Ketone Body Metabolism in CD8+ T Cell Responses

CD8 T 细胞反应中的酮体代谢

基本信息

批准号：
10522730
负责人：
Russell Jones
金额：
$ 65.08万
依托单位：
VAN ANDEL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-08 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522730
关键词：
Acetoacetates Acetyl Coenzyme A Adenosine Triphosphate Animals Bacteria Bioenergetics Blood Blood Circulation CD8-Positive T-Lymphocytes CD8B1 gene Caloric Restriction Cell Lineage Cell physiology Cells Cellular Metabolic Process Citric Acid Cycle Coenzyme A Communicable Diseases Communities Couples Data Diet Diet Modification Dietary Intervention Drops Effectiveness Enzymes Epigenetic Process Eragrostis Esters Fasting Gene Expression Genetic Transcription Glucose Goals Histone Acetylation Host Defense Immune Immune response Immunity Immunization In Vitro Infection Interferon Type II Intervention Ketone Bodies Ketones Knock-out Knowledge Listeria Listeriosis Lymphocytic choriomeningitis virus Malignant Neoplasms Mediating Memory Metabolic Metabolism Mitochondria Modeling Mus Outcome Oxides Pathogenicity Pathway interactions Pharmacology Phase Primary Infection Process Production Research Role Stable Isotope Labeling Supplementation System T cell differentiation T cell response T-Lymphocyte Techniques Testing Therapeutic Human Experimentation Virus acute infection adaptive immunity base beta-Hydroxybutyrate cell mediated immune response cytokine dietary effector T cell fighting histone modification in vivo mouse model novel opportunistic pathogen pathogen prevent response vaccination strategy

项目摘要

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.

抽象的人们认为，抗感染 T 细胞主要利用葡萄糖来增强宿主对病毒的防御和细菌；然而，使用新的体内代谢物分析技术，最近发现葡萄糖不是 CD8+ T 细胞响应线粒体能量 (ATP) 产生的主要燃料体内感染，特别是在感染的后期阶段，这给免疫代谢界带来了挑战。迫切需要定义和了解维持抗感染 CD8+ T 细胞的代谢物。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/或增强免疫策略的初步数据指向酮体——一种丰富的代谢物。血液中对感染、禁食和某些饮食的反应——作为 CD8+ T 细胞效应功能的关键燃料，数据表明酮体可用性通过调节影响 T 细胞介导的适应性免疫然而，T 细胞内在的效应功能（即细胞因子产生）的全面影响。酮体代谢对 CD8+ T 细胞反应的影响仍然未知。总体目标：表征 T 细胞内在酮体代谢的机制（“酮解作用”）在对感染的免疫反应过程中影响 CD8+ T 细胞的代谢和功能，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 细胞内在酮体代谢是支持宿主防御的非冗余途径通过促进和指导 CD8+ T 细胞体内生物能和效应器功能：(1) 表征 CD8+ T 细胞中的酮体代谢及其对 CD8+ T 细胞介导的免疫的影响 (2) 解构酮体代谢影响 T 细胞效应功能的机制， (3)剖析全身酮体代谢对CD8+T细胞反应的影响。影响：完成后，这项拟议的研究将确定激活的 CD8+ T 细胞如何利用酮体，剖析酮体对CD8+T细胞效应功能的影响（初次感染清除率）和记忆反应（长期免疫），并定义了全身酮体可用性如何通过定义酮体代谢的作用来控制和影响 CD8+ T 细胞介导的宿主防御。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的药物干预措施，以促进感染的清除加强免疫策略。