Mechanisms of T Cell Memory Quiescence

T 细胞记忆静止机制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的细胞毒性 T 淋巴细胞 (CTL) 是抵抗细胞内感染的适应性免疫的关键要素癌症。它们是有效的抗原导向杀伤细胞，可以特异性消除感染或患病的靶细胞。病原体控制后，效应 CTL 的子集逐渐关闭其直接细胞毒功能，同时保持对未来遇到相同病原体的高度反应能力。长期坚持静态 CTL 记忆哨兵的出现被认为是疫苗和现代收养的非常理想的结果细胞免疫疗法，维持持久的保护性免疫力。该提案的目标是获得机械深入了解功能活跃的效应器 CTL 如何转化为静态记忆。经典范例是效应器到记忆的转换是默认的分化途径抗原清除后的记忆前体效应细胞（MPEC）。据信，发生这种情况的原因很简单 T 细胞受体 (TCR) 刺激丧失。然而，我们小组和其他人最近的研究表明 Tregs 在抗原清除后效应器到记忆的转变过程中发挥关键作用。 Tregs 促进通过抑制效应细胞和增殖细胞，形成静止但功能稳定的记忆细胞受内存影响的 CTL 中的程序。在效应器到记忆转变过程中缺乏 Tregs 的情况下，关键代谢和转录重塑不会发生，从而导致记忆障碍。基于最亮的 CTLA-4 在 Tregs（所有免疫细胞中）的表达水平，以及最近的人类研究指出 CTLA-4 单倍体不足个体中 Tregs 的失调以及 T 细胞和 B 细胞的过度激活，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 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 可恢复体内平衡并充分逆转与 Treg 消融相关的 CD8 T 细胞记忆缺陷，支持 CTLA- 图4是Treg介导的记忆CD8 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、转录和代谢程序在协调 Treg 中的相互作用记忆 CD8 T 细胞发育过程中介导的帮助。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发生。然而，对于效应 CTL 是如何形成静态记忆细胞的，人们知之甚少。一旦抗原被清除，以及如何维持静态记忆细胞的终生。顺利完成拟议的研究将揭示在免疫过程中增强 CD8 T 细胞记忆的新策略，以及还将提供针对癌症和维持体内稳态的新免疫治疗方法自身免疫性疾病。