Antigen-specific CD8 T cell migration and protective immunity in permissive and r

为了对感染产生有效的反应，病原体特异性淋巴细胞必须首先能够有效地到达感染部位。由于许多病原体在特定组织内入侵和复制，动员CD8T细胞并将其靶向感染组织的能力对于控制最初的感染至关重要。此外，在特定组织内建立一个长期存活的CD8 T细胞群对于预防未来的再次感染非常重要。越来越多的证据表明，单个组织可以通过产生特定的趋化因子和通过‘印迹’CD8T细胞来表达组织归巢标记来调节CD8T细胞的进入。然而，CD8T细胞进入和滞留到生殖器粘膜等许多组织的规则尚不清楚。本项目的目标是1)通过检测CD8 T细胞、局部组织微环境和其他免疫细胞类型之间的相互作用，确定局部感染背景下CD8 T细胞进入不同组织的要求；2)检测局部攻击后组织特异性和招募记忆性CD8 T细胞提供的保护性免疫。利用单纯疱疹病毒2型感染的模型，我们将通过不同的途径进行免疫，以产生局部感染，并评估炎症和CD4T细胞帮助效应CD8T细胞进入不同组织的需求。由于女性生殖道等器官的粘膜衬里是抵御病原体入侵的主要屏障，我们将重点了解将CD8 T细胞引导到生殖器粘膜的要求，以及长期驻留在组织中的CD8 T细胞赋予保护性免疫的能力。了解CD8T细胞向单个组织迁移的要求及其建立记忆CD8T细胞群的能力对于制定疫苗接种策略具有重要意义，特别是对HIV-1、单纯疱疹病毒和人乳头状瘤病毒等感染。

In order to mount an effective response against an infection, pathogen-specific lymphocytes must first be able to efficiently reach the site of infection. As many pathogens invade and replicate within a specific tissue, the ability to mobilize and target CD8 T cells to an infected tissue is critical for controlling the initial infection. Furthermore, the establishment of a long-lived memory CD8 T cell population within that specific tissue is important for protection against future re-infection. Mounting evidence suggests that individual tissues can regulate the entry of CD8 T cells through the production of specific chemokines and by 'imprinting' the CD8 T cells to express tissue- homing markers. However, the rules that govern CD8 T cell entry and retention to many tissues such as the genital mucosa are unknown. This project will aim to 1) determine the requirements for CD8 T cell entry into different tissues in the context of a localized infection by examining the interaction amongst CD8 T cells, the local tissue microenvironment and other immune cell types and 2) examine the protective immunity provided by tissue-specific vs. recruited memory CD8 T cells after localized challenge. Using a model of herpes simplex virus-2 infection, we will immunize through different routes to generate localized infections and assess the requirement of inflammation and CD4 T cell help for effector CD8 T cell trafficking into different tissues. As the mucosal lining of organs such as the female genital tract stand as major barriers against invading pathogens, we will focus our efforts on understanding the requirements for directing CD8 T cells to the genital mucosa and the ability of long-lived tissue-resident memory CD8 T cells to confer protective immunity. Understanding of the requirements of CD8 T cell migration to individual tissues and their ability to establish memory CD8 T cell populations has important implications for the development of vaccination strategies, notably to infections such as HIV-1, herpes simplex virus and human papillomavirus.