新生期天然调节性B细胞激活的分子机制及其免疫调节功能研究

Neonatal period is characterized by high susceptibility to microbial pathogens such as bacteria and viruses, but the underlying key mechanism is poorly understood. B cells are traditionally considered to play their roles in adaptive antibody responses, but in recent years it has been revealed that there exists a population of innate regulatory B cells in the body, which produce high amount of negatively regulatory cytokine IL-10 following rapid activation by TLR agonists. Up to now, the molecular mechanisms that lead to the rapid activation of these innate regulatory B cells and their roles in infectious diseases have been barely studied. Our previous studies have found a population of IL-10-secreting innate regulatory B cells in both neonatal mice and human cord blood. Based on these findings, the current research project will perform the following studies: 1) to characterize the key protein kinases and transcriptional factors responsible for the rapid expression of IL-10 in neonatal regulatory B cells following innate activation; 2) to establish both human cord blood and mouse Escherichia coli infection models, in order to explore the immune regulatory roles of these neonatal regulatory B cells in the context of infection. This project will not only provide important information to deeply understand the mechanisms of anti-infectious immunity and the functions of innate regulatory B cells at neonatal stage, but also provide new clues to the prevention and treatment of neonatal infectious diseases.

新生期的一大特征是易被细菌和病毒等病原微生物感染，但目前对造成新生期免疫力低下的关键原因还不清楚。B细胞传统上被认为只在获得性免疫的抗体应答中起作用，近年来的研究发现体内存在一群天然调节性B细胞，它们在TLR配体的刺激下迅速活化，并分泌大量的免疫负调节分子白介素10(IL-10)。目前对激活这些天然调节性B细胞的分子机制及其在感染性疾病中的作用还缺乏深入了解。我们的前期工作发现在新生期小鼠和人类存在一群分泌IL-10的天然调节性B细胞。在此基础上，本项目拟开展如下研究:1)鉴定出新生期天然调节性B细胞活化后导致IL-10表达的关键性激酶和转录因子;2)建立人类脐带血和新生期小鼠大肠杆菌败血症感染模型，研究在感染状态下新生期天然调节性B细胞的免疫调节功能。本研究不但对于阐明新生期的抗感染免疫应答的规律及深入理解调节性B细胞的功能有着重要的意义，而且也可为新生期感染性疾病的防治提供新的线索。

新生儿对病原微生物高度易感，其原因一方面是新生儿的免疫系统尚未完全发育成熟，另一方面则是可能存在着新生期特定的免疫调控机制，目前对于后者的研究尚不深入。近年来的研究发现，机体内存在着调节性B细胞，该群细胞可通过分泌IL-10等方式发挥免疫负调控作用。本研究针对新生期小鼠和人类新生期的一群分泌IL-10的天然调节性B细胞的发育和功能进行了研究，取得了以下的研究成果：(1)发现mTOR通路是调控新生期天然调节性B细胞发育和免疫调节功能的关键通路；(2)阐明了人类新生期天然调节性B细胞的表型和免疫生物学特征；(3)发现呼吸道合胞病毒RSV可通过靶向CX3CR1受体特异性感染人类新生期天然调节性B细胞，继而分泌IL-10发挥其免疫负调控作用；(4)明确了新生儿败血症B细胞亚群变化特征，发现败血症患儿未成熟B细胞降低，记忆B细胞增加。以上研究不但拓展了对B细胞发育和功能的认识，也为新生期感染性疾病的诊断和病情监测提供了新的思路。本项研究按计划总体执行良好，已在国际期刊Immunity, Cell Mol Immunol等杂志发表论文三篇，人类新生期天然调节性B细胞特性研究论文和人类新生儿败血症B细胞论文目前分别修回和准备中，后续研究也正在积极进行。