Regulation of germinal center responses and B-cell memory by the chromatin modifier MOZ
Regulation of germinal center responses and B-cell memory by the chromatin modifier MOZ
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DOI：
10.1073/pnas.1402485111
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发表时间：
2014-07-01
影响因子：
11.1
通讯作者：
Tarlinton, David
中科院分区：
文献类型：
--
作者：
Good-Jacobson, Kim L.;Chen, Yunshun;Tarlinton, David
记忆B细胞和长寿命的骨髓浆细胞维持体液免疫。对于形成记忆B细胞或赋予它们在再暴露时快速分化的能力同时随着时间的推移维持种群的内在机制，人们知之甚少。组蛋白修饰已被证明可以调节淋巴细胞发育，但它们在免疫应答期间调节B细胞亚群的分化和维持中的作用尚不清楚。使用阶段特异性删除单核细胞白血病锌指蛋白（MOZ），组蛋白乙酰转移酶，我们证明了这种染色质修饰剂的突变改变了原发性和继发性反应的命运决定。在没有MOZ的情况下，生发中心B细胞产生暗区中心母细胞的能力显著受损，伴随着细胞周期进程和BCL-6表达的减少。相反，向IgM和低亲和力IgG1（+）记忆B细胞的分化增加。MOZ的缺乏影响了体液免疫应答的功能结果，次级生殖中心增加，次级高亲和力抗体分泌细胞形成相应减少。因此，这些数据提供了强有力的证据，操纵表观遗传修饰剂可以调节体液反应过程中的命运决定，因此可以靶向治疗干预。
Memory B cells and long-lived bone marrow-resident plasma cells maintain humoral immunity. Little is known about the intrinsic mechanisms that are essential for forming memory B cells or endowing them with the ability to rapidly differentiate upon reexposure while maintaining the population over time. Histone modifications have been shown to regulate lymphocyte development, but their role in regulating differentiation and maintenance of B-cell subsets during an immune response is unclear. Using stage-specific deletion of monocytic leukemia zinc finger protein (MOZ), a histone acetyltransferase, we demonstrate that mutation of this chromatin modifier alters fate decisions in both primary and secondary responses. In the absence of MOZ, germinal center B cells were significantly impaired in their ability to generate dark zone centroblasts, with a concomitant decrease in both cell-cycle progression and BCL-6 expression. In contrast, there was increased differentiation to IgM and low-affinity IgG1(+) memory B cells. The lack of MOZ affected the functional outcome of humoral immune responses, with an increase in secondary germinal centers and a corresponding decrease in secondary high-affinity antibody-secreting cell formation. Therefore, these data provide strong evidence that manipulating epigenetic modifiers can regulate fate decisions during humoral responses, and thus could be targeted for therapeutic intervention.