美国范安德尔研究所Russell G. Jones团队近期取得重要工作进展，他们研究发现，酮解作用通过对组蛋白乙酰化的影响驱动CD8⁺T细胞效应功能。相关研究成果2023年7月28日在线发表于《免疫》杂志上。

据介绍，环境营养物质的可用性影响T细胞代谢和功能以及塑造免疫结果。

研究人员确定酮体（KB），包括β-羟基丁酸酯（βOHB）和乙酰乙酸酯（AcAc）），是支持CD8⁺ T细胞代谢和效应器功能的必要燃料。βOHB直接增加CD8⁺ T效应细胞（Teff）细胞因子的产生和细胞溶解活性，并且KB氧化（酮症酸解）是Teff细胞对细菌感染和肿瘤攻击的反应所必需的。CD8⁺ Teff细胞优先使用KB而不是葡萄糖来在体外和体内为三羧酸（TCA）循环提供燃料。KB直接增强呼吸能力和TCA循环依赖性代谢途径，为CD8⁺ T细胞功能提供燃料。从机制上讲，βOHB是CD8⁺ T细胞中乙酰辅酶a产生的主要底物，并通过对组蛋白乙酰化的影响调节效应反应。

总之，这一研究结果表明，细胞固有酮症酸中毒是最佳CD8⁺ T细胞效应反应的代谢和表观遗传学驱动因素。

附：英文原文

Title: Ketolysis drives CD8+ T cell effector function through effects on histone acetylation

Author: Katarzyna M. Luda, Joseph Longo, Susan M. Kitchen-Goosen, Lauren R. Duimstra, Eric H. Ma, McLane J. Watson, Brandon M. Oswald, Zhen Fu, Zachary Madaj, Ariana Kupai, Bradley M. Dickson, Lisa M. DeCamp, Michael S. Dahabieh, Shelby E. Compton, Robert Teis, Irem Kaymak, Kin H. Lau, Daniel P. Kelly, Patrycja Puchalska, Kelsey S. Williams, Connie M. Krawczyk, Dominique Lévesque, Franois-Michel Boisvert, Ryan D. Sheldon, Scott B. Rothbart, Peter A. Crawford, Russell G. Jones

Issue&Volume: 2023-07-28

Abstract: Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)—including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)—as essential fuels supporting CD8+ T cell metabolism and effector function. βOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.

DOI: 10.1016/j.immuni.2023.07.002

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00314-X