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）是针对细胞内感染的适应性免疫的关键要素，癌症。它们是有效的抗原指导的杀伤细胞，专门消除了感染或患病的靶细胞。遵循病原体控制，一部分效应子CTL逐渐关闭其直接的细胞毒性功能，同时保留对同一病原体对未来相遇的反应性的提高。长期持久性静态的CTL记忆前哨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，以保持持久的保护性免疫。该提议的目的是获得机械深入了解功能活动效应器CTL如何转换为静态内存。经典范式是效应器到内存转换是默认的差异途径抗原清除后记忆前体效应细胞（MPEC）。据信这仅仅是因为 T细胞受体（TCR）刺激的丧失。但是，我们小组和其他人的最新研究表明Tregs 在抗原清除后的效应子到内存过渡过程中发挥关键作用。 Tregs促进通过抑制效应器和增殖来发展静止的，但功能齐全的记忆细胞内存命令的CTL中的程序。在效应器到内存过渡期间没有Treg的情况下，关键没有发生代谢和转录重塑，因此导致记忆力失败。基于最亮 CTLA-4在Tregs（所有免疫细胞中）的表达水平，最近的人类研究指出 Tregs的失调和CTLA-4单倍弹性个体中T和B细胞的过度激活，我们建议该CTLA-4是从效应子到内存状态的MPEC的Treg依赖性重编程的关键介体。我们进一步假设CTLA-4通过直接和间接影响CD8 T细胞介导了其影响。我们的初步研究表明，CTLA-4的外源给药可恢复体内平衡和完全逆转与Treg消融相关的CD8 T细胞存储器中的缺陷，对CTLA-的概念的支持 4是Treg介导的内存CD8 T细胞静脉的主要启动信号。使用唯一的鼠标模型以及高吞吐量的细胞和生化读数，该提案的目标是严格研究细胞网络的相互作用以及在策划Treg-的转录和代谢程序记忆CD8 T细胞发育过程中介导的帮助。在过去的十年中，了解记忆何时以及如何命运方面取得了重大进展承诺发生。但是，关于如何由效应子CTL形成静态记忆单元的知之甚少一旦清除了抗原，以及如何维持静止的记忆细胞。成功完成拟议的研究将发现新的策略，以增加免疫过程中CD8 T细胞记忆的增强，并且还将提供针对癌症的新免疫治疗方法并维持体内平衡自身免疫性疾病。