Role of T cells in self-limited mucosal infections

描述(申请人提供)：我们发现早期适应性血清免疫球蛋白反应在非侵袭性粘膜病原体感染存活中起着重要作用。B细胞和CD4+T细胞是在感染轮状柠檬酸杆菌后存活所需的，轮状柠檬酸杆菌是肠道致病性大肠杆菌(EPEC)的小鼠同源物。野生型小鼠在感染过程中会出现上皮完整性的微小破坏，使轮状芽胞杆菌和正常菌群成员有一个直接进入宿主的门户。然而，具有免疫功能的小鼠早期和强烈的血清IgM反应，并在包括肝和脾在内的终末器官中有很少的集落形成单位(CFU)。相比之下，感染在缺乏B细胞或CD4+T细胞的小鼠中被证明是致命的。结肠感染会导致严重的多菌败血症，并对末端器官造成损害。与野生型小鼠不同，在活动性感染期间，CD4缺乏的动物无法产生病原体特异性的血清IgM或Ig G反应。这些结果暗示了系统适应性免疫反应在存活并最终清除粘膜感染中的关键作用。这项研究计划概述了如下策略：(1)确定血清免疫球蛋白在活动性感染期间的保护能力；(2)确定CD_4+T细胞在过继转移的CD_4缺陷小鼠中刺激病原体特异性体液反应的功能和位置(S)；(3)确定过继转移的CD_4+T细胞的位置、免疫表型和细胞因子分泌模式；以及(4)确定在这种反应中重要的T细胞共刺激分子和Th细胞因子。与这些目标相结合，候选人提出了一项课程，以进一步培训免疫学、淋巴细胞生物学、病理学和研究中的伦理行为。应聘者已经完成了作为病理学住院医师的核心临床培训，并将至少75%的精力投入到研究中。这一培训为候选人成为一名独立研究人员的目标提供了必要的一步，该研究员研究肠道环境中的粘膜免疫学和宿主-微生物串扰问题。

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.