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.

摘要