Regulation of CD8+ T cell exhaustion by let-7/Lin28b in different stages of life

let-7/Lin28b 在生命不同阶段对 CD8 T 细胞耗竭的调节

基本信息

批准号：
10594406
负责人：
Viviana Isabel Maymi
金额：
$ 4.34万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594406
关键词：
Adoptive Transfer Adult Affect Antigens Behavior Biological Assay Bone Marrow CD8-Positive T-Lymphocytes Cell Compartmentation Cells Cellular Metabolic Process Cellular biology Cellular immunotherapy Chronic Chronic Disease Clinical Data Data Development Disease Effector Cell Epigenetic Process Etiology Family Fetal Liver Flow Cytometry Foundations Genus Hippocampus Glycolysis Glycolysis Inhibition Hematologic Neoplasms Hematopoietic stem cells Heterogeneity Human Immunity Immunotherapy Individual Infant Infection Interferon Type II Life Longevity Lymphocytic choriomeningitis virus Malignant Neoplasms Measures Mediating Memory Metabolic Metabolism MicroRNAs Molecular Neonatal Oxidative Phosphorylation Pathway interactions Patients Phenotype Physiological Play Predisposition Production Proliferating RNA-Binding Proteins Regulation Regulator Genes Regulatory Pathway Repression Resistance Respiratory Tract Infections Role Source System T cell response T-Lymphocyte Testing Therapeutic Virus Diseases Work acute infection aerobic glycolysis age related aged cell age chronic infection cytokine design exhaust exhaustion experimental study extracellular extracellular vesicles immunopathology imprint innovation insight metabolic profile metabolomics mouse model neonatal death neonate novel overexpression pathogen patient response pharmacologic programmed cell death protein 1 programs protective pathway response transcriptome sequencing tumor

项目摘要

Project Summary / Abstract Though CD8+ T cell-based immunotherapies have revolutionized treatment for hematologic cancers and chronic viral infections, T cell exhaustion remains a barrier to fully realizing their therapeutic potential. T cell exhaustion is the hierarchical loss of proliferation, cytokine production, and effector function of CD8+ T cells after chronic antigen stimulation. Not every T cell becomes exhausted to the same degree or at the same rate, but the factors governing heterogeneity in susceptibility to exhaustion are undefined. The Rudd lab was the first to show that a previously-overlooked source of heterogeneity within the naïve CD8+ T cell pool—developmental origin—is deterministic in a CD8+ T cell’s fate after acute infection. We believe that developmental origin is also consequential in chronic infection, for our preliminary data shows that neonatal CD8+ T cells (derived from the fetal liver) are resistant to phenotypic and functional exhaustion, whereas adult cells (derived from adult bone marrow) are more susceptible. We also showed that overexpressing Lin28b, an oncofetal RNA-binding protein that negatively regulates let-7 microRNAs and is only expressed in fetal liver HSCs, is sufficient to convert the adult phenotype to the neonatal one. Our objective is therefore to dissect the developmentally-regulated programs underlying differential responses to chronic stimulation. We will use innovative approaches to test our hypothesis that adult CD8+ T cells are more susceptible to exhaustion than neonatal cells due to age-related differences in let-7/Lin28b expression that program metabolism away from aerobic glycolysis. In Aim 1, we will determine how developmental origin and Lin28b expression impact propensity for CD8+ T cell exhaustion. Results from this aim will make clear how distinct subsets of exhausted cells arise among differently-aged CD8+ T cells, and shed light on whether developmental pathways protect against irreversible exhaustion. In Aim 2, we will determine how Lin28b-mediated metabolic programs underlie differently-aged cells’ susceptibility to become exhausted. These results will provide a mechanistic explanation for how developmental imprinting affects T cell exhaustion dynamics. By investigating the developmentally-distinct CD8+ T cell response to chronic infection, and the role that let-7, Lin28b, and metabolic programing play in said response, this proposal will uncover a previously-unexplored factor in determining T cell exhaustion. Because developmentally-ingrained pathways are common to all T cells, understanding these pathways—and finding strategies to fine-tune them—will have wide- reaching implications for neonatal disease, chronic infection, and cancer alike.

项目概要/摘要尽管基于 CD8+ T 细胞的免疫疗法已经彻底改变了血液癌症和慢性病毒感染后，T 细胞耗竭仍然是 T 细胞充分发挥其治疗潜力的障碍。耗竭是指 CD8+ T 细胞在增殖、细胞因子产生和效应功能等方面的分层丧失。慢性抗原刺激并非每个 T 细胞都以相同程度或相同速率耗尽，但控制疲劳敏感性异质性的因素尚不清楚，陆克文实验室是第一个这样做的。表明先前被忽视的幼稚 CD8+ T 细胞库中的异质性来源——发育起源——急性感染后 CD8+ T 细胞的命运是决定性的，我们相信发育起源也是决定性的。慢性感染的后果，因为我们的初步数据显示新生儿 CD8+ T 细胞（源自胎儿肝脏）对表型和功能衰竭具有抵抗力，而成体细胞（源自成体骨）我们还发现过表达 Lin28b（一种肿瘤胎儿 RNA 结合蛋白）更容易受到影响。负调节let-7 microRNA并且仅在胎儿肝脏HSC中表达，足以将因此，我们的目标是剖析发育调节的表型。我们将使用创新的方法来测试我们对慢性刺激的不同反应的程序。假设由于年龄相关，成人 CD8+ T 细胞比新生儿细胞更容易衰竭 let-7/Lin28b 表达的差异使新陈代谢远离有氧糖酵解在目标 1 中，我们将确定发育起源和 Lin28b 表达如何影响 CD8+ T 细胞耗竭的倾向。这一目标的结果将清楚地表明不同年龄的 CD8+ 中不同的耗竭细胞亚群是如何产生的 T 细胞，并阐明发育途径是否可以防止不可逆的衰竭。将确定 Lin28b 介导的代谢程序如何影响不同年龄细胞的易感性这些结果将为发育印记如何影响 T 细胞提供机制解释。通过研究发育上不同的 CD8+ T 细胞对慢性感染的反应，以及 let-7、Lin28b 和代谢编程在所述响应中发挥的作用，该提案将揭示因为发育过程中根深蒂固的途径是以前未探索过的决定 T 细胞耗竭的因素。所有 T 细胞共有的，了解这些途径并找到微调它们的策略将具有广泛的意义。其影响涉及新生儿疾病、慢性感染和癌症等。