FCRL1 in B cell differentiation

项目摘要 B淋巴细胞负责对疫苗接种产生的抗原做出反应而产生抗体 和感染适应性免疫包括激活和扩增B细胞， 这些抗原，产生中和和调理抗体，并提供免疫 记忆发生这种情况的过程涉及内部信号的复杂相互作用， 在细胞外指导B细胞何时扩增、修饰其抗原受体和分化 转化为记忆细胞或分泌抗体的浆细胞。这种分化过程的大部分发生在 在一个叫做生发中心的特殊淋巴结构中。我们的研究旨在了解 B细胞如何操纵生长和分化过程以优化抗体反应。我们 正在研究一种细胞表面蛋白质FCRL 1，它存在于外周B细胞的所有亚群中。当 B细胞受体（BCR）与抗原结合，FCRL 1增强细胞内钙信号， 抑制ERK 1/2的激活。FCRL 1缺陷小鼠的抗体应答受损 免疫后生殖中心B细胞减少。我们假设FCRL 1控制着 B细胞发出信号以在分化之前使克隆扩增最大化。使用模型抗原系统 和Fcrl 1-/-小鼠，本研究将跟踪整个过程中B细胞活化和分化的动力学 生发中心对记忆细胞和浆细胞的产生作出反应。它将研究如何 FCRL 1介导的ERK抑制改变了B细胞分化，这将开始揭示FCRL 1介导的ERK抑制对B细胞分化的影响。 FCRL 1使用的信号传导通路，使用BCR诱导的ERK 1/2活化下调 基因靶向和转基因B细胞系。这项研究将提高我们对信号的理解 提供最佳的抗体对感染的反应，其长期目标是改善 疫苗和免疫疗法的有效性和持久性。

PROJECT SUMMARY B lymphocytes are responsible for making antibodies in response to antigens from vaccination and infection. Adaptive immunity involves activating and expanding B cells that can recognize those antigens, produce neutralizing and opsonizing antibodies, and provide immunological memory. The process by which this occurs involves a complex interplay of signals inside and outside the cell to instruct B cells when to expand, modify their antigen receptor, and differentiate into memory cells or antibody-secreting plasma cells. Much of this differentiation process occurs in a specialized lymphoid structure called the germinal center. Our study seeks to understand how B cells navigate the growth and differentiation process to optimize antibody responses. We are studying a cell surface protein, FCRL1, found on all subsets of peripheral B cells. When the B cell receptor (BCR) is engaged by antigen, FCRL1 enhances intracellular calcium signals while suppressing the activation of ERK1/2. Mice deficient in FCRL1 have impaired antibody responses and fewer germinal center B cells after immunization. We hypothesize that FCRL1 is controlling B cell signals to maximize clonal expansion prior to differentiation. Using a model antigen system and Fcrl1-/- mice, this study will track the kinetics of B cell activation and differentiation throughout the germinal center response to the production of memory and plasma cells. It will examine how FCRL1-mediated ERK inhibition alters B cell differentiation, and it will begin to uncover the signaling pathway(s) used by FCRL1 to down-modulate BCR-induced ERK1/2 activation using gene-targeted and transgenic B cell lines. This study will improve our understanding of signals that provide optimal antibody responses to infection with the long-term aim of improving the efficacy and durability of vaccines and immunotherapies.