Ketone Body Metabolism in CD8+ T Cell Responses

摘要 人们一直认为，抗感染的T细胞主要利用葡萄糖为宿主抵御病毒的能力提供燃料 和细菌；然而，使用新的体内代谢物图谱技术，最近发现 葡萄糖不是CD8+T细胞产生线粒体能量(ATP)的主要燃料 体内感染，特别是在感染的后期。这为免疫新陈代谢社区提供了 迫切需要定义和了解维持抗感染CD8+T细胞的代谢物。这 知识对于开发有效的免疫代谢干预措施以加强宿主防御至关重要 和/或加强免疫战略。初步数据指向酮体-一种富含代谢物的类别 在血液中对感染、禁食和某些饮食做出反应--作为CD8+T细胞效应器功能的关键燃料， 有数据表明，酮体的可用性通过调节T细胞介导的获得性免疫 表观遗传水平上的效应器功能(即细胞因子的产生)。然而，T细胞的全面影响--内在 酮体代谢对CD8+T细胞反应的影响尚不清楚。 总体目标：描述T细胞内源性酮体代谢的机制 (“酮溶解”)影响CD8+T细胞的新陈代谢和功能，在感染的免疫反应中，并 确定全身酮体代谢在CD8+T细胞功能和宿主防御中的作用。 假设：T细胞内源性酮体代谢是支持宿主防御的非冗余途径 在体内通过补充和引导CD8+T细胞的生物能量和效应器功能。具体目标：(1) CD8+T细胞酮体代谢特征及其对CD8+T细胞免疫的影响 反应，(2)解构酮体代谢影响T细胞效应器功能的机制， (3)分析全身酮体代谢对CD8+T细胞应答的影响。 影响：完成后，这项拟议的研究将确定激活的CD8+T细胞如何利用 酮小体，解剖了酮小体对CD8+T细胞效应器功能的影响(原发感染 清除)和记忆反应(长期免疫)，并定义了全身酮体的可利用性 控制和影响CD8+T细胞介导的宿主防御。通过定义酮体代谢在体内的作用 保护性CD8+T细胞介导的免疫反应，我们将为定义饮食和 优化内源性宿主防御以促进感染清除的药物干预 加强免疫战略。

ABSTRACT It has been believed that infection-fighting T cells primarily use glucose to fuel host defense against viruses and bacteria; however, using new in vivo metabolite profiling techniques, it has recently been found that glucose is not the primary fuel for mitochondrial energy (ATP) production in CD8+ T cells responding to infection in vivo, particularly in later phases of infection. This presents the immunometabolism community with a critical need to define and understand the metabolites that sustain infection-fighting CD8+ T cells. This knowledge is crucial for developing effective immuno-metabolic interventions that strengthen host defense and/or enhance immunization strategies. Preliminary data point to ketone bodies—a metabolite class enriched in the blood in response to infection, fasting, and certain diets—as a key fuel for CD8+ T cell effector function, with data suggesting that ketone body availability influences T cell-mediated adaptive immunity by regulating effector function (i.e., cytokine production) at the epigenetic level. However, the full impact of T cell-intrinsic ketone body metabolism on CD8+ T cell responses remains uncharacterized. OVERALL OBJECTIVE: to characterize the mechanisms by which T cell-intrinsic ketone body metabolism (“ketolysis”) impacts CD8+ T cell metabolism and function during immune responses to infection, and to determine the role of systemic ketone body metabolism in CD8+ T cell function and host defense. HYPOTHESIS: T cell-intrinsic ketone body metabolism is a non-redundant pathway supporting host defense by fueling and directing CD8+ T cell bioenergetics and effector function in vivo. SPECIFIC AIMS: (1) Characterize ketone body metabolism in CD8+ T cells and its impact on CD8+ T cell-mediated immune responses, (2) Deconstruct the mechanisms by which ketone body metabolism impacts T cell effector function, (3) Dissect the impact of systemic ketone body metabolism on CD8+ T cell responses. IMPACT: Upon completion, this proposed research will have determined how activated CD8+ T cells utilize ketone bodies, dissected the impact of ketone bodies on CD8+ T cell effector function (primary infection clearance) and memory responses (long-term immunity), and defined how systemic ketone body availability is controlled and impacts CD8+ T cell-mediated host defense. By defining the role of ketone body metabolism in protective CD8+ T cell-mediated immune responses, we will have laid the groundwork for defining dietary and pharmacological interventions to optimize endogenous host defenses to boost clearance of infections as well as enhance immunization strategies.