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

DCM/整合素 TFH 定位线索支持生发中心反应

• 批准号: 10287490
• 负责人: Deborah J Fowell
• 金额: $ 48.87万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287490
• 关键词: Acute; Address; Adhesions; Affinity; Anatomy; Antibodies; Antibody Affinity; Antibody Formation; Antibody Response; Antibody-mediated protection; Antigens; Attenuated; Autoimmunity; Avidity; B cell repertoire; B-Lymphocytes; BLR1 gene; Binding; Cell Communication; Cell Culture Techniques; Cells; Cre lox recombination system; Cues; Defect; Dependence; Development; Effector Cell; Extracellular Matrix; Failure; Follicular Dendritic Cells; Generations; Goals; Helper-Inducer T-Lymphocyte; Immune; Immunization; Immunoglobulin G; Individual; Infection; Influenza A virus; Integrin Binding; Integrin alphaV; Integrin alphaVbeta3; Integrins; Knowledge; Lead; Ligands; Location; Maintenance; Mediating; Methods; Modeling; Movement; Mus; Output; Pathogenicity; Pathology; Play; Positioning Attribute; Production; Proteins; RGD (sequence); Regulation; Role; Shapes; Signal Transduction; Sphingosine-1-Phosphate Receptor; Structure of germinal center of lymph node; T-Lymphocyte; Tamoxifen; Time; Up-Regulation; Vaccines; Virus Diseases; Vitronectin; base; draining lymph node; fitness; inhibiting antibody; lymph nodes; multiphoton imaging; novel; photoactivation; programs; real-time images; response; therapeutic target; tool; vaccination strategy; vaccine development

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.

项目总结/摘要 产生强有力的高亲和力抗体应答是大多数疫苗接种策略的目标 抵抗感染滤泡辅助性T细胞在为B细胞提供帮助以进行选择中起关键作用。 高亲和力B细胞在生发中心（GC）。虽然人们越来越了解需要的信号， 产生Tfh，在GC内定位或保留Tfh的信号还没有很好地理解。优雅 光活化研究已经揭示了进入特定GC的大多数Tfh细胞停留在该GC中 长期的。Tfh如何在GC中持续多日尚不清楚。识别调节Tfh停留时间的信号 可能是调节或促进Tfh细胞向GC定位的重要靶点， 在Ab介导的自身免疫中产生稳健的保护性抗体应答或限制Tfh。 我们已经确定了一个ECM/整合素轴，似乎可以调节Tfh与GC的关系。 并且对GC形成和抗体产生有重要影响。RGD-motif ECM（细胞外基质） 免疫激发后，这些成分高度局限于GC，并与滤泡树突状细胞共定位。 细胞（FDC）。相应地，T细胞表达基质结合整联蛋白αVβ3，其结合到 ECM组件。T细胞整合素αV缺陷导致GC发育明显缺陷，减弱GC B， 细胞和减少的抗原特异性IgG至蛋白免疫和甲型流感感染。而且在 整合素αV缺失时，LLPC丢失，但BCLs仍存在。改变的B细胞反应与 αV cKO T细胞不能分化成Tfh，而是αV cKO Tfh不能积累， 在GC中。基于这些新的观察，我们假设Tfh细胞整合素αV的表达， 通过与FDC的相互作用，为GC的定位或保留/存活提供定位线索。 相关ECM。总体目标是使用该模型来定义影响Tfh的免疫机制 在GC内的定位或停留时间，并确定Tfh在 发育B细胞库。 具体目标1。整联蛋白αV对生长激素中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？ 具体目标3。整合素αV Tfh定位对B细胞效应子命运的影响， 保留曲目。 关于ECM/整合素轴在Tfh GC支持中的作用的知识应该提供新的靶点 用于开发优化Tfh的疫苗，有助于提高高亲和力抗体的产生。