DEVELOPMENT AND FUNCTION OF INTESTINAL T-CELLS

胃肠道作为许多细菌、寄生虫、真菌和病毒病原体的入口，并且是健康和免疫受损宿主的重要感染部位。 由体液和细胞成分组成的复杂的特异性免疫系统被宿主用来维持小肠的完整性以抵抗微生物的入侵。特异性粘膜免疫应答的体液臂由伊加抗体的分泌主导，但特异性粘膜免疫的细胞臂的许多功能潜力知之甚少。 我们将使用实验性呼肠孤病毒感染小鼠，解剖肠道T细胞在粘膜免疫应答过程中的功能。本提案描述了一项计划，旨在实现根据上一个供资期提出和报告的意见制定的3个具体目标。 这一建议的中心假设是肠道感染激发了不同的肠道T细胞群体，这些T细胞调节局部和全身免疫反应的发展。 在目的1中，我们将通过检查口服或全身感染呼肠孤病毒的小鼠中的IgG亚类和细胞因子应答，并将这些应答与感染肠道细菌和非肠道病毒的小鼠进行比较，来检验感染途径影响T辅助细胞应答的发展的假设。 在目标2中，我们将检验CD8+ T细胞调节对呼肠孤病毒感染的粘膜免疫应答的假设。 我们将继续研究CD8缺陷小鼠对肠道病毒感染的免疫反应，并研究过继转移的CD8+ T细胞调节CD8缺陷小鼠粘膜免疫反应的能力。 在目标3中，我们将检验感染途径影响细胞毒性T淋巴细胞（CTL）上表达的T细胞受体（TCR）库的假设。 我们将通过使用Vbeta和CDR 3分析来分析在口服或全身感染后产生的CTL上的TCR表达。 这项工作将有助于了解粘膜免疫的发病机制，特别是关于T细胞在肠道中的功能。 了解肠道T细胞的发育和功能以及肠道中的细胞免疫将提供可用于合理设计口服疫苗的信息，所述口服疫苗可以通过肠道中的免疫效应物靶向适当的应答，特别是针对细胞内病原体。

The gastrointestinal tract serves as a portal of entry for many bacterial, parasitic, fungal, and viral pathogens, and is a significant site of infection in healthy and immunocompromised hosts. An elaborate specific immune system consisting of both humoral and cellular components is used by the host to maintain the integrity of the small intestine against microbial invasion. The humoral arm of the specific mucosal immune response is dominated by secretion of IgA antibodies, but much of the functional potential of the cellular arm of specific mucosal immunity is poorly understood. We will use experimental reovirus infection in mice to dissect the function of intestinal T cells during a mucosal immune response. This proposal describes a plan to accomplish 3 specific aims that are developed from observations made and reported in the previous funding period. The central hypothesis of this proposal is that enteric infection elicits distinct populations of intestinal T-cells that regulate the development of local and systemic immune responses. In aim 1, we will test the hypothesis that the route of infection affects the development of T-helper cell responses by examining IgG subclass and cytokine responses in mice orally or systemically infected with reovirus, and compare these responses to mice infected with enteric bacteria and non-enteric virus. In aim 2, we will test the hypothesis that CD8+ T cells regulate the mucosal immune response to reovirus infection. We will continue to characterize immune responses to enteric virus infection in CD8-deficient mice, and examine the ability of adoptively transferred CD8+ T-cells to regulate mucosal immune responses in CD8-deficient mice. In aim 3, we will test the hypothesis that the route of infection affects the repertoire of T cell receptors (TCR) expressed on cytotoxic T lymphocytes (CTL). We will by analyze TCR expression on CTL that are generated following oral or systemic infection using Vbeta and CDR3 analysis. This work will contribute to understanding mucosal immunity in pathogenesis, particularly with regards to T cell function in the gut. Understanding the development and function of intestinal T-cells and cellular immunity in the gut will provide information that can be used for the rational design of oral vaccines that can target appropriate responses by immunologic effectors in the intestine, particularly against intracellular pathogens.