CD4 T Cell Response to Salmonella

描述(申请人提供)：先天和获得性免疫系统对微生物的识别可以导致感染的解决和长期免疫的发展。许多微生物病原体通过穿透肺、肠和生殖器-尿路的粘膜表面进入宿主。然而，粘膜表面对微生物病原体的免疫反应的诱导还不是很清楚。该提案的具体目的是：目的1.鉴定体内呈现沙门氏菌抗原的细胞类型，以验证淋巴树突状细胞激活沙门氏菌特异性CD4T细胞的假说。这些研究将直接检查沙门氏菌编码抗原在体内的呈递情况，以检验淋巴树突状细胞在口腔感染后负责激活沙门氏菌特异性CD4T细胞的假设。目的2.检测沙门氏菌特异性T细胞在脾中的激活情况，并确定该器官中T细胞无反应的机制。我们的初步数据表明，尽管细菌在脾组织中复制，但沙门氏菌特异性的CD4T细胞在脾中被低效激活。我们推测，细菌在脾红髓中的位置在物理上将抗原与沙门氏菌特异性T细胞分开。这将使用一种新型的沙门氏菌特异性TCR过继转移系统进行测试。目的3.检测CD4T细胞的分化和迁移，以验证沙门氏菌感染后不能有效地产生效应/记忆T细胞的观点。我们的初步数据表明，口腔感染后沙门氏菌特异性T细胞的非淋巴迁移存在缺陷。我们假设，由于局部粘膜启动环境的原因，T细胞效应器功能不能有效地发展。这个问题将通过检测口腔感染后沙门氏菌特异性T细胞的效应细胞因子的产生和非淋巴样迁移来检验。这些研究将为发展对粘膜病原体的免疫提供新的见解。

DESCRIPTION (provided by applicant): The recognition of microbes by the innate and adaptive immune system can lead to the resolution of infection and development of long-lived immunity. Many microbial pathogens gain entry to the host by penetrating mucosal surfaces of the lung, intestine and genito-urinary tract. However, the induction of immune responses to microbial pathogens at mucosal surfaces is not well understood. The specific aims of the proposal are: Aim 1. To identify the cell types that present Salmonella antigens in vivo in order to test the hypothesis that lymphoid dendritic cells activate Salmonella-specific CD4 T cells. These studies will directly examine the presentation of a Salmonella encoded antigen in vivo, in order to test the hypothesis that lymphoid dendritic cells are responsible for activating Salmonella-specific CD4 T cells after oral infection. Aim 2. To examine Salmonella-specific T cell activation in the spleen and define mechanisms that account for T cell unresponsiveness in this organ. Our preliminary data indicate that Salmonella-specific CD4 T cells are inefficiently activated in the spleen, despite bacterial replication in this organ. We hypothesize that the location of bacteria in the spleen red pulp physically separates antigen from Salmonella-specific T cells. This will be tested using a novel Salmonella-specific TCR adoptive transfer system. Aim 3. To examine CD4T cell differentiation and migration in order to test the idea that effector/memory T cells are not efficiently generated after Salmonella infection. Our preliminary data indicate a defect in non-lymphoid migration of Salmonella-specific T cells following oral infection. We hypothesize that T cell effector functions do not develop efficiently, due to the local mucosal priming environment. This issue will be tested by examining the effector cytokine production and non-lymphoid migration of Salmonella-specific T cell after oral infection. These studies will provide new insight into the development of immunity to mucosal pathogens.