Chemokines and Lymphoid Tissue Organization and Function

描述（由申请人提供）：次级淋巴器官促进细胞-细胞和细胞-抗原相互作用，这是启动适应性免疫反应所必需的。趋化因子在继发性淋巴组织的发育和组织中起着重要的作用。本提案的长期目标是确定次级淋巴器官如何组织起来，并确定这种组织如何促进适应性免疫所必需的细胞-细胞相遇。三个目标中的第一个旨在确定CXCR5在引导辅助性T细胞进入B细胞区域中的作用，并确定这种趋化因子受体对辅助性T细胞功能的重要性。该目标的第二部分将使用双光子显微镜研究活淋巴组织中B细胞和T细胞之间的相互作用。B细胞衍生的趋化因子(s)参与促进活化的T细胞和B细胞之间的相遇也将被表征。脾淋巴样趋化因子的诱导是淋巴素（LT）依赖性的，发生在出生后的最初几周。在目的2中，主要的细胞类型的功能作为源肝移植在新生儿脾脏将被表征。淋巴样趋化因子在组织发育中的白髓中的作用将被研究，包括对新产生的ELC敲除小鼠的分析。此外，将生成BLC报告小鼠品系，以允许跟踪表达BLC的细胞的出现。淋巴器官内的许多细胞处于持续运动状态，这种行为有利于它们对抗原的监视。第三个目标将探讨趋化因子和整合素在促进淋巴器官细胞运动中的作用。通过提高我们对促进淋巴组织发育和组织的因素的理解，以及进一步了解B淋巴细胞和T淋巴细胞如何相互作用以产生抗体反应，这些研究将导致增强对病原体和疫苗抗原的免疫反应的方法，并阻止对过敏原或自身抗原的不必要反应。

DESCRIPTION (provided by applicant): Secondary lymphoid organs promote cell-cell and cell-antigen interactions that are necessary for the initiation of adaptive immune responses. Chemokines have recently been established to have a central role in the development and organization of secondary lymphoid tissues. The long-term objective of this proposal is to define how secondary lymphoid organs become organized and to determine how this organization fosters the cell-cell encounters that are necessary for adaptive immunity. The first of three aims seeks to determine the role of CXCR5 in guiding helper T cells to B cell areas, and to determine the importance of this chemokine receptor for T helper cell function. A second part of this aim will use 2-photon microscopy to study interactions between B cells and T cells within viable lymphoid tissue. B-cell derived chemokine(s) involved in promoting encounters between activated T and B cells will also be characterized. Lymphoid chemokine induction in the spleen is lymphotoxin (LT) dependent and occurs during the first few weeks after birth. In aim 2 the major cell types functioning as sources of LT within the neonatal spleen will be characterized. The role of lymphoid chemokines in organizing the developing white-pulp will be investigated, including an analysis of newly generated ELC knockout mice. In addition, a BLC reporter mouse strain will be generated to permit the appearance of BLC expressing cells to be tracked. Many of the cells within lymphoid organs are in a state of continual motility, a behavior that facilitates their surveillance for antigen. The third aim will explore the role of chemokines and integrins in promoting cell motility within lymphoid organs. By improving our understanding of the factors that promote lymphoid tissue development and organization and by further developing understanding of how B and T lymphocytes interact to mount antibody responses, these studies should lead to approaches to augment immune responses against pathogens and vaccine antigens, and to thwart unwanted responses against allergens or autoantigens.