FCRL1 in B cell differentiation

项目概要 B 淋巴细胞负责产生针对疫苗接种抗原的抗体 和感染。适应性免疫涉及激活和扩展能够识别的 B 细胞 这些抗原，产生中和和调理抗体，并提供免疫学 记忆。这种情况发生的过程涉及内部和外部信号的复杂相互作用。 在细胞外指导 B 细胞何时扩增、修饰其抗原受体以及分化 进入记忆细胞或分泌抗体的浆细胞。这种分化过程大部分发生在 位于称为生发中心的特殊淋巴结构中。我们的研究旨在了解 B 细胞如何引导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 FCRL1，该蛋白存在于所有外周 B 细胞亚群中。当 B 细胞受体 (BCR) 与抗原结合，FCRL1 增强细胞内钙信号，同时 抑制 ERK1/2 的激活。 FCRL1 缺陷的小鼠抗体反应受损 免疫后生发中心 B 细胞减少。我们假设 FCRL1 正在控制 B 细胞在分化前发出信号以最大化克隆扩增。使用模型抗原系统 和 Fcrl1-/- 小鼠，这项研究将全程跟踪 B 细胞激活和分化的动力学 生发中心对记忆细胞和浆细胞产生的反应。它将检查如何 FCRL1 介导的 ERK 抑制改变 B 细胞分化，并且它将开始揭示 FCRL1 使用信号通路下调 BCR 诱导的 ERK1/2 激活 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 提供针对感染的最佳抗体反应，长期目标是改善 疫苗和免疫疗法的功效和持久性。

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.