Requirement for cyclin D3 in germinal center formation and function.
Requirement for cyclin D3 in germinal center formation and function.
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作者：
次级淋巴组织的生发中心 (GC) 对于产生高亲和力体液免疫反应至关重要。 GC 内的 B 细胞经历快速克隆扩增和选择，同时使其抗体基因多样化。尽管人们普遍认为 GC B 细胞采用独特的增殖程序来适应这些过程，但人们对 GC 相关细胞周期是如何协调的知之甚少。 D型细胞周期蛋白构成细胞周期引擎的重要组成部分，使细胞能够对生理变化做出反应。 D 型细胞周期蛋白的细胞类型和发育阶段特异性作用已被描述，但 GC 反应期间细胞周期蛋白 D 的要求尚未得到解决。在这项研究中，我们报告说，细胞周期蛋白 D3 对于体外激活的 B 细胞的增殖和 Ig 类别转换来说基本上是可有可无的。相比之下，Ccnd3−/− 小鼠的 GC 发育明显受损，T 细胞依赖性抗体反应也明显受损。在 GC 内，尽管转换和未转换的 B 细胞均受到细胞周期蛋白 D3 失活的影响，但 IgM− 池的减少更为严重。有趣的是，尽管细胞周期蛋白 D2 表达补偿性增加，但大量 Ccnd3−/− GC B 细胞积聚在静态 G0 状态。最后，虽然cyclin D3失活不会破坏GC B细胞中BCL6的表达，但它完全阻断了BCL6过表达的GC促进作用，表明cyclin D3在BCL6下游发挥作用来调节GC形成。这是首次证明细胞周期蛋白 D3 在 B 细胞发育的 GC 阶段发挥着重要而独特的作用。
Germinal Centers (GC) of secondary lymphoid tissues are critical to mounting a high-affinity humoral immune response. B cells within the GC undergo rapid clonal expansion and selection while diversifying their antibody genes. Although it is generally believed that GC B cells employ a unique proliferative program to accommodate these processes, little is known about how the GC-associated cell cycle is orchestrated. The D-type cyclins constitute an important component of the cell cycle engine that enables the cells to respond to physiological changes. Cell type- and developmental stage-specific roles of D-type cyclins have been described but the cyclin D requirement during GC reaction has not been addressed. In this study, we report that cyclin D3 is largely dispensable for proliferation and Ig class switching of in vitro activated B cells. In contrast, GC development in Ccnd3−/− mice is markedly impaired, as is the T cell-dependent antibody response. Within the GC, although both switched and unswitched B cells are affected by cyclin D3 inactivation, the IgM− pool is more severely reduced. Interestingly, despite a compensatory increase in cyclin D2 expression, a significant numbers of Ccnd3−/− GC B cells accumulate in quiescent G0 state. Lastly, although cyclin D3 inactivation did not disrupt BCL6 expression in GC B cells, it completely blocked the GC promoting effect of BCL6 overexpression, suggesting that cyclin D3 acts downstream of BCL6 to regulate GC formation. This is the first demonstration that cyclin D3 plays an important and unique role at the GC stage of B cell development.
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DOI：
10.1126/science.1176676
发表时间：
2009-08-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Nurieva RI;Chung Y;Martinez GJ;Yang XO;Tanaka S;Matskevitch TD;Wang YH;Dong C
通讯作者：
Dong C
影响因子：
64.5
作者：
Lamb, J;Ramaswamy, S;Ewen, ME
通讯作者：
Ewen, ME
影响因子：
30.5
作者：
Bardwell, PD;Woo, CJ;Scharff, MD
通讯作者：
Scharff, MD
影响因子：
4.3
作者：
Mullany, Lisa K.;White, Peter;Albrecht, Jeffrey H.
通讯作者：
Albrecht, Jeffrey H.
影响因子：
30.5
作者：
Cooper, AB;Sawai, CM;Aifantis, I
通讯作者：
Aifantis, I