Longevity and Functionality of CD8+ Tissue-resident Memory T cells in the Intestinal Tract

项目摘要/摘要 急性胃肠炎，可归因于肠道细胞内病原体，是发病率和 死亡率，特别是儿童和老年人的死亡率。仅诺沃克病毒本身就对近20%的 全世界每年有200,000例以上的死亡病例。疫苗可能会调节对病毒的保护 通过建立永久位于细胞内的记忆CD8 T细胞群 肠道组织的实质。这个记忆T细胞的子集被称为组织驻留记忆T细胞 (TRM)，可以在病原体扩散和表现出来之前，介导感染细胞的快速清除 从临床上看。事实上，新的证据支持CD8TRM在动物局部病原体保护中的作用 肠道感染模型。然而，目前尚不清楚TRM是否为流动人口。对于理性的 疫苗设计要在临床上成功开发CD8 TRM，CD8 TRM的寿命必须是 地址。广泛的初步分析现在表明，肠道TRM人群经历了 指数衰减，而血液中的记忆T细胞保持稳定。《特定目标1》将测试这一点 通过一种新的基于聚合酶链式反应的肠道TRM定量的问题和潜在的初步证实 调查结果。此外，我们还将评估长寿肠道记忆T细胞的解剖学来源。特定的 目标2将解决原有的CD8 TRM细胞被新的CD8 TRM细胞取代的程度。 总而言之，这些研究将解决长期存在的寿命、耐用性和功能性问题 CD8TRM细胞。长期存活的肠道TRM的保护能力将被测试以对抗生理上的 相关病原体。结果将对预防细胞内肠道感染的疫苗策略产生直接影响 病原体。组织驻留记忆T细胞在很大程度上被研究不足，更倾向于 血源性淋巴细胞群。现在越来越多的人达成共识，细胞之间的接口- 介导性免疫和组织实质值得重新关注。从长远来看，这些研究概述了 这将对CD8 TRM细胞如何介导保护性免疫、自身免疫具有更广泛的意义 发病机制、超敏反应和肿瘤控制，不仅在肠道，而且在整个 尸体。

Project Summary/Abstract Acute gastroenteritis, attributable to enteric intracellular pathogens, is a significant cause of morbidity and mortality, particularly in children and the elderly. By itself, norovirus is accountable for nearly 20% of worldwide cases and upwards of 200,000 deaths annually. Vaccines may mediate protection against intracellular pathogens by establishing memory CD8 T cell populations that are permanently situated within the intestinal tissue parenchyma. This subset of memory T cells, known as tissue-resident memory T cells (TRM), could mediate rapid clearance of infected cells before the pathogen disseminates and manifests clinically. Indeed, emerging evidence supports a role for CD8 TRM in local pathogen protection in animal models of intestinal infection. However, it is unknown whether TRM are a transient population. For rational vaccine design to successfully exploit CD8 TRM in a clinical context, the longevity of CD8 TRM must be addressed. Extensive preliminary analysis now indicates that the intestinal TRM population undergoes exponential decay, in contrast to bloodborne memory T cells which remain stable. Specific Aim 1 will test this question through a novel PCR-based quantification of intestinal TRM and potentially substantiate preliminary findings. Additionally, we will evaluate the anatomic origin of long-lived intestinal memory T cells. Specific Aim 2 will address the extent to which preexisting CD8 TRM cells are displaced by new CD8 TRM cells. Collectively, these studies will address the long-standing questions of longevity, durability, and functionality of CD8 TRM cells. The protective capacity of long-lived intestinal TRM will be tested against a physiologically relevant pathogen. Results will have a direct impact on vaccine strategies to protect against intracellular enteric pathogens. Tissue-resident memory T cells have largely been understudied with preference given to bloodborne lymphocyte populations. There is now a growing consensus that the interface between cell- mediated immunity and the tissue parenchyma warrants renewed focus. In the long-term, the studies outlined here will have broader implications as to how CD8 TRM cells mediate protective immunity, autoimmune pathogenesis, hypersensitivity reactions, and tumor control, not only in the intestinal tract, but throughout the body.