组蛋白H3赖氨酸27去甲基化酶Jmjd3在肠道IgA产生的关键作用及其调控机制研究

IgA+ B cells in gut-associated lymphoid tissues differentiate into IgA-producing plasma cell, secreting IgA that plays important roles in intestinal homeostasis and mucosal defenses and controls the diversity of intestinal microbiota together with the development of intestinal inflammation and cancers. However, the mechanisms underlying the development and differentiation of IgA+ B cells and IgA production remain unclear. We previously generated the B cell conditional knockout mice deficient of H3K27 demethylase, Jmjd3 in B cells. We found that the severe impairment in the production of IgA, not IgM or other types of IgG, in primary and secondary response to TD antigen in cKO mice. The selective impaired IgA production in Jmjd3 cKO mice has been confirmed in other two mouse models of pathogen infection and CT challenge. These primary data indicated that the H3K27 demethylation mediated by Jmjd3 was essential for the development and differentiation of IgA+ B cells in GALT and IgA production. In this project we will utilize the unique mouse model with selective impairment in IgA production and investigate the signals that regulate the development and differentiation of IgA+ B cells and class type switch recombination. And finally we will decipher the mechanisms by which H3K27 demethylation plays in the process. Our study is expected to provide the theoretical basis for vaccine design and the control of intestinal inflammation and inflammation-associated cancer.

肠道相关淋巴组织（GALT）中IgA+B细胞分化为浆细胞，产生IgA，维持肠道粘膜稳态和粘膜防御，调控肠道微生态和炎症甚至肿瘤的发生发展。但GALT中IgA+B细胞的发育分化过程和IgA产生的调控机制仍不清楚。申请者利用B细胞条件性敲除组蛋白H3K27去甲基化酶Jmjd3的小鼠发现，T细胞依赖抗原初次免疫或再次免疫后，缺少Jmjd3的B细胞分化的浆细胞分泌IgA严重缺陷，但分泌IgM和各种类型的IgG不受影响，并在肠道细菌感染或毒素处理等模型中确证，显示GALT中IgA+B细胞发育分化或IgA的类型转换重组过程受Jmjd3介导的H3K27去甲基化修饰的表观遗传机制调控。本研究将利用该独特的选择性产生IgA缺陷的小鼠模型，深入研究GALT中IgA+B细胞发育分化和IgA类型转换的调控信号，揭示H3K27去甲基化修饰在其中的调控机制，为设计肠道疫苗，控制肠道炎症和肿瘤发生发展提供理论依据。

肠道相关淋巴组织中IgA+ B细胞分化为浆细胞产生IgA，维持肠道粘膜稳态和粘膜防御，调控肠道微生态和炎症甚至肿瘤的发生发展。但目前IgA+ B细胞的发育分化过程和调控机制仍不清楚。我们利用B细胞条件敲除组蛋白H3K27去甲基化酶Jmjd3小鼠研究发现，T细胞依赖抗原免疫小鼠后，Jmjd3缺失小鼠分泌IgA严重缺陷，但IgM和各类型IgG不受影响;并在肠道细菌感染模型中确证，IgA的产生受Jmjd3的调控。.基于上述发现，本项目利用Jmjd3条件敲除小鼠深入研究Jmjd3对IgA+ B细胞发育分化和IgA产生的调控，并阐明背后的调控机制。具体研究发现如下：.1，在B细胞中，Jmjd3受LPS，anti-IgM，anti-CD40的调控。.2，Jmjd3调控IgA+ B细胞的分化，调控IgA的产生, 并在肠道病原感染模型中验证。.3，Jmjd3的缺失并不影响B细胞的增殖存活以及分化。.4，Jmjd3不影响生发中心B细胞的发育以及功能。.5，进一步研究发现Jmjd3通过直接调控Tgfbr1 的表达影响IgA的产生。.6, Jmjd3的缺失会造成肠道菌群的改变，调控小鼠对DSS诱导的急性肠炎的敏感性。.本项目进一步探究了组蛋白H3K27去甲基化酶Jmjd3在IgA+ B细胞发育分化以及IgA产生中的调控作用；阐明了其表观遗传调控机制；揭示了肠道免疫的一个新的调控机制——H3K27去甲基化修饰调控IgA的产生；首次发现了Jmjd3缺失会改变小鼠肠道菌群，特别是乳酸杆菌的变化，从而调控小鼠的肠道炎症发生发展。本项目的研究成果为设计肠道疫苗，控制肠道炎症，肿瘤的发生发展提供了坚实的理论基础。