CD4+ T cell-based immunity to gastrointestinal infection

描述（由申请人提供）：虽然在描述调节CD4+ T细胞对某些急性感染反应的机制方面取得了相当大的进展，但对胃肠道慢性感染反应的知识仍然难以捉摸。本研究计划的总体目标是直接测试在重要病原体的慢性胃肠道感染期间产生和维持保护性CD4+ T细胞反应的需求。该领域的两个主要问题使这种性质的明确研究变得复杂：1)具有识别特定病原体来源抗原的独特T细胞抗原受体（TCRs）的CD4+ T细胞的频率相对较低，使得这些细胞难以检测；2)缺乏准确复制人类感染的相关小鼠模型。这些问题将通过采用尖端的富集方法来分离和表征体内对慢性沙门氏菌感染特异性反应的CD4+ T细胞来克服。本应用的中心假设是，慢性、局部感染产生高度分化的“多功能”CD4+ T细胞，通过分泌巨噬细胞激活因子（干扰素-3/肿瘤坏死因子-1）和生长促进因子（白细胞介素-2）来控制病原体负担和预防疾病。因此，我的具体目标是解决1)哪个CD4+ T细胞亚群能够对沙门氏菌提供最好的免疫保护，以及2)是否重复的TCR刺激增加了应答T细胞的细胞因子生产能力。该建议通过关注CD4+ T细胞反应来支持NIDDK的使命，CD4+ T细胞反应对控制胃肠道病原体肠沙门氏菌至关重要，并可以为如何开发更有效的疫苗提供有用的信息。

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.