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
• 负责人: Irina Leonidovna Grigorova
• 金额: $ 41.62万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8693336
• 关键词: Acceleration; Address; Affect; Affinity; Antibodies; Antibody Formation; Antigens; Appearance; B cell differentiation; B-Lymphocytes; Bacterial Infections; CCL3 gene; CCR5 gene; CD4 Positive T Lymphocytes; Cell Communication; Chemokine (C-C Motif) Receptor 5; Cirrhosis; Cues; Data; Data Analyses; Development; Disease; Ebola virus; Escape Mutant; Exposure to; Generations; Goals; HIV Infections; Helper-Inducer T-Lymphocyte; Humoral Immunities; Image; Immune response; Immune system; Immunization; Immunocompromised Host; Individual; Infection; Interferons; Knowledge; Lead; Learning; Length; Life; Lymphocyte; Lymphopenia; Memory; Memory B-Lymphocyte; Modeling; Molecular; Mus; Mutate; Norovirus; Outcome; Patients; Plasma Cells; Prophylactic treatment; RNA Viruses; Recruitment Activity; Recurrence; Regulation; Research; Resistance; Role; Signal Transduction; Speed; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Time; Transgenic Organisms; Vaccination; Vaccines; Viral; Virus Diseases; Work; adaptive immunity; base; chemokine; fighting; improved; in vivo; insight; intravital imaging; lymph nodes; mutant; novel; novel strategies; pandemic disease; public health relevance; response; transcription factor; two-photon; vaccination strategy

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（由申请人提供）：T 依赖性体液免疫反应中 B 细胞募集的动态调节。 （同源 B-Th 细胞相互作用、2 光子成像、病毒逃逸突变体） 项目摘要 在本项目中，我们将研究 T 依赖性体液（抗体）免疫反应 (THIR) 的调节，以了解如何操纵它来促进高效健康以及慢性病或免疫功能低下的个体免受感染的体液保护。为了产生长期、高亲和力的体液反应，罕见的抗原特异性 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，但对于体内将 B 细胞募集到 THIR 中的重要分子机制仍知之甚少。当抗原或 T 细胞辅助可用性有限时，发现优化 B 细胞和 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 至关重要。此外，在大流行性感染迅速蔓延的情况下，疫苗预防也很重要。因此，本申请的目的是确定哪些因素调节 B 细胞募集到 THIR 中，以及当 Ag 或 T 细胞帮助可用性有限时它们的命运。我们的中心假设是，B 细胞募集到 THIR 取决于 (i) Ag 对 B 细胞的可及性，以及 (ii) 调节 B 细胞对 T 细胞帮助的反应性，(iii) 促进 B-T 细胞相遇的分子因素，以及 ( iv) 如果未获得 T 细胞帮助，则确定 B 细胞的命运。我们的初步体内数据表明，B 细胞单次瞬时 Ag 获取可能足以为 B 细胞提供 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 B 细胞在体内的分化命运尚不清楚；罕见的活化 B 细胞和 Th 细胞之间的相互作用是否是由分子线索促进的，这些分子信号将它们相互吸引或稳定同源相互作用，这一点尚未得到解决。此外，在持续的病毒感染过程中，体液免疫系统是否能够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定量分析来解决这些问题，并将描述控制 THIR 的新机制。这些结果预计将产生重要的积极影响，因为除了总体上推进适应性免疫领域之外，它们还可能导致现有疫苗接种策略的改进，并提出增强免疫系统以快速对抗持续感染的新方法。