Chemokines and Lymphoid Tissue Organization and Function

描述（由申请方提供）：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应答所必需的。趋化因子最近被证实在次级淋巴组织的发育和组织中具有中心作用。这项计划的长期目标是确定次级淋巴器官是如何组织起来的，并确定这种组织是如何促进获得性免疫所必需的细胞-细胞接触的。三个目标中的第一个试图确定CXCR 5在引导辅助性T细胞到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来研究活淋巴组织内B细胞和T细胞之间的相互作用。还将表征参与促进活化的T和B细胞之间相遇的B细胞衍生的趋化因子。脾脏中的类环磷酰胺趋化因子诱导是光敏素（LT）依赖性的，并且发生在出生后的最初几周。在目标2中，将表征作为新生儿脾脏内LT来源的主要细胞类型。淋巴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基因敲除小鼠的分析。此外，将生成BLC报告基因小鼠品系，以允许跟踪BLC表达细胞的出现。淋巴器官内的许多细胞处于持续运动状态，这种行为有助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内细胞运动中的作用。通过提高我们对促进淋巴组织发育和组织化的因素的理解，并通过进一步发展对B和T淋巴细胞如何相互作用以产生抗体应答的理解，这些研究应该导致增加针对病原体和疫苗抗原的免疫应答的方法，并阻止针对过敏原或自身抗原的不必要的应答。

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.