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

• 批准号: 10389670
• 负责人: Viviana Isabel Maymi
• 金额: $ 4.25万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 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/10389670
• 关键词: Regulation; CD8+; cell; exhaustion; let

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.

项目摘要/摘要 尽管基于CD8+T细胞的免疫疗法已经彻底改变了血液病的治疗方法， 对于慢性病毒感染，T细胞耗尽仍然是充分发挥其治疗潜力的障碍。T细胞 衰竭是指CD8+T细胞在以下情况下的增殖、细胞因子产生和效应功能的分级丧失 慢性抗原刺激。并不是每个T细胞都会以相同的程度或速度耗尽，但 影响精疲力竭易感性的异质性的因素尚不明确。陆克文实验室是第一个 表明在幼稚的CD8+T细胞池中一个以前被忽视的异质性来源-发育 起源-在急性感染后CD8+T细胞的命运是决定性的。我们认为，发育的起源也是 对于我们的初步数据显示，新生儿CD8+T细胞(来源于 胎肝)对表型和功能衰竭有抵抗力，而成体细胞(来自成骨) (骨髓)更易受影响。我们还发现，过表达肿瘤胎儿RNA结合蛋白Lin28b 负向调节let-7 microRNAs并且仅在胎肝HSCs中表达，足以将 成体表型向新生儿表型转变。因此，我们的目标是剖析受发育调节的 对慢性刺激的不同反应的潜在程序。我们将使用创新的方法来测试我们的 由于年龄相关，成人CD8+T细胞比新生儿细胞更容易耗尽的假设 使代谢远离有氧糖酵解的let-7/Lin28b表达的差异。在目标1中，我们将 确定发育起源和Lin28b表达如何影响CD8+T细胞耗竭倾向。 这一目标的结果将清楚地表明不同年龄的CD8+中如何产生不同的耗尽细胞亚群 T细胞，并阐明发育途径是否能防止不可逆转的衰竭。在目标2中，我们 将决定Lin28b介导的代谢程序如何影响不同年龄细胞的易感性 筋疲力尽。这些结果将为发育印记如何影响T细胞提供一个机制解释 力竭动力学。通过研究发育不同的CD8+T细胞对慢性感染的反应， 以及let-7、Lin28b和代谢编程在上述反应中所起的作用，该提案将揭示一种 决定T细胞耗竭的未知因素。因为在发育上根深蒂固的路径 对于所有T细胞来说，了解这些途径并找到微调策略将有广泛的- 对新生儿疾病、慢性感染和癌症的影响。