Intestinal IgA B cell receptor-specific signals integrate germinal center selection with humoral responses to commensals

肠道 IgA B 细胞受体特异性信号将生发中心选择与对共生体的体液反应结合起来

• 批准号: 10574777
• 负责人: Andrea Reboldi
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-09 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574777
• 关键词: Adaptive Immune System; Affinity; Antibodies; Antibody Response; Antigen Receptors; Antigens; B Cell Proliferation; B cell differentiation; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocyte Subsets; B-Lymphocytes; Bacterial Antigens; Biochemical; Cell Compartmentation; Cell Death; Cell Survival; Cells; Chronic; Clone Cells; Complex; Data; Equilibrium; Event; Exclusion; Follicular Dendritic Cells; Foundations; Gastrointestinal tract structure; Generations; Helper-Inducer T-Lymphocyte; Homeostasis; Homing; Humoral Immunities; IgA Deficiency; Immune system; Immunoglobulin A; Immunoglobulin-Secreting Cells; Immunology; In Vitro; Individual; Infection; Intestines; Light; Maintenance; Maps; Mediating; Membrane; Memory; Memory B-Lymphocyte; Molecular; Mucosal Immunity; Mucous Membrane; Mus; Peptides; Peyer' s Patches; Phenotype; Plasma Cells; Predisposition; Process; Production; Reaction; Receptor Signaling; Reporter; Resistance; Role; Shapes; Signal Transduction; Specificity; Step Tests; Structure of germinal center of lymph node; Surface; Surface Immunoglobulins; System; Techniques; Testing; Time; Tissues; Toxin; adaptive immunity; antigen binding; autoinflammation; cell motility; deep sequencing; enteric infection; enteric pathogen; expectation; experience; flexibility; gut microbiome; immunogenic; immunogenicity; imprint; in vivo; in vivo Model; insight; intestinal homeostasis; intravital microscopy; microbiome composition; microorganism antigen; novel; overexpression; pathogen; permissiveness; prevent; recruit; response; secondary lymphoid organ

Abstract B lymphocytes in the gastrointestinal tract are constantly stimulated by microbial antigens. In order to prevent commensal outgrowth and maintain intestinal homeostasis, B cells need to mount a rapid antibody response against bacterial antigens. To achieve this task, the humoral immune system relies on a complex multistep process of B cell proliferation and selection in the germinal center, which eventually gives rise to either antibody-secreting plasma cells or memory B cells. Intestinal B cells are mainly expressing immunoglobulin A (IgA), but how this specific antigen receptor isotype shapes B cell fate and antibody response in the gut is poorly understood. Moreover, dysregulation of IgA response is associated with increased infection susceptibility and autoinflammation at the mucosal interfaces. Therefore, elucidating the fundamental mechanisms that intrinsically regulate the fate and function of individual B cell clones in the gut remains a central question in immunology with clear translational implications. Several lines of evidence indicate that distinct B cell receptor isotypes act as intrinsic regulators of germinal center B cell response. However, how B cells integrate IgA antigen receptor signaling with germinal center dynamics and antibody response remains undefined to date. In this application we test the hypothesis that surface IgA directly controls germinal center B cell response through its enhanced intracellular signaling and Ca2+ release. This leads to the generation of a lower threshold of B cell activation, therefore allowing B cell specific for poorly immunogenic commensal species to be recruited into the germinal center and to participate to the humoral response. We also hypothesize that IgA signaling prevents counterselection mediated by FAS, allowing survival of low affinity B cells. Accumulating evidence indicates IgA coating of commensals is less dependent on antigen affinity, but the mechanisms underpinning this phenotype have not been investigated so far. Our aims are: 1) to dissect the role of IgA-dependent BCR signaling on cell migration into the intestinal tissue and on the quality of the antibody response; and 2) to define the role of Fas-FasL axis in counter- selecting mucosal IgA+ germinal center B cells for efficient intestinal response. The proposed studies examine a very poorly understood crosstalk between IgA signaling and adaptive immune system activation in the gut. It is our expectation that these studies will increase our understanding of how intestinal antigen recognition shapes B cell responses and adaptive immunity both at steady state and during enteric infections. Furthermore, our studies will provide a foundation for better understanding of the relationship between BCR-intracellular signaling and differentiation of gut-homing B lymphocytes that assure mucosal humoral immunity.

抽象的 胃肠道中的B淋巴细胞不断受到微生物抗原的刺激。为了防止 为了共生生长并维持肠道稳态，B 细胞需要快速产生抗体反应 针对细菌抗原。为了实现这一任务，体液免疫系统依赖于复杂的多步骤 B 细胞在生发中心增殖和选择的过程，最终产生 分泌抗体的浆细胞或记忆 B 细胞。 肠道 B 细胞主要表达免疫球蛋白 A (IgA)，但这种特异性抗原受体如何同种型 肠道中 B 细胞命运和抗体反应的影响尚不清楚。此外，IgA 失调 反应与感染易感性增加和粘膜界面自身炎症有关。 因此，阐明内在调节命运和功能的基本机制 肠道中的单个 B 细胞克隆仍然是免疫学的一个中心问题，具有明确的翻译意义 影响。 多项证据表明，不同的 B 细胞受体同种型可作为生发的内在调节因子。 中枢B细胞反应。然而，B 细胞如何将 IgA 抗原受体信号与生发中心整合 迄今为止，动力学和抗体反应仍不确定。 在此应用中，我们测试了表面 IgA 直接控制生发中心 B 细胞反应的假设 通过其增强的细胞内信号传导和 Ca2+ 释放。这导致了较低的生成 B 细胞激活阈值，因此允许对免疫原性较差的共生物种具有特异性的 B 细胞 被招募到生发中心并参与体液反应。我们还假设 IgA 信号传导可防止 FAS 介导的反选择，从而允许低亲和力 B 细胞存活。 越来越多的证据表明共生体的 IgA 涂层对抗原亲和力的依赖性较小，但 迄今为止，尚未研究支撑这种表型的机制。 我们的目标是：1) 剖析 IgA 依赖性 BCR 信号传导对细胞迁移到肠道的作用 组织和抗体反应的质量； 2）定义Fas-FasL轴在反作用中的作用 选择粘膜 IgA+ 生发中心 B 细胞以实现有效的肠道反应。 拟议的研究探讨了 IgA 信号传导和适应性之间的串扰，人们对此知之甚少。 肠道内的免疫系统激活。我们期望这些研究能够增加我们的理解 研究肠道抗原识别如何在稳态和稳态下塑造 B 细胞反应和适应性免疫 肠道感染期间。此外，我们的研究将为更好地理解 BCR 细胞内信号传导与肠道归巢 B 淋巴细胞分化之间的关系 粘膜体液免疫。