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应答在非侵入性粘膜病原体感染的存活中起重要作用。B细胞和CD 4 + T细胞是感染啮齿柠檬酸杆菌（Citrobacter rodentium）后存活所必需的，啮齿柠檬酸杆菌是肠致病性大肠杆菌的小鼠同源物。coli（EPEC）。野生型小鼠在感染过程中上皮完整性出现小的破坏，使得C。啮齿动物和正常植物群的成员是进入宿主的直接门户。然而，免疫活性小鼠产生早期和稳健的血清IgM应答，并且在包括肝脏和脾脏的终末器官中具有很少的集落形成单位（CFU）。相比之下，在缺乏B细胞或CD4+ T细胞的小鼠中，感染证明是致命的。结肠感染导致显著的多微生物败血症，并损害终末器官。与野生型小鼠不同，CD4缺陷型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。这些结果暗示了全身适应性免疫应答在粘膜感染的存活和最终清除中的关键作用。本研究计划概述了一项策略，以（1）建立活动性感染期间血清免疫球蛋白的保护能力，（2）建立过继转移的CD4缺陷小鼠中CD4+ T细胞刺激病原体特异性体液应答的功能和位置，（3）确定过继转移的CD4+ T细胞的位置、免疫表型和细胞因子分泌谱，和（4）鉴定在该应答中重要的T细胞共刺激分子和Th细胞因子。与这些目标相结合，候选人提出了一个课程，以进一步培训免疫学，淋巴细胞生物学，病理学和道德行为的研究。候选人已经完成了核心临床培训，作为病理学住院医师，并将投入至少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一步，成为一名独立的研究人员，调查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.