Defining the Protective CD4+ T cell Responses to Salmonella typhimurium

描述(申请人提供)：对粘膜病原体的适应性免疫反应仍然知之甚少，限制了针对重要人类病原体的新疫苗的开发，例如B类生物恐怖主义制剂沙门氏菌。我建议使用新开发的试剂来检测肠道粘膜和全身组织中沙门氏菌特异性CD4T细胞的激活和记忆。这项建议的具体目的是：目的1.确定沙门氏菌蛋白在不同位置的差异表达是否允许部位特异性CD4T细胞的启动。目的2.检测沙门氏菌特异性记忆CD4T细胞在快速清除毒力细菌后是否受到损害。我的初步数据表明，我可以开发新的MHC-II类四聚体试剂来跟踪体内粘膜和全身沙门氏菌特异性T细胞反应。我的两个具体目标将使用尖端技术，首次研究内源性沙门氏菌特异性T细胞的启动和记忆发育。 与公共卫生相关：伤寒是一种由口腔沙门氏菌感染引起的潜在致命疾病，在美国被认为是潜在的生物恐怖威胁。这项建议将使用沙门氏菌感染的小鼠模型和新开发的免疫学工具来检测粘膜和全身反应，以检查对这种生物的保护性CD4T细胞反应。因此，这项建议将增加我们对这些保护性的CD4T细胞如何在面对粘膜细菌感染时被激活和发挥作用的理解。

DESCRIPTION (provided by applicant): The adaptive immune response to mucosal pathogens is still poorly understood, limiting the development of new vaccines for important human pathogens such as the category B bioterrorism agent Salmonella. I propose to use newly developed reagents to examine the Salmonella-specific CD4 T cells activation and memory in the intestinal mucosa and systemic tissues. The specific aims of this proposal are: Aim 1. Determine whether differential expression of Salmonella proteins in different locations allows priming of site-specific CD4 T cells. Aim 2. Examine whether Salmonella-specific memory CD4 T cell development is impaired after rapid clearance of virulent bacteria. My preliminary data demonstrate that I can develop novel MHC class-II tetramer reagents to track the mucosal and systemic Salmonella-specific T cell response in vivo. My two specific aims will use cutting-edge technology, to examine the priming, and memory development of endogenous Salmonella- specific T cells for the first time. PUBLIC HEALTH RELEVANCE: Typhoid is a potentially fatal disease caused by oral Salmonella infection and recognized as a potential bioterrorist threat in the US. This proposal will examine the protective CD4 T cell response to this organism using a mouse model of Salmonella infection and newly developed immunological tools to detect mucosal and systemic responses. This proposal will therefore increase our understanding of how these protective CD4 T cells are activated and function in the face of mucosal bacterial infection.