Dynamic regulation of B cell recruitment in T-dependent humoral immune response
T依赖性体液免疫反应中B细胞募集的动态调节
基本信息
- 批准号:9088320
- 负责人:
- 金额:$ 41.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-01 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAddressAffectAffinityAntibodiesAntibody ResponseAntigensAppearanceB cell differentiationB-LymphocytesBacterial InfectionsCCL3 geneCCR5 geneCD4 Positive T LymphocytesCell CommunicationCirrhosisCuesDataData AnalysesDevelopmentDiseaseEbola virusEscape MutantExposure toGenerationsGoalsHIV InfectionsHealthHelper-Inducer T-LymphocyteHumoral ImmunitiesImageImmune responseImmune systemImmunizationImmunocompromised HostIndividualInfectionInterferon-alphaKnowledgeLeadLearningLengthLifeLymphocyteLymphopeniaMemoryMemory B-LymphocyteModelingMolecularMusMutateNorovirusOutcomePatientsPlasma CellsProphylactic treatmentRNA VirusesRecruitment ActivityRecurrenceRegulationResearchResistanceRoleSignal TransductionSpeedStructure of germinal center of lymph nodeT-LymphocyteTestingTimeTransgenic OrganismsVaccinationVaccinesViralVirus DiseasesWorkadaptive immunitybasechemokinefightingimprovedin vivoinsightintravital imaginglymph nodesmouse modelmutantnovelnovel strategiespandemic diseaseresponsetranscription factortwo-photonvaccination strategy
项目摘要
DESCRIPTION (provided by applicant): Dynamic regulation of B cell recruitment in T-dependent humoral immune response. (cognate B-Th cells interactions, 2-photon imaging, viral escape mutants) Project summary In this project we will study the regulation of T-dependent humoral (antibody) immune response (THIR) to learn how it can be manipulated to promote efficient humoral protection of healthy, as well as chronically sick or immunocompromised, individuals against infections. For generation of long-term, high-affinity humoral response, rare antigen-specific B cells have to acquire foreign antigen and then receive help from cognate Th cells. While the signaling and transcription factors promoting B - Th cell interactions and long-term humoral immunity have been extensively investigated, the molecular mechanisms important for recruitment of B cells into THIR in vivo are still poorly understood. Discovering novel ways to optimize the speed and efficiency of initial cognate interactions between B and Th cells is critical for induction of THIR when antigen or T cell help availability is limited. In addtion, it is important for vaccine prophylaxis in the case of rapidly spreading pandemic infections. Therefore, the objective of this application is to determine which factors regulate recruitment of B cells into THIR, and their fate when Ag or T cell help availability is limited. Our central hypothesis is that recruitment of B cells into THIR depends on (i) accessibility of Ag to B cells, and on molecular factors that (ii) regulate B cell responsiveness to T cell help, (iii) promote B-T cell encounters, and (iv) determine B cell fate if T cell help is not acquired. Our preliminary in vivo data suggests that single transient Ag acquisition by B cells may be sufficient to prime B cells for T cell help and participate in the germinal center and B cell memory responses. However, which molecular factors regulate the time that B cells are capable of acquiring T cell help and B cell differentiation fate in vivo is not known; and whether interactions between rare activated B and Th cells are promoted by molecular cues that attract them to each other or stabilize cognate interactions have not been addressed. In addition, whether limiting amounts of viral escape mutants could be recognized by the humoral immune system during ongoing viral infection is unclear. We will address these questions using transgenic lymphocytes and model antigens, as well as the natural mouse viral infection model - Murine Norovirus, two- photon intravital imaging and quantitative analysis of the data, and will characterize novel mechanisms that control THIR. Such results are expected to have an important positive impact because in addition to advancing the field of adaptive immunity in general, they could lead to improvements in existing vaccination strategies and suggest new ways to boost the immune system to rapidly fight ongoing infections.
描述(由申请方提供):T依赖性体液免疫应答中B细胞募集的动态调节。(同源B-Th细胞相互作用,双光子成像,病毒逃逸突变体)项目总结在本项目中,我们将研究T依赖性体液(抗体)免疫应答(THIR)的调节,以了解如何操纵它来促进健康的有效体液保护,以及慢性病或免疫功能低下的个体对抗感染。为了产生长期、高亲和力的体液应答,稀有抗原特异性B细胞必须获得外源抗原,然后接受同源Th细胞的帮助。虽然促进B - Th细胞相互作用和长期体液免疫的信号传导和转录因子已被广泛研究,但对于体内B细胞募集为THIR的重要分子机制仍然知之甚少。当抗原或T细胞辅助可用性有限时,发现优化B和Th细胞之间初始同源相互作用的速度和效率的新方法对于诱导THIR是关键的。此外,在快速传播的大流行性感染的情况下,疫苗预防也很重要。因此,本申请的目的是确定哪些因子调节B细胞向THIR的募集,以及当Ag或T细胞辅助可用性受限时它们的命运。我们的中心假设是,B细胞向THIR的募集取决于(i)Ag对B细胞的可接近性,以及(ii)调节B细胞对T细胞帮助的反应性,(iii)促进B-T细胞相遇,以及(iv)如果没有获得T细胞帮助,则决定B细胞命运的分子因子。我们的初步体内数据表明,B细胞的单次瞬时Ag采集可能足以引发B细胞的T细胞帮助,并参与生发中心和B细胞记忆反应。然而,哪些分子因子调节B细胞能够获得T细胞帮助的时间和体内B细胞分化命运尚不清楚;并且稀有活化的B和Th细胞之间的相互作用是否由将它们彼此吸引或稳定同源相互作用的分子线索促进尚未解决。此外,在持续的病毒感染过程中,体液免疫系统是否能识别有限数量的病毒逃逸突变体尚不清楚。我们将使用转基因淋巴细胞和模型抗原,以及天然小鼠病毒感染模型-鼠诺如病毒,双光子活体成像和数据的定量分析来解决这些问题,并将表征控制THIR的新机制。这些结果预计将产生重要的积极影响,因为除了推进一般的适应性免疫领域外,它们还可能导致现有疫苗接种策略的改进,并提出新的方法来增强免疫系统,以快速对抗正在发生的感染。
项目成果
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Irina Leonidovna Grigorova其他文献
Irina Leonidovna Grigorova的其他文献
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{{ truncateString('Irina Leonidovna Grigorova', 18)}}的其他基金
Virus-Like Nanoparticles for Non-Capsid Antigen Delivery with Virus Structure/Functional Mimicry to Activate B Cell Immunity
用于非衣壳抗原递送的病毒样纳米颗粒,具有病毒结构/功能拟态以激活 B 细胞免疫
- 批准号:
10044823 - 财政年份:2020
- 资助金额:
$ 41.49万 - 项目类别:
Virus-Like Nanoparticles for Non-Capsid Antigen Delivery with Virus Structure/Functional Mimicry to Activate B Cell Immunity
用于非衣壳抗原递送的病毒样纳米颗粒,具有病毒结构/功能拟态以激活 B 细胞免疫
- 批准号:
10212209 - 财政年份:2020
- 资助金额:
$ 41.49万 - 项目类别:
Dynamic regulation of B cell recruitment in T-dependent humoral immune response
T依赖性体液免疫反应中B细胞募集的动态调节
- 批准号:
8693336 - 财政年份:2014
- 资助金额:
$ 41.49万 - 项目类别:
Dynamic regulation of B cell recruitment in T-dependent humoral immune response
T依赖性体液免疫反应中B细胞募集的动态调节
- 批准号:
8878162 - 财政年份:2014
- 资助金额:
$ 41.49万 - 项目类别:
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