Metabolic Regulation of CD8 T Cell Memory Development

CD8 T 细胞记忆发育的代谢调节

• 批准号: 8258242
• 负责人: Erika L Pearce
• 金额: $ 38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-11-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258242
• 关键词: 5' -AMP-activated protein kinase; Address; Antigens; Bacterial Antigens; Bacterial Infections; Biochemical; CD8B1 gene; Catabolic Process; Catabolism; Cells; Cellular Immunity; Chronic; Citric Acid Cycle; Communicable Diseases; Data; Defect; Development; Disease; FDA approved; Failure; Family; Generations; Genes; Genetic; Goals; Immune response; Immunity; Immunologic Memory; Immunotherapy; Infection; Interleukin-1; Journals; Life; Link; Lipids; Maintenance; Malignant Neoplasms; Memory; Metabolic; Metabolism; Metformin; Mitochondria; Molecular; Mus; Nature; Pathway interactions; Pharmaceutical Preparations; Phase; Play; Population; Process; Public Health; Publishing; Regulation; Role; Signal Transduction; Sirolimus; T cell response; T memory cell; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Time; Tumor Necrosis Factor Receptor; Vaccination; adapter protein; base; fatty acid metabolism; fatty acid oxidation; gain of function; improved; in vivo; instrumentation; loss of function; mouse model; novel; pathogen; programs; public health relevance; research study; response; tool; vaccine efficacy

DESCRIPTION (provided by applicant): Immunological memory is the basis of vaccination, which may be the most significant public health tool available today. CD8 T cells play a crucial role in immunity to infections with intracellular pathogens. Upon stimulation, these T cells undergo a developmental program characterized by distinct phases encompassing first the expansion, and then contraction, of antigen-specific effector T cell populations, followed by the persistence of long-lived memory T cells that mediate immunity to re-infection. The mechanisms underlying the generation and maintenance of memory CD8 T cells remain unclear. Previously we demonstrated that mice lacking Traf6 (a TNFR and IL-1/TLR family adapter protein) in T cells mount effector CD8 T cell responses to infection, but are unable to establish memory CD8 T cells. Our experiments revealed that this CD8 T cell intrinsic failure of memory development was tightly linked to the inability of Traf6-deficient CD8 T cells to initiate mitochondrial fatty acid oxidation, a pathway of lipid catabolism that fuels the TCA cycle. Based on our observations, and a panel of supportive preliminary data, we hypothesize that catabolic processes of energy generation are essential for the development of memory CD8 T cells after infection and that Traf6 plays a key role regulating this process. We will test this hypothesis through the following specific aims: 1) Determine how fatty acid metabolism regulates memory CD8 T cell development; 2) Determine the extent of Traf6-dependent regulation of memory CD8 T cell development; and 3) Establish that pharmacological manipulation of CD8 T cell metabolism can be therapeutic. The long-term goal of these studies is to facilitate the development of immunotherapies against infectious diseases. PUBLIC HEALTH RELEVANCE: Immunological memory is the basis of vaccination, which may be the most significant public health tool available today. Nevertheless, the detailed underlying mechanisms regulating the generation and persistence of long-lived immunological memory remain largely undefined. Our proposal aims to build on our recent novel findings that strongly implicate a requirement for catabolic energy generating processes in the establishment of immunological memory and seeks to provide proof of principle that existing FDA approved drugs that are currently widely prescribed for metabolic and other disorders can be used to great effect to improve vaccine efficacy.

描述（由申请人提供）：免疫记忆是疫苗接种的基础，疫苗接种可能是当今最重要的公共卫生工具。 CD8 T 细胞在细胞内病原体感染的免疫中发挥着至关重要的作用。受到刺激后，这些 T 细胞会经历一个发育程序，其特征是不同的阶段，首先是抗原特异性效应 T 细胞群的扩张，然后收缩，然后是介导对再次感染的免疫的长寿命记忆 T 细胞的持续存在。记忆 CD8 T 细胞产生和维持的机制仍不清楚。之前我们证明，T 细胞中缺乏 Traf6（一种 TNFR 和 IL-1/TLR 家族衔接蛋白）的小鼠会产生效应 CD8 T 细胞对感染的反应，但无法建立记忆 CD8 T 细胞。我们的实验表明，CD8 T 细胞内在的记忆发育失败与 Traf6 缺陷的 CD8 T 细胞无法启动线粒体脂肪酸氧化（一种促进 TCA 循环的脂质分解代谢途径）密切相关。根据我们的观察和一组支持性初步数据，我们假设能量产生的分解代谢过程对于感染后记忆 CD8 T 细胞的发育至关重要，并且 Traf6 在调节这一过程中发挥着关键作用。我们将通过以下具体目标来检验这一假设：1）确定脂肪酸代谢如何调节记忆CD8 T细胞发育； 2) 确定Traf6依赖性记忆CD8 T细胞发育的调节程度； 3) 确定 CD8 T 细胞代谢的药理学操作可以具有治疗作用。这些研究的长期目标是促进针对传染病的免疫疗法的开发。 公共卫生相关性：免疫记忆是疫苗接种的基础，这可能是当今可用的最重要的公共卫生工具。然而，调节长期免疫记忆的产生和持续的详细的潜在机制在很大程度上仍然不明确。我们的提案旨在建立在我们最近的新发现的基础上，该发现强烈暗示了在建立免疫记忆中分解代谢能量生成过程的要求，并寻求提供原理证明，证明目前广泛用于治疗代谢和其他疾病的 FDA 批准的现有药物可以用于提高疫苗功效有很大效果。