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）：在T依赖性体液免疫反应中B细胞募集的动态调节。 （认知B三细胞相互作用，2光片成像，病毒逃生突变体）项目摘要在​​该项目中，我们将研究对T依赖性的体液（抗体）免疫反应（THIR）的调节，以学习如何被操纵以促进对健康的有效的体液保护，以及慢性病患病或持续性生病或免疫成分的人，以及对临床或免疫成分的人进行反感。为了产生长期，高亲和力的体液反应，罕见的抗原特异性B细胞必须获得外抗原，然后从同源物TH细胞中获得帮助。尽管已经广泛研究了促进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，但对在体内募集B细胞募集到THIR中很重要的分子机制仍然知之甚少。在抗原或T细胞帮助可用性时，发现B和TH细胞之间初始认知相互作用的速度和效率的新颖方法至关重要。另外，在迅速扩散大流行感染的情况下，对预防疫苗很重要。因此，本应用的目的是确定哪些因素调节B细胞募集到thir中，并且当Ag或T细胞帮助可用性受到限制时，它们的命运。我们的中心假设是，将B细胞募集到THIR中取决于（i）Ag对B细胞的可及性，以及（II）调节B细胞对T细胞帮助的反应性的分子因素，（iii）促进B-T细胞的遇到，以及（IV）确定B细胞命运如果未获得T细胞的帮助，则确定B细胞的命运。我们的初步体内数据表明，B细胞的单个瞬态Ag获取可能足以使B细胞促进T细胞帮助并参与生发中心和B细胞记忆反应。但是，哪些分子因子调节B细胞能够获得T细胞帮助的时间，而体内尚不清楚B细胞分化的命运。尚未解决稀有活化的B和Th细胞之间的相互作用，这是通过吸引它们相互吸引或稳定同源相互作用的分子提示促进的。此外，在持续的病毒感染过程中，体液免疫系统是否可以识别出限制病毒逃生突变体的量。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 - 诺如菌病毒，两光子光子静脉内成像和数据的定量分析，并将表征控制THIR的新型机制。预计此类结果将产生重要的积极影响，因为除了提高适应性免疫的领域外，它们还可以改善现有的疫苗接种策略，并提出新的方法来增强免疫系统以快速抗击正在进行的感染。