Role of T cells in self-limited mucosal infections

描述（由申请人提供）：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的存活中起重要作用。B细胞和CD4+ T细胞是小鼠感染致病性大肠杆菌（EPEC）的同源物，在感染啮齿柠檬酸杆菌（Citrobacter rodentium）后存活所必需的。野生型小鼠在感染期间上皮完整性出现小的断裂，使啮齿鼠和正常菌群的成员能够直接进入宿主。然而，免疫功能正常的小鼠会产生较早且强劲的血清IgM反应，并且在末端器官（包括肝脏和脾脏）中很少有菌落形成单位（CFU）。相反，在缺乏B细胞或CD4+ T细胞的小鼠中，感染被证明是致命的。结肠感染可导致严重的多微生物败血症，并对终末器官造成损害。与野生型小鼠不同，cd4缺陷动物在活动性感染期间不能产生病原体特异性血清IgM或IgG反应。这些结果暗示了系统性适应性免疫反应在存活和最终清除粘膜感染中的关键作用。本研究计划概述了一项策略：(1)在活动性感染期间建立血清免疫球蛋白的保护能力；(2)在过继性转移CD4缺陷小鼠中建立CD4+ T细胞刺激病原体特异性体液反应的功能和位置；(3)确定过继性转移CD4+ T细胞的位置、免疫表型和细胞因子分泌谱；(4)鉴定T细胞共刺激分子和在该反应中重要的Th细胞因子。结合这些目标，候选人提出了进一步培训免疫学、淋巴细胞生物学、病理学和研究伦理行为的课程。候选人已完成病理住院医师的核心临床培训，并将投入至少75%的精力用于研究。该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，该研究人员研究了肠道环境中粘膜免疫学和宿主-微生物串扰的问题。

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.