Role of T cells in self-limited mucosal infections

T细胞在自限性粘膜感染中的作用

• 批准号: 7096555
• 负责人: LYNN BRY
• 金额: $ 12.85万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096555
• 关键词: Enterobacteriaceae; bacteria infection mechanism; bacterial cytopathogenic effect; bactericidal immunity; cytokine; enzyme linked immunosorbent assay; flow cytometry; helper T lymphocyte; host organism interaction; humoral immunity; immunoglobulins; laboratory mouse; mucosal immunity; passive immunization; septicemia

DESCRIPTION (provided by applicant): We have found that the early adaptive serum immunoglobulin response plays an important role in surviving infection with non-invasive mucosal pathogens. B cells and CD4+ T cells are required to survive infection with Citrobacter rodentium, the mouse homolog for the enteropathogenic E. coli (EPEC). Wild-type mice develop small breaks in epithelial integrity during infection, allowing C. rodentium and members of the normal flora a direct portal of entry into the host. However, immunocompetent mice develop an early and robust serum IgM response and have few colony forming units (CFU) in end organs including liver and spleen. In contrast, infection proves lethal in mice lacking B cells or CD4+ T cells. Colonic infection leads to significant polymicrobial sepsis with damage to end organs. Unlike wild-type mice, CD4-deficient animals fail to mount pathogen-specific serum IgM or IgG responses during active infection. These results implicate a critical role for the systemic adaptive immune response in surviving and eventually clearing a mucosal infection. This research plan outlines a strategy to (1) establish the protective capacity of serum immunoglobulins during active infection, (2) establish the function and location(s) where CD4+ T cells stimulate a pathogen-specific humoral response in adoptively transferred CD4-deficient mice, (3) determine the location, immunophenotype, and cytokine secretion profiles of adoptively transferred CD4+ T cells, and (4) identify T cell co-stimulatory molecules and Th cytokines important in this response. In conjunction with these aims the candidate proposes a curriculum to further training in immunology, lymphocyte biology, pathology and ethical conduct in research. The candidate has completed the core clinical training as a resident in pathology and will devote at least 75% effort towards research. This training provides a necessary step in the candidate's goal to become an independent researcher investigating questions in mucosal immunology and host-microbial cross-talk in intestinal environments.

描述（由申请人提供）：我们发现，早期的自适应血清免疫球蛋白反应在幸存的非侵入性粘膜病原体中幸存下来起着重要作用。 B细胞和CD4+ T细胞需要在肠啮齿动物（EPEC）的小鼠同源物（EPEC）的小鼠同源物中生存。野生型小鼠在感染过程中会在上皮完整性中出现微小的断裂，使啮齿动物杆菌和正常植物群的成员直接进入宿主。然而，免疫能力的小鼠在包括肝脏和脾在内的末端器官中产生了早期且强大的血清IgM反应，并且很少有菌落形成单位（CFU）。相比之下，缺乏B细胞或CD4+ T细胞的小鼠证明感染是致命的。结肠感染会导致明显的多数型败血症，并损坏终端器官。与野生型小鼠不同，CD4缺陷的动物在活性感染过程中无法安装病原体特异性血清IgM或IgG反应。这些结果暗示了全身适应性免疫反应在存活中并最终清除粘膜感染的关键作用。该研究计划概述了（1）在主动感染过程中建立血清免疫球蛋白的保护能力，（2）建立功能和位置，其中CD4+ T细胞刺激了在收养的CD4缺陷型小鼠中刺激病原体特异性体液反应，（3）确定采用转移的CD4+ T细胞的位置，免疫表型和细胞因子分泌谱，（4）在此反应中确定T细胞共刺激分子和Th细胞因子。结合这些目的，候选人提出了一项课程，以进一步培训有关研究中免疫学，淋巴细胞生物学，病理学和伦理行为的课程。候选人已完成了病理学居民的核心临床培训，并将至少将75％的精力用于研究。这项培训为候选人的目标提供了必要的步骤，即成为一名独立研究人员，研究粘膜免疫学和宿主微生物跨言中的问题。