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）是针对细胞内感染的获得性免疫的关键要素， 癌的它们是有效的抗原定向杀伤细胞，特异性消除感染或患病的靶细胞。 在病原体控制之后，效应CTL的子集逐渐关闭其立即细胞毒性功能， 同时保持对未来遇到相同病原体的高度反应性。长期坚持 静止CTL记忆哨兵被认为是疫苗和现代过继免疫的高度理想的结果。 细胞免疫疗法，以维持持久的保护性免疫。该提案的目标是获得机械性 深入了解功能活性效应CTL如何转化为静态记忆。 经典的范例是效应器到记忆转换是细胞的默认分化途径。 记忆前体效应细胞（MPEC）。据信，这仅仅是因为 T细胞受体（TCR）刺激的丧失。然而，我们小组和其他人最近的研究表明， 在抗原清除后效应子向记忆转换的过程中发挥关键作用。Tumblr promote 通过抑制效应细胞和增殖细胞， 在内存中运行的CTL。在效应器到记忆转换期间不存在TdR， 代谢和转录重塑不会发生，从而导致记忆力衰退。基于最聪明的 CTLA-4在T细胞上的表达水平（在所有免疫细胞中），最近的人类研究指出， 在CTLA-4单倍不足的个体中，T淋巴细胞的失调和T和B细胞的过度活化，我们提出， CTLA-4是MPEC从效应器状态到记忆状态的Treg依赖性重编程的关键介质。 我们进一步假设CTLA-4通过对CD 8 T细胞的直接和间接作用介导其作用。 我们的初步研究表明，外源性给予CTLA-4可以恢复体内平衡， 逆转了与Treg消融相关的CD 8 T细胞记忆缺陷，支持CTLA- 4是Treg介导的记忆性CD 8 T细胞静止的主要起始信号。使用独特的鼠标 模型，以及高通量细胞和生化读数，该提案的目标是严格 研究细胞网络的相互作用，转录和代谢程序在编排Treg- 介导的帮助记忆CD 8 T细胞的发展。 在过去的十年里，在理解记忆的命运何时以及如何发生方面取得了重大进展。 承诺发生。然而，很少有人知道静态记忆细胞是如何从效应细胞毒性T淋巴细胞形成的 一旦抗原被清除，以及静止的记忆细胞如何维持生命。成功完成 提出的研究将揭示在免疫过程中增强CD 8 T细胞记忆的新策略， 还将提供新的免疫方法来对抗癌症和维持体内平衡， 自身免疫性疾病