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

项目总结/摘要 尽管基于CD 8 + T细胞的免疫疗法已经彻底改变了血液癌症的治疗， 在慢性病毒感染中，T细胞耗竭仍然是充分实现其治疗潜力的障碍。T细胞 衰竭是在免疫后CD 8 + T细胞的增殖、细胞因子产生和效应子功能的分级损失。 慢性抗原刺激不是每个T细胞都以相同的程度或相同的速度耗尽， 控制耗竭敏感性的异质性的因素是不确定的。陆克文实验室是第一个 表明一个以前被忽视的幼稚CD 8 + T细胞库内异质性的来源-发育 来源-在急性感染后CD 8 + T细胞的命运中是决定性的。我们认为，发展的起源也是 我们的初步数据显示，新生儿CD 8 + T细胞（来源于新生儿T细胞）在慢性感染中是重要的。 胚胎肝）对表型和功能衰竭具有抗性，而成体细胞（来自成体骨 骨髓）更易受感染。我们还发现过表达Lin 28 b，一种癌胚RNA结合蛋白， 负调节let-7 microRNA，并且仅在胎肝HSC中表达，足以将 成人表型到新生儿表型。因此，我们的目标是剖析发展调节 对慢性刺激的潜在差异反应的程序。我们将使用创新的方法来测试我们的 假设成人CD 8 + T细胞比新生儿细胞更容易因年龄相关的 let-7/Lin 28 b表达的差异，其使代谢远离有氧糖酵解。在目标1中，我们 确定发育起源和Lin 28 b表达如何影响CD 8 + T细胞耗竭的倾向。 这一目标的结果将阐明不同年龄的CD 8+细胞中耗尽细胞的不同亚群是如何产生的。 T细胞，并阐明发育途径是否能防止不可逆的衰竭。在目标2中， 将确定Lin 28 b介导的代谢程序如何成为不同年龄细胞易感性的基础， 耗尽.这些结果将为发育印迹影响T细胞的机制提供一个解释 衰竭动力学通过研究发育不同的CD 8 + T细胞对慢性感染的反应， 以及let-7，Lin 28 b和代谢编程在所述反应中所起的作用，该提案将揭示一种新的方法， 以前未探索的因素在确定T细胞耗竭。因为发育中根深蒂固的途径 所有的T细胞都是如此，了解这些途径并找到微调它们的策略，将有广泛的 影响到新生儿疾病、慢性感染和癌症等。

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.