Role of CD11c in CD8 T cell response to infection

CD11c 在 CD8 T 细胞对感染的反应中的作用

• 批准号: 7762238
• 负责人: Leo Lefrancois
• 金额: $ 47.1万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7762238
• 关键词: Anatomy; Automobile Driving; Bacterial Infections; CD8B1 gene; Cell Adhesion Molecules; Cells; Confocal Microscopy; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Event; Homeostasis; ITGAX gene; Immune response; Immune system; Immunity; In Situ; Infection; Integrins; Listeria monocytogenes; Lymphocyte; MHC Class I Genes; Memory; Movement; Mus; Names; Play; Principal Investigator; Proteins; Public Health; Reporter; Research; Role; Series; Staining method; Stains; Stream; Sum; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Transgenic Mice; Vaccines; Virus Diseases; design; in vivo; killings; programs; promoter; response

DESCRIPTION (provided by applicant): Integrins are critical components of the immune system through their activities in directing lymphocyte development, movement and activation. The function of the b2-integrin CD11c in vivo is largely unexplored. Our data show that CD11c is induced on primary and memory CD8 T cells responding to infection. Moreover, in the absence of CD11c, the CD8 T cell response is severely diminished indicating an integral costimulatory role for CD11c in driving CD8 T cell activation. The studies proposed here will test the hypothesis that CD11c controls CD8 T cell response by promoting T cell- DC interactions early after activation. Three specific aims are proposed to analyze the mechanisms of CD11c costimulation: Specific Aim 1. To determine the role of CD11c in the early CD8 T cell response to infection. Using bacterial and viral infections in conjunction with CD11c-deficient CD8 T cells, the role of CD11c in promoting proliferation, differentiation and survival of CD8 T cells will be tested. Specific Aim 2. To analyze the role of CD11c expressed by CD8 T cells in determining the anatomy of the immune response to infection. Our preliminary results using in situ MHC class I tetramer staining identified a series of stepwise events that drive CD8 T cell activation in response to infection with Listeria monocytogenes. In situ analysis using confocal microscopy will be performed to assess the role of CD11c in activation and movement of responding endogenous and adoptively transferred CD8 T cells. Specific Aim 3. To analyze the role of CD11c in development and function of dendritic cells. The high level expression of CD11c by DC strongly suggests an important role for CD11c in DC function. However, the analysis of CD11c-deficient DC is complicated due to the lack of a reliable marker for DC identification. We have produced transgenic mice expressing a fluorescent reporter protein under control of the CD11c promoter to circumvent this issue. These mice, when rendered CD11c-deficient, will provide the means to track and analyze CD11c-/- DC under conditions of homeostasis or infection. In sum, these studies will provide the first analysis of the role of CD11c in CD8 T cell and DC activation. PUBLIC HEALTH RELEVENCE: This proposal is focused on understanding the role of a specialized adhesion molecule, the integrin CD11c, in CD8 T cell activation in response to a bacterial infection. CD8 T cells are cytotoxic lymphocytes involved in killing of infected cells and play a central role in protection against intracellular bacterial infections. Therefore, this research has substantial impact on understanding immunity to infection and holds implications for design of effective vaccines.

描述（由申请人提供）：整合素是免疫系统的重要组成部分，通过它们的活动来指导淋巴细胞的发育、运动和激活。b2整合素CD11c在体内的功能在很大程度上是未知的。我们的数据表明，CD11c在原代和记忆CD8 T细胞上被诱导对感染作出反应。此外，在缺乏CD11c的情况下，CD8 T细胞的反应严重减弱，这表明CD11c在驱动CD8 T细胞活化方面具有整体的共刺激作用。本文提出的研究将验证CD11c在激活后早期通过促进T细胞- DC相互作用来控制CD8 T细胞反应的假设。本文提出了分析CD11c共刺激机制的三个具体目标：确定CD11c在早期CD8 T细胞对感染的反应中的作用。利用细菌和病毒感染结合CD11c缺陷的CD8 T细胞，CD11c在促进CD8 T细胞增殖、分化和存活中的作用将被测试。具体目标2。分析CD8 T细胞表达的CD11c在确定感染免疫反应解剖中的作用。我们使用原位MHC I类四聚体染色的初步结果确定了一系列驱动CD8 T细胞激活以响应单核细胞增生李斯特菌感染的逐步事件。将使用共聚焦显微镜进行原位分析，以评估CD11c在响应内源性和过继转移CD8 T细胞的激活和运动中的作用。具体目标3。分析CD11c在树突状细胞发育及功能中的作用。DC中CD11c的高水平表达强烈提示CD11c在DC功能中的重要作用。然而，由于缺乏可靠的DC识别标记物，cd11c缺陷DC的分析是复杂的。我们已经生产了转基因小鼠，在CD11c启动子的控制下表达一种荧光报告蛋白，以避免这个问题。这些小鼠，当CD11c缺失时，将提供在稳态或感染条件下跟踪和分析CD11c-/- DC的手段。总之，这些研究将首次分析CD11c在CD8 T细胞和DC活化中的作用。公共卫生相关性：本提案的重点是了解一种特殊的粘附分子，整合素CD11c，在CD8 T细胞活化对细菌感染的反应中的作用。CD8 T细胞是细胞毒性淋巴细胞，参与杀死被感染的细胞，并在防止细胞内细菌感染方面发挥核心作用。因此，这项研究对了解感染免疫具有重大影响，并对有效疫苗的设计具有启示意义。