Mucosal Lymphocyte Homing in the Head and Neck

描述：我们之前的研究表明，鼻相关淋巴组织（NALT）和各种头颈部淋巴结（LN）表达独特的寻址模式。来自这些淋巴组织的高内皮小静脉（HEV）与广泛存在MAdCAM-1的Peyer's patch (PP) HEV不同。相反，外周淋巴结寻址蛋白（PNAd）在这些组织中占主导地位，这表明粘膜淋巴细胞归巢的另一种模式，特别是考虑到其他研究者过去的研究表明，粘膜B细胞迁移到小肠固有层（iLP）依赖于MAdCAM- 1-alpha4beta7的相互作用，在较小程度上依赖于l -选择素。事实上，效应B细胞免疫分离具有alpha4beta7/高表型。在此应用中，我们提出至少存在两种其他粘膜B细胞亚群，它们不是alpha4beta7/high。一个B细胞亚群鉴定为L-selectin/low alpha4beta7/low，另一个鉴定为alphaEbeta7+。在经霍乱毒素（CT）鼻内免疫的小鼠中，我们发现在鼻腔（NP）、生殖道（RT）和颌下腺（SMG）中主要存在l -选择素/低α 4 β 7/低效应B细胞。对免疫ct的l -选择蛋白缺陷小鼠的评估显示，NP中没有粘膜效应细胞B细胞，但iLP反应维持为alphaEbeta7+，而不是alpha4beta7/高。总的来说，这些数据表明l -选择素对于抗原（Ag）特异性效应B细胞在非肠粘膜组织中的迁移是重要的。因此，本研究将对L-selectinlow alpha4beta7/low和alpha4beta7 +B细胞在CT免疫或口服免疫后的功能属性进行表征。特异性目的1的研究将确定l -选择素和alpha4beta7在体内或口服免疫后诱导和效应B细胞免疫发展中的相对重要性。Specific Aim 2的研究将确定所描述的新型l -选择素/低alpha4beta7/低或alpha4beta7 + B细胞是否可以归巢到非肠和肠粘膜效应组织。特异性Aim 3的研究将确定哪种B细胞亚群，l -选择素/低alpha4beta7/低或alphaEbeta7+，对CT的侵袭具有保护作用。从这项工作中，我们将了解如何利用免疫途径有效地将疫苗靶向非肠粘膜部位。

DESCRIPTION: Work from our previous studies has shown that the nasal-associated lymphoid tissue (NALT) and the various head and neck lymph nodes (LN) express unique addressin patterns. The high endothelial venules (HEV) from these lymphoid tissues do not resemble Peyer's patch (PP) HEV with the extensive presence of MAdCAM-1. Instead, the peripheral node addressin (PNAd) dominates these tissues, suggesting an alternative mode of mucosal lymphocyte homing especially in light of past studies by other investigators showing that mucosal B cell migration to small intestinal lamina propria (iLP) is dependent upon MAdCAM- 1-alpha4beta7 interactions, and to a lesser degree, upon L-selectin. In fact, effector B cell immunity segregated with the alpha4beta7/high phenotype. Herein this application, we propose that at least two other mucosal B cell subsets exist that are not alpha4beta7/high.One B cell subset is identified as L-selectin/low alpha4beta7/low, the other, alphaEbeta7+. In mice intranasally (i.n.) immunized with cholera toxin (CT), we show primarily L-selectin/low alpha4beta7/low effector B cells in the nasal passages (NP), reproductive tract (RT), and submaxillary gland (SMG). Evaluation of i.n. CT-immunized L-selectin-deficient mice show an absence of mucosal effector B ceils in the NP, but iLP responses were maintained as alphaEbeta7+, not alpha4beta7/high. Collectively, these data suggest that L-selectin is important for the migration of antigen (Ag)-specific effector B cells in nonintestinal mucosal tissues. Thus, this proposal will characterize the functional attributes of L-selectinlow alpha4beta7/low and alphaEbeta7+B cells subsequent to i.n. or oral immunization with CT. Studies in Specific Aim 1 will determine the relative importance of L-selectin and alpha4beta7 to the development of both inductive and effector B cell immunity subsequent to i.n. or oral immunization. Studies in Specific Aim 2 will determine determine if the described novel L-selectin/low alpha4beta7/low or alphaEbeta7+ B cells can home to nonintestinal as well as intestinal mucosal effector tissues. Studies in Specific Aim 3 will determine which B cell subset, L-selectin/low alpha4beta7/low or alphaEbeta7+, is protective against i.n. challenge with CT. From this work, we will learn how routes of immunizations can be used to effectively target vaccines to nonintestinal mucosal sites.