DCM/Integrin TFH Positioning Cues for Support of the Germinal Center Response
DCM/Integrin TFH Positioning Cues for Support of the Germinal Center Response
批准号:
10509381
负责人:
Deborah J Fowell
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
项目状态:
已结题
起止时间:
2018-11-01 至 2024-10-31
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
中文摘要
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。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Remodeling of Lymph Node-Derived Cytokine Responses at the Infected Tissue Site
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批准号:10271765
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项目类别:
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资助金额:$23.29万
-
财政年份:2020
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负责人:Deborah J Fowell
-
依托单位:
DCM/Integrin TFH Positioning Cues for Support of the Germinal Center Response
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批准号:10316662
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项目类别:
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资助金额:$48.31万
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负责人:Deborah J Fowell
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依托单位:
ECM/Integrin Tfh positioning cues for support of the germinal center response
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批准号:10053300
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项目类别:
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资助金额:$0.33万
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负责人:Deborah J Fowell
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Spatial optimization of T cell activation at inflamed sites via cytokine/chemokine-dependent cellular clustering
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资助金额:$40.23万
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依托单位:
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批准号:9791597
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依托单位:
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批准号:10689168
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依托单位:
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批准号:10477313
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资助金额:$9.83万
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负责人:Deborah J Fowell
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依托单位:
Spatial optimization of T cell activation at inflamed sites via cytokine/chemokine-dependent cellular clustering
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批准号:10477325
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项目类别:
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资助金额:$40.24万
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依托单位:
Regulation of effector T cell migration within inflamed tissues
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资助金额:$15.35万
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批准号:10002172
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资助金额:$242.22万
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资助金额:$164.3万
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依托单位:
Spatial optimization of T cell activation at inflamed sites via cytokine/chemokine-dependent cellular clustering
-
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资助金额:$37.36万
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依托单位:
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资助金额:$242.03万
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依托单位:
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资助金额:$10.0万
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负责人:Deborah J Fowell
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依托单位:
海外基金