸润淋巴细胞也具有这种适应性。

通过缺失Fdft1或过表达PDSS2来加强辅酶Q的合成，促进了线粒体呼吸、病毒感染后记忆T细胞的形成以及抗肿瘤免疫力的增强。总之，通过对T_RM细胞新陈代谢的系统探索，研究人员揭示了如何利用这些程序在急性感染的情况下促进记忆CD8⁺ T细胞的形成并增强抗肿瘤免疫力。

据介绍，T_RM细胞可在再感染部位提供快速和长期的保护。具有T_RM细胞特征的肿瘤浸润淋巴细胞可保持增强的效应功能，预测对免疫疗法的反应，并伴随更好的预后。因此，如果能更好地了解T细胞驻留组织的代谢策略，就能为增强组织和实体瘤免疫反应的新方法提供依据。

附：英文原文

Title: Metabolic programs of T cell tissue residency empower tumour immunity

Author: Reina-Campos, Miguel, Heeg, Maximilian, Kennewick, Kelly, Mathews, Ian T., Galletti, Giovanni, Luna, Vida, Nguyen, Quynhanh, Huang, Hongling, Milner, J. Justin, Hu, Kenneth H., Vichaidit, Amy, Santillano, Natalie, Boland, Brigid S., Chang, John T., Jain, Mohit, Sharma, Sonia, Krummel, Matthew F., Chi, Hongbo, Bensinger, Steven J., Goldrath, Ananda W.

Issue&Volume: 2023-08-30

Abstract: Tissue resident memory CD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8+ T cell populations. We found that memory CD8+ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate–cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8+ T cell formation in the context of acute infections and enhance antitumour immunity.

DOI: 10.1038/s41586-023-06483-w

Source: https://www.nature.com/articles/s41586-023-06483-w