CD4+ T cell-based immunity to gastrointestinal infection

描述(由申请人提供)：尽管在表征调节CD4+T细胞对某些急性感染的反应的机制方面已经取得了相当大的进展，但对胃肠道慢性感染的反应的知识仍然难以捉摸。这项研究计划的总体目标是直接测试在一种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细胞反应的要求。这一性质的明确研究因该领域的两个主要问题而变得复杂：1)具有识别特定病原体衍生抗原的独特T细胞抗原受体(TCR)的CD4+T细胞的频率相对较低，使得这些细胞很难被检测到；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一种尖端的浓缩方法来分离和表征体内对慢性沙门氏菌感染特异反应的CD4+T细胞来克服。这一应用的中心假设是，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(干扰素-3/肿瘤坏死因子-1)和促进生长(白介素2)淋巴因子来控制病原体负担并预防疾病。因此，我的特定目标是为了解决1)哪个CD4+T细胞亚群能够为沙门氏菌提供最好的免疫保护，以及2)如果重复TCR刺激增加反应T细胞的细胞因子产生能力。这项建议支持NIDDK的使命，将重点放在对控制胃肠道病原体肠沙门氏菌至关重要的CD4+T细胞反应上，并可能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.