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
基本信息
- 批准号:10509381
- 负责人:
- 金额:$ 49.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-11-01 至 2024-10-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdhesionsAffinityAntibodiesAntibody AffinityAntibody FormationAntibody ResponseAntibody-mediated protectionAntigensAttenuatedAutoimmunityAvidityB cell repertoireB-LymphocytesBLR1 geneBindingCell CommunicationCell Culture TechniquesCellsCre lox recombination systemCuesDefectDependenceDevelopmentEffector CellExtracellular MatrixFailureFollicular Dendritic CellsGenerationsGoalsHelper-Inducer T-LymphocyteImmuneImmunizationImmunoglobulin GIndividualInfectionInfluenza A virusIntegrin BindingIntegrin alphaVIntegrin alphaVbeta3IntegrinsKnowledgeLeadLigandsLocationMaintenanceMediatingMemory B-LymphocyteMethodsMicroanatomyModelingMovementMusOutputPathogenicityPathologyPlayPositioning AttributeProductionProteinsRGD (sequence)Regional AnatomyRegulationRoleShapesSignal TransductionSphingosine-1-Phosphate ReceptorStructure of germinal center of lymph nodeT-LymphocyteTamoxifenTimeUp-RegulationVaccinesVirus DiseasesVitronectindraining lymph nodefitnessinducible Creinhibiting antibodylymph nodesmultiphoton imagingnovelphotoactivationprogramsreal-time imagesresponsetherapeutic targettoolvaccination strategyvaccine development
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Deborah J Fowell其他文献
Deborah J Fowell的其他文献
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{{ truncateString('Deborah J Fowell', 18)}}的其他基金
Remodeling of Lymph Node-Derived Cytokine Responses at the Infected Tissue Site
受感染组织部位淋巴结衍生细胞因子反应的重塑
- 批准号:
10271765 - 财政年份:2020
- 资助金额:
$ 49.13万 - 项目类别:
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:
10316662 - 财政年份:2018
- 资助金额:
$ 49.13万 - 项目类别:
ECM/Integrin Tfh positioning cues for support of the germinal center response
ECM/整合素 Tfh 定位线索支持生发中心反应
- 批准号:
10053300 - 财政年份:2018
- 资助金额:
$ 49.13万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 49.13万 - 项目类别:
Spatial optimization of T cell activation at inflamed sites via cytokine/chemokine-dependent cellular clustering
通过细胞因子/趋化因子依赖性细胞聚类对炎症部位 T 细胞激活进行空间优化
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10241369 - 财政年份:2014
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Tissue regulation of T cell function - Administrative Core
T 细胞功能的组织调节 - 管理核心
- 批准号:
10477313 - 财政年份:2014
- 资助金额:
$ 49.13万 - 项目类别:
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