DCM/Integrin TFH Positioning Cues for Support of the Germinal Center Response

项目摘要/摘要 产生强健的高亲和力抗体反应是大多数疫苗接种策略的目标。 抗感染。T滤泡辅助细胞在为B细胞的选择提供帮助方面起着关键作用 生发中心(GC)的高亲和力B细胞。虽然人们对信号的理解越来越多，但 产生TFH时，在GC内定位或保持TFH的信号并不被很好地理解。雅致 光激活研究表明，大多数进入特定GC的TFH细胞停留在该GC中 长期的。TFH如何在GC中持续很多天还不清楚。识别调节TFH驻留时间的信号 在单个GCs中可能是调节或促进TFH细胞定位到GCs的重要靶点，以促进 在抗体介导的自身免疫中产生强大的保护性抗体反应或限制转铁蛋白。 我们已经确定了一个ECM/整合素轴，它似乎调节了TFH与GC的联系 并对GC的形成和抗体的产生有重大影响。RGD基序ECM(细胞外基质) 免疫攻击时，成分高度受限于GC，并与滤泡树突状细胞共同定位 细胞(FDC)。相应地，T细胞表达与RDG基序结合的基质结合整合素αVβ3 ECM组件。T细胞整合素αV缺乏导致GC发育明显缺陷，减弱GC B 细胞和减少抗原特异性的免疫球蛋白和甲型流感病毒感染。此外，在 缺乏整合素αV，LLPC丢失，但BMEM保留。改变的B细胞反应与 αV CKO T细胞不能分化为TFH，而是αV CKO TFH不能积聚 在GC内部。基于这些新的观察结果，我们推测TFH细胞表达整合素αV 通过与FDC的交互，为GC定位或在GC内保留/存活提供定位提示- 关联的ECM。总体目标是使用这个模型来定义影响转铁蛋白的免疫机制。 定位或驻留在GC内的时间，并确定TFH定位失误对 发展B细胞谱系。 具体目的1.生发细胞中整合素αV对TFH细胞动力学的调节 具体目标2.αV在TFH命运和功能中的作用？ 特定目的3.整合素αV Tfh定位对B细胞效应器命运的影响 曲目。 关于ECM/整合素轴在TFH GC支持中的作用的知识应该会提供新的靶点 用于开发优化转铁蛋白的疫苗，以帮助和增强高亲和力抗体的产生。

Project Summary/Abstract The generation of a robust high-affinity antibody response is the goal of most vaccination strategies against infection. T follicular helper cells play a critical role in provision of help to B cells for the selection of high-affinity B cells in germinal centers (GC). While there is a growing understanding of the signals required to generate Tfh, the signals that position or retain Tfh within the GC are not well understood. Elegant photoactivation studies have revealed that the majority of Tfh cells entering a particular GC stay in that GC long-term. How Tfh persist for many days in the GC is unclear. Identifying signals that regulate Tfh dwell time in individual GCs could be important targets to regulate or boost the positioning of Tfh cells to GCs to facilitate the generation of a robust protective antibody response or limit Tfh in Ab mediated autoimmunity. We have identified an ECM/integrin axis that appears to modulate the association of Tfh with the GC and has a major impact on GC formation and antibody production. The RGD-motif ECM (extracellular matrix) components are highly restricted to the GC upon immune challenge and co-localize with follicular dendritic cells (FDC). Correspondingly, T cells express the matrix-binding integrin αVβ3 that binds to the RDG-motif in ECM components. Integrin αV deficiency in T cells led to a striking defect in GC development, attenuated GC B cells and reduced antigen-specific IgG to protein immunization and Influenza A infection. Moreover, in the absence of integrin αV, LLPCs were lost but Bmem remained. The altered B cell response was not associated with a failure of αV cKO T cells to differentiate into Tfh, but rather, the failure of αV cKO Tfh to accumulate within the GC. Based on these novel observations, we hypothesize that integrin αV expression by Tfh cells provides a positioning cue for location to, or retention/survival within, the GC via interaction with FDC- associated ECM. The overall goal is to use this model to define immune mechanisms that influence Tfh positioning or dwell time within the GC and to determine the consequence of Tfh miss-positioning on the developing B cell repertoire. Specific Aim 1. Integrin αV regulation of Tfh cell dynamics in germinal genters. Specific Aim 2. The role of αV in Tfh fate and function? Specific Aim 3. The consequence of integrin αV Tfh positioning on the B cell effector fate and repertoire. Knowledge gained on the role of this ECM/integrin axis in Tfh GC support should provide novel targets for the development of vaccines that optimize Tfh help and enhance high affinity antibody production.