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: 8013512
• 负责人: Leo Lefrancois
• 金额: $ 46.63万
• 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/8013512
• 关键词: Anatomy; Automobile Driving; Bacterial Infections; CD8B1 gene; Cell Adhesion Molecules; Cells; Confocal Microscopy; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Event; Health; 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; 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）：整合素通过其指导淋巴细胞发育、运动和激活的活性而成为免疫系统的关键组成部分。β 2-整合素CD 11 c在体内的功能在很大程度上是未开发的。我们的数据表明，CD 11 c诱导的主要和记忆CD 8 T细胞响应感染。此外，在不存在CD 11 c的情况下，CD 8 T细胞应答严重减弱，表明CD 11 c在驱动CD 8 T细胞活化中的整体共刺激作用。本文提出的研究将检验CD 11 c通过在活化后早期促进T细胞- DC相互作用来控制CD 8 T细胞应答的假设。提出了三个具体目标来分析CD 11 c共刺激的机制：具体目标1。目的探讨CD 11 c在CD 8 T细胞感染应答中的作用。使用细菌和病毒感染与CD 11 c缺陷型CD 8 T细胞，将测试CD 11 c在促进CD 8 T细胞增殖、分化和存活中的作用。具体目标2。分析CD 8 T细胞表达的CD 11 c在确定感染免疫应答的解剖学中的作用。我们的初步结果，使用原位MHC I类四聚体染色确定了一系列的逐步事件，驱动CD 8 T细胞激活响应单核细胞增生李斯特菌感染。将使用共聚焦显微镜进行原位分析，以评估CD 11 c在应答内源性和过继转移的CD 8 T细胞的活化和运动中的作用。具体目标3。探讨CD 11 c在树突状细胞发育和功能中的作用。DC高水平表达CD 11 c，强烈提示CD 11 c在DC功能中的重要作用。然而，CD 11 c缺陷型DC的分析是复杂的，因为缺乏可靠的DC鉴定标记物。我们已经产生了在CD 11 c启动子控制下表达荧光报告蛋白的转基因小鼠，以规避这个问题。这些小鼠，当呈现CD 11 c缺陷时，将提供在稳态或感染条件下跟踪和分析CD 11 c-/- DC的手段。总之，这些研究将首次分析CD 11 c在CD 8 T细胞和DC活化中的作用。公共卫生救济：该提案的重点是了解一个专门的粘附分子，整合素CD 11 c，在CD 8 T细胞激活响应细菌感染的作用。CD 8 T细胞是参与杀死感染细胞的细胞毒性淋巴细胞，并在保护免受细胞内细菌感染方面发挥核心作用。因此，这项研究对理解感染免疫力具有重大影响，并对有效疫苗的设计具有重要意义。