Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY.
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
J Exp Med. 2021 Apr 5;218(4). doi: 10.1084/jem.20201699.
During affinity maturation, germinal center (GC) B cells alternate between proliferation and somatic hypermutation in the dark zone (DZ) and affinity-dependent selection in the light zone (LZ). This anatomical segregation imposes that the vigorous proliferation that allows clonal expansion of positively selected GC B cells takes place ostensibly in the absence of the signals that triggered selection in the LZ, as if by "inertia." We find that such inertial cycles specifically require the cell cycle regulator cyclin D3. Cyclin D3 dose-dependently controls the extent to which B cells proliferate in the DZ and is essential for effective clonal expansion of GC B cells in response to strong T follicular helper (Tfh) cell help. Introduction into the Ccnd3 gene of a Burkitt lymphoma-associated gain-of-function mutation (T283A) leads to larger GCs with increased DZ proliferation and, in older mice, clonal B cell lymphoproliferation, suggesting that the DZ inertial cell cycle program can be coopted by B cells undergoing malignant transformation.
在亲和力成熟过程中，生发中心（GC）B 细胞在暗区（DZ）中经历增殖和体细胞超突变，以及在亮区（LZ）中进行亲和力依赖性选择。这种解剖学上的分隔使得允许阳性选择的 GC B 细胞克隆扩增的剧烈增殖表面上发生在 LZ 中触发选择的信号不存在的情况下，就好像是“惯性”一样。我们发现，这种惯性循环特别需要细胞周期调节剂细胞周期蛋白 D3。细胞周期蛋白 D3 剂量依赖性地控制 B 细胞在 DZ 中增殖的程度，对于 GC B 细胞对强滤泡辅助性 T 细胞（Tfh）细胞帮助的有效克隆扩增是必不可少的。在 Burkitt 淋巴瘤相关获得性功能突变（T283A）的 Ccnd3 基因中引入该突变会导致更大的 GC，DZ 增殖增加，并且在老年小鼠中会导致克隆性 B 细胞淋巴增生，这表明正在发生恶性转化的 B 细胞可以被 DZ 惯性细胞周期程序所利用。
