The role of dendritic cells in T cell immunity to Cryptosporidium

描述(由申请人提供)： 标题：树突状细胞在T细胞对隐孢子虫免疫中的作用本申请是关于隐孢子虫的导师研究科学家发展奖(KO1)，隐孢子虫是一种肠道感染，在世界范围内与严重的人类发病率和死亡率有关，目前还没有有效的预防方法。我们的目标是阐明免疫细胞对隐孢子虫病的抵抗机制，以期更好地了解免疫反应的各个组成部分，从而开发出有效的疫苗和佐剂来对抗人类感染。我们的中心假设是，DC暴露在隐孢子虫感染下时会获得寄生虫抗原，从而启动特异性T细胞免疫。我们基于以下观察结果：1)位于固有层的肠道树突状细胞通过将树突突入肠腔直接采样病原体。Peyer氏斑中的DC获得由M细胞传递的肠道抗原；2)主要由树突状细胞产生的IL-12在诱导伽玛干扰素和控制微小隐孢子虫感染方面起关键作用；3)T细胞只能由树突状细胞启动，在控制隐孢子虫感染方面不可或缺。在这些观察的基础上，设计了专门的目标，以提供对树突状细胞与隐孢子虫相互作用和诱导T细胞免疫的性质的全面评估。这些研究包括：1)研究DC感染后对隐孢子虫抗原的摄取；2)确定DC在感染隐孢子虫后的活化和迁移方式；3)研究树突状细胞介导的T细胞对隐孢子虫感染的反应。拟议的研究将为理解诱导T细胞介导的抗隐孢子虫免疫的机制提供基础，这是未来设计疫苗和其他干预方法所必需的。

DESCRIPTION (provided by applicant): Title: The role of dendritic cells in T cell immunity to Cryptosporidium This application is for a Mentored Research Scientist Development Award (KO1) on Cryptosporidium, an enteric infection linked with serious human morbidity and mortality worldwide, and against which there is no effective therapy of prevention. Our goal is to elucidate the mechanisms by which immune cells initiate resistance against cryptosporidiosis with a view that a better understanding of the various components of the immune response will lead to development of effective vaccines and adjuvants to combat the infection in humans. Our central hypothesis is that DCs acquire parasite antigens when exposed to Cryptosporidium infection thereby priming specific T cell immunity. We base this on the observations that: 1) intestinal DCs located in the lamina propria directly sample pathogens by protruding dendrites into the gut lumen. DCs in Peyer's patch acquire intestinal antigens transferred by M cells; 2) IL-12, which is produced predominantly by dendritic cells, is critical in inducing gamma interferon and controlling C. parvum infection; 3) T cells, which can only be primed by dendritic cells, are indispensable in controlling the infection of Cryptosporidium. Based on these observations, the specific aims are designed to provide a comprehensive assessment of the nature of dendritic cell interaction with Cryptosporidium and induction of T cell immunity. They include: 1) Investigate Cryptosporidium antigen uptake by DCs following infection; 2) Determine the mode of activation and migration of DCs after exposure to Cryptosporidium infection; 3) Investigate dendritic cell-mediated T cell activation in response to Cryptosporidium infection. The proposed studies will provide the basis for understanding the mechanisms for the induction of T cell- mediated anti-Cryptosporidium immunity necessary for future design of vaccines and other methods of interventions.