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。

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.