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

项目总结/摘要 急性胃肠炎，可归因于肠细胞内病原体，是发病的重要原因， 死亡率，特别是儿童和老年人。就其本身而言，诺如病毒是近20%的 全球范围内的病例和每年超过200，000例死亡。疫苗可以介导对 通过建立记忆性CD 8 T细胞群， 肠组织实质。这种记忆T细胞亚群，称为组织驻留记忆T细胞， (TRM)，可以在病原体传播和表现之前介导感染细胞的快速清除 临床上事实上，新出现的证据支持CD 8 TRM在动物中局部病原体保护中的作用。 肠道感染模型。然而，目前还不清楚TRM是否是一个短暂的人口。为合理 为了在临床背景下成功利用CD 8 TRM的疫苗设计，CD 8 TRM的寿命必须是 处理。现在广泛的初步分析表明，肠道TRM群体经历了 指数衰减，与保持稳定的血源性记忆T细胞相反。具体目标1将测试这一点 通过一种新的基于PCR的定量肠道TRM的问题，并可能证实初步 调查结果。此外，我们将评估长寿命肠道记忆T细胞的解剖起源。具体 目标2将解决预先存在的CD 8 TRM细胞被新的CD 8 TRM细胞置换的程度。 总的来说，这些研究将解决长期存在的寿命，耐用性和功能性问题 CD 8 TRM细胞将测试长寿命肠道TRM的保护能力， 相关病原体结果将对疫苗策略产生直接影响，以防止细胞内肠 病原体组织驻留记忆T细胞在很大程度上没有得到充分研究， 血淋巴细胞群。现在有一个越来越多的共识，即细胞之间的界面- 介导的免疫和组织实质值得重新关注。从长远来看，研究概述了 这将对CD 8 TRM细胞如何介导保护性免疫、自身免疫 发病机制，超敏反应和肿瘤控制，不仅在肠道，但在整个 身体

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.