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

摘要 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 为了维持肠道内环境的稳定，B细胞需要快速的抗体反应 对抗细菌抗原。为了完成这项任务，体液免疫系统依赖于一个复杂的多步骤 B细胞在生发中心增殖和选择的过程，最终导致 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（伊加），但这种特异性抗原受体如何同种型 肠内B细胞命运和抗体反应的形状知之甚少。此外，伊加的失调 应答与粘膜界面处的感染易感性和自身炎症增加相关。 因此，阐明内在调节细胞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中心问题， 影响 几条证据表明，不同的B细胞受体同种型作为内源性调节剂的germination 中心B细胞应答。然而，B细胞如何整合伊加抗原受体信号与生发中心， 动力学和抗体反应至今仍不明确。 在本申请中，我们检验了表面伊加直接控制生殖中心B细胞应答的假设 通过其增强的细胞内信号传导和Ca 2+释放。这导致了较低的 B细胞活化的阈值，因此允许对免疫原性差的肿瘤物种特异性的B细胞， 被招募到生殖中心并参与体液反应。我们还假设， 伊加信号传导阻止FAS介导的反选择，允许低亲和力B细胞存活。 越来越多的证据表明，伊加包被的抗原亲和力的依赖性较低，但 到目前为止还没有研究支持这种表型的机制。 我们的目的是：1）分析IgA依赖的BCR信号在细胞迁移到肠道中的作用， 组织和抗体应答的质量;和2）确定Fas-FasL轴在抗- 选择粘膜伊加+生发中心B细胞用于有效的肠应答。 拟议的研究检查了伊加信号传导和适应性之间的一个非常不清楚的串扰。 肠道免疫系统激活。我们期望这些研究将增进我们对 肠抗原识别如何在稳态和稳态下塑造B细胞应答和适应性免疫， 在肠道感染期间。此外，我们的研究将为更好地了解 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

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.