CD4+ T cell-based immunity to gastrointestinal infection

基于 CD4 T 细胞的胃肠道感染免疫

• 批准号: 8370171
• 负责人: Ryan William Nelson
• 金额: $ 3.45万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370171
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Adoptive Transfer; Antigen Presentation; Antigens; Bacteria; Bacterial Counts; Bacterial Infections; CD4 Positive T Lymphocytes; Cell Count; Cell physiology; Cells; Cellular Immunity; Chronic; Disease; Exhibits; Focal Infection; Frequencies; Gastrointestinal tract structure; Generations; Goals; Growth; Human; Immune; Immune response; Immunity; Individual; Infection; Interferons; Interleukin-2; Knowledge; Lead; Lymphokines; Measures; Mediating; Methods; Microbe; Mission; Modeling; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Opportunistic Infections; Patients; Phenotype; Production; Research; Role; Salmonella; Salmonella enterica; Salmonella infections; Site; System; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; T-bet protein; Testing; Th1 Cells; Tumor Necrosis Factor-alpha; Vaccines; base; cytokine; design; exhaustion; gastrointestinal; gastrointestinal infection; gastrointestinal system; improved; in vivo; macrophage; mouse model; novel; pathogen; prevent; research study; response

DESCRIPTION (provided by applicant): While considerable progress has been made in characterizing the mechanisms that regulate CD4+ T cell responses to some acute infections, knowledge of the response to chronic infections of the gastrointestinal tract remains elusive. The overall goal of this research plan is to directly test the requirements for generating and maintaining a protective CD4+ T cell response during a chronic gastrointestinal infection with an important pathogen. A definitive study of this nature is complicated by two major issues in the field: 1) the relatively low frequency of CD4+ T cells with unique T cell antigen receptors (TCRs) recognizing specific pathogen-derived antigens makes the cells difficult to detect and 2) the lack of relevant mouse models that accurately reproduce human infection. These issues will be overcome by employing a cutting edge enrichment method to isolate and characterize the CD4+ T cells specifically responding to a chronic Salmonella infection in vivo. The central hypothesis of this application is that chronic, localized infection generates highly differentiated "multifunctional" CD4+ T cells that control pathogen burden and prevent disease by secreting macrophage-activating (interferon-3/tumor necrosis factor-1) and growth promoting (interleukin-2) lymphokines. Therefore, my specific aims are designed to address 1) which CD4+ T cell subset is capable of providing the best immune protection to Salmonella and 2) if repeated TCR stimulation increases the cytokine production capacity of responding T cells. This proposal supports the mission of the NIDDK by focusing on CD4+ T cell responses that are critical for controlling the gastrointestinal pathogen Salmonella enterica and could provide useful information on how to develop a more effective vaccine.

描述（由申请人提供）：虽然在表征调节CD4+ T细胞对某些急性感染的机制方面取得了很大进展，但了解对胃肠道慢性感染的反应的了解仍然难以捉摸。该研究计划的总体目标是直接测试具有重要病原体的慢性胃肠道感染期间生成和维持保护性CD4+ T细胞反应的要求。对这种性质的确切研究使该领域的两个主要问题变得复杂：1）识别具有特定病原体衍生的抗原的独特T细胞抗原受体（TCRS）的CD4+ T细胞相对较低的频率，使细胞难以检测到难以检测，2）缺乏相关的小鼠模型，这些模型可以准确地再现人类感染。这些问题将通过采用尖端富集方法来隔离和表征特异性反应体内慢性沙门氏菌感染的CD4+ T细胞。该应用的中心假设是，慢性局部感染会产生高度分化的“多功能” CD4+ T细胞，这些CD4+ T细胞通过分泌巨噬细胞激活（干扰素3/肿瘤坏死因子1）和促进（interukinkin-2）淋巴因子来控制病原体负担并预防疾病。因此，我的特定目的旨在解决哪个CD4+ T细胞子集能够为沙门氏菌提供最佳免疫保护，并且2）如果重复的TCR刺激会增加响应T细胞的细胞因子产生能力。该提案通过关注CD4+ T细胞反应来支持NIDDK的任务，CD4+ T细胞反应对于控制胃肠道病原体肠肠肠肠肠肠情节至关重要，并可以提供有关如何开发更有效疫苗的有用信息。