Mechanisms of T Cell Memory Quiescence

T 细胞记忆静止机制

• 批准号: 10333343
• 负责人: Surojit Sarkar
• 金额: $ 51.48万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333343
• 关键词: Ablation; Acquired Immunodeficiency Syndrome; Adjuvant; Adoptive Immunotherapy; Adoptive Transfer; Alpha Interleukin 2 Receptor; Antibodies; Antigens; Autoimmune Diseases; B-Lymphocytes; Biochemical; Bioenergetics; Biological Assay; CD28 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CTLA4 gene; CTLA4-Ig; Cells; Chimerism; Communicable Diseases; Competitive Binding; Cytotoxic T-Lymphocytes; Data; Defect; Development; Disease; Effector Cell; Elements; Environment; FRAP1 gene; Failure; Future; Genes; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; Hepatitis C virus; Homeostasis; Human; Immune; Immune system; Immunity; Immunization; Immunologic Memory; Immunologist; Immunosuppression; Immunotherapeutic agent; Impairment; Individual; Infection; Intervention; Killer Cells; Laboratories; Life; Ligands; Longevity; Lymphocyte Function; Maintenance; Malaria; Malignant Neoplasms; Maps; Marker Discovery; Mediating; Mediator of activation protein; Memory; Metabolic; Metabolic Pathway; Mitochondria; Modernization; Molecular; Pathway interactions; Peptide/MHC Complex; Pharmacology; Physiological; Process; Property; Regulatory T-Lymphocyte; Reporter; Reporting; Role; Sentinel; Signal Transduction; T cell differentiation; T memory cell; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Techniques; Tuberculosis; Up-Regulation; Vaccination; adaptive immune response; adaptive immunity; aerobic glycolysis; base; cell type; cytotoxic; cytotoxicity; in vivo; insight; mouse model; novel; novel strategies; pathogen; preservation; programs; public health relevance; tool; vaccination outcome; vaccine-induced immunity

ABSTRACT Cytotoxic T lymphocytes (CTLs) are a key element of adaptive immunity against intracellular infections and cancers. They are potent antigen-directed killer cells that specifically eliminate infected or diseased target cells. Following pathogen control, a subset of effector CTLs gradually shutdown their immediate cytotoxic functions, while retaining heightened responsiveness to future encounter with the same pathogen. Long-term persistence of quiescent CTL memory sentinels is deemed a highly desirable outcome for vaccines and modern adoptive cell immunotherapies, to maintain durable protective immunity. The goal of this proposal is to gain mechanistic insight into how functionally active effector CTLs convert into quiescent memory. The classic paradigm is that effector-to-memory conversion is the default differentiation pathway for memory precursor effector cells (MPECs) after antigen clearance. This is believed to occur simply because of loss of T cell receptor (TCR) stimulation. However, recent studies from our group and others show that Tregs exert a critical role in the process of effector-to-memory transition following antigen clearance. Tregs promote the development of quiescent, yet functionally poised memory cells by suppressing effector and proliferative programs in memory-fated CTLs. In the absence of Tregs during effector-to-memory transition, critical metabolic and transcriptional remodeling does not occur, thus leading to memory failure. Based on brightest expression levels of CTLA-4 on Tregs (amongst all immune cells), and recent human studies noting dysregulation of Tregs and hyperactivation of T and B cells in CTLA-4 haploinsufficient individuals, we propose that CTLA-4 is a critical mediator of Treg-dependent reprogramming of MPECs from effector-to-memory state. We further hypothesize that CTLA-4 mediates its effects through direct as well indirect effects on CD8 T cells. Our preliminary studies showing that exogenous administration of CTLA-4 restores homeostasis and fully reverses the defects in CD8 T cell memory associated with Treg ablation, lend support to the notion that CTLA- 4 is the primary initiating signal for Treg-mediated memory CD8 T cell quiescence. Using unique mouse models, and high throughput cellular and biochemical readouts, the goal of this proposal is to rigorously investigate the interplay of cellular networks, and transcriptional and metabolic programs in orchestrating Treg- mediated help during memory CD8 T cell development. Over the last decade, there has been significant progress in understanding when and how memory fate commitment occurs. However, less is known about how quiescent memory cells are formed from effector CTLs once antigen is cleared, and how quiescent memory cells are maintained for life. Successful completion of proposed studies will uncover novel strategies for augmenting CD8 T cell memory during immunization, and will also afford newer immunotherapeutic approaches against cancers and for maintaining homeostasis in autoimmune disorders.

摘要 细胞毒性T淋巴细胞(CTL)是抵抗细胞内感染和 癌症。它们是强大的抗原导向的杀伤细胞，专门清除感染或患病的目标细胞。 在病原体控制之后，效应CTL的一个子集逐渐关闭其直接的细胞毒功能， 同时保持对未来遇到相同病原体的高反应性。长期持之以恒 静止的CTL记忆哨兵被认为是疫苗和现代采用者非常理想的结果 细胞免疫疗法，以维持持久的保护性免疫。这项提议的目的是获得机械化的 深入了解功能活跃的效应器CTL如何转化为静态内存。 经典的范例是效应器到记忆的转换是 抗原清除后的记忆前体效应细胞(MPECs)。据信，这种情况的发生只是因为 失去T细胞受体(TCR)刺激。然而，我们小组和其他人最近的研究表明，特雷格 在抗原清除后效应器向记忆的转变过程中发挥关键作用。Tregs促销 通过抑制效应器和增殖来发展静止的、但功能稳定的记忆细胞 内存命中注定的CTL中的程序。在效应器到内存转换期间没有Tregs的情况下，关键 代谢和转录重塑不会发生，因此会导致记忆衰竭。基于最聪明的 CTLA-4在Treg上的表达水平(在所有免疫细胞中)，最近的人类研究注意到 我们认为在CTLA-4单倍体不足的个体中，Tregs的失调和T、B细胞的过度激活 CTLA-4是依赖Treg的MPEC从效应器到记忆状态重编程的关键介质。 我们进一步假设CTLA-4通过对CD8 T细胞的直接和间接作用来介导其作用。 我们的初步研究表明，外源性给予CTLA-4可以恢复体内平衡并完全 逆转与Treg消融相关的CD8T细胞记忆缺陷，支持CTLA- 4是Treg介导的记忆CD8 T细胞静止的主要启动信号。使用独特的鼠标 模型，以及高通量细胞和生化读数，这项提议的目标是严格 研究细胞网络、转录和代谢程序在协调Treg-2过程中的相互作用 在记忆性CD8 T细胞发育过程中的中介帮助。 在过去的十年里，在理解记忆何时以及如何命运方面取得了重大进展 承诺就会发生。然而，关于静态存储单元是如何由效应器CTL形成的知之甚少 一旦抗原被清除，以及如何保持静止的记忆细胞的生命。成功完成 拟议的研究将揭示在免疫期间增强CD8 T细胞记忆的新策略，以及 还将提供更新的抗癌免疫治疗方法，并维持体内的动态平衡 自身免疫性疾病。