CD19+CD11b+B细胞在自身免疫性肠炎中的分化机制以及调节作用研究

B cell is one of the important immune cells. Recent studies have identified that B cells display a regulatory function in response to inflammatory cues. However, little is currently known about its phenotypic markers. Moreover, the mechanisms of B cell differentiation and regulatory function are urgent to be revealed. Our previous study has identified a regulatory B cell subset with a unique CD19+CD11b+ phenotype that may be induced by intestinal bacterial metabolites. This new B cell subset could ameliorate the autoimmune diseases by restricting effector T-cell proliferation and promoting regulatory T-cell proliferation. In this project, we will use murine inflammatory bowel disease (IBD) model to study the regulotory B cell phenotypes with cellular experiments and the regulatory mechanisms with molecular technologies. We will also investigated the mechanisms by which naive B cells are induced to differentiate into CD19+CD11b+ B cells by intestinal bacteria and their metabolites and explored the transcription factor, CD11b ligand and the signaling pathways that are involved in B cell differentiation. We aim to solve two hot spots in the field of Breg research: 1.the mechanisms by which naive B cells are induced to differentiate into a regulatory B cell subset with a unique CD19+CD11b+ phenotype. 2.the mechanisms by which CD19+CD11b+ B cells negatively regulate immune response, providing the theoretical basis to research and application of Breg.

B细胞是重要的免疫细胞，近来研究发现它具有调节功能。但是有关它的表型、分化及调节机制是免疫学研究的重大热点和难点。我们在自身免疫性疾病中发现一群新的具有调节功能的CD19+CD11b+B细胞亚群，该亚群可由肠道菌群代谢产物诱导，并通过抑制效应性T细胞的活化以及促进调节性T细胞增殖发挥调节效应，缓解疾病进程。在本项目中我们拟通过小鼠自身免疫性肠炎模型，在细胞水平进行表型研究以及在分子水平进行机制研究，探索肠道菌代谢产物对于初始B细胞向CD19+CD11b+B细胞分化的驱动机制，调控B细胞分化的特异性转录因子，以及CD11b分子行使调控的关键配体和相应的信号通路。以解决Breg研究领域两大热点问题：1.初始B细胞是在何种因素驱动下，分化为具有CD19+CD11b+表面标志的具有调节功能的B细胞亚群；2.CD19+CD11b+发挥其负性调节的功能的机制，为Breg的全面研究和应用提供理论基础。

B细胞是重要的免疫细胞，近来研究发现它具有调节功能，但是有关它的表型、驱动分化及调节机制是免疫学研究的重大热点和难点。我们在自身免疫性疾病中发现一群新的具有调节功能的CD19+CD11b+B细胞亚群，该亚群在自身免疫性肝炎和炎症性肠病中均存在高表达，通过抑制效应性T细胞的过度活化以及促进调节性T细胞增殖缓解疾病进程，发挥调节效应。在本项目中我们通过建立小鼠自身免疫性肠炎和肺炎模型，发现了CD19+CD11b+B细胞在粘膜免疫中倾向于向IgA+细胞方向分化，维持肠和肺部稳态，而CD19+CD11b-B细胞则没有这个功能；更进一步，我们发现了以CD19+CD11b+B细胞为代表的调节性B细胞高表达HSP70，并依赖HSP70调控免疫格局；最为重要的是，我们通过体内外实验证实了CD19+CD11b+B细胞是一群特殊的B细胞亚群，ZBTB32可能是他的转录因子。这些发现试图解决了Breg研究领域两大热点问题：1. Breg是否有独特的亚型和表面标记；2它的转录因子是很么，这些发现为Breg功能研究和临床应用提供理论基础。