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

抗原特异性 CD8 T 细胞迁移和保护性免疫

• 批准号: 7993772
• 负责人: HAINA SHIN
• 金额: $ 4.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993772
• 关键词: Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Communicable Diseases; Development; Female; Focal Infection; Future; Genital system; HIV-1; Homing; Human Herpesvirus 2; Human Papillomavirus; Immune; Immune response; Immunity; Individual; Infection; Infection Control; Inflammation; Invaded; Knowledge; Life; Lymphocyte; Memory; Modeling; Mucous Membrane; Organ; Population; Production; Recruitment Activity; Route; Simplexvirus; Site; T-Lymphocyte; Tissues; Vaccines; burden of illness; cell motility; cell type; chemokine; design; disorder control; imprint; improved; pathogen; public health relevance; response; trafficking; vaccination strategy

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Pathogens that are sexually transmitted, such as HIV-1, herpes simplex virus and human papillomavirus, must pass through the mucosal lining of the genital tract. Developing immunological strategies to control these infections will be critical for controlling disease burden around the world. By increasing our knowledge of how CD8 T cell migrate to the genital tract and how immune responses there may be optimized, we can improve our chances of designing effective vaccines and providing protection against globally prevalent infectious diseases.

描述（由申请人提供）：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侵入和复制，因此动员和靶向CD 8 T细胞到受感染组织的能力对于控制初始感染至关重要。此外，在该特定组织内建立长寿命记忆性CD 8 T细胞群对于防止未来再感染是重要的。越来越多的证据表明，个体组织可以通过产生特异性趋化因子和通过“印记”CD 8 T细胞以表达组织归巢标志物来调节CD 8 T细胞的进入。然而，CD 8 T细胞进入和保留到许多组织（如生殖器粘膜）的规则尚不清楚。该项目旨在1）通过检查CD 8 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CD 8 T细胞进入不同组织的要求，以及2）检查组织特异性与募集记忆CD 8 T细胞在局部攻击后提供的保护性免疫。使用单纯疱疹病毒-2感染的模型，我们将通过不同的途径免疫以产生局部感染，并评估炎症和CD 4 T细胞帮助效应CD 8 T细胞运输到不同组织中的需求。由于女性生殖道等器官的粘膜衬里是抵御入侵病原体的主要屏障，我们将集中精力了解将CD 8 T细胞引导至生殖器粘膜的要求以及长寿命组织驻留记忆CD 8 T细胞赋予保护性免疫的能力。了解CD 8 T细胞迁移到单个组织的要求及其建立记忆CD 8 T细胞群的能力对于疫苗接种策略的发展具有重要意义，特别是对于HIV-1，单纯疱疹病毒和人乳头瘤病毒等感染。 公共卫生相关性：性传播的病原体，如HIV-1、单纯疱疹病毒和人乳头瘤病毒，必须通过生殖道粘膜层。制定免疫策略来控制这些感染对于控制世界各地的疾病负担至关重要。通过增加我们对CD 8 T细胞如何迁移到生殖道以及如何优化免疫反应的了解，我们可以提高设计有效疫苗的机会，并为全球流行的传染病提供保护。