Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA.
Department of Immunology, University of Washington School of Medicine, Seattle, WA.
J Exp Med. 2018 Sep 3;215(9):2445-2461. doi: 10.1084/jem.20180230. Epub 2018 Aug 20.
Activating mutations in the adapter protein CARD11 associated with diffuse large B cell lymphomas (DLBCLs) are predicted to arise during germinal center (GC) responses, leading to inappropriate activation of NF-κB signaling. Here, we modeled the B cell-intrinsic impact of the L251P activating mutation in CARD11 (aCARD11) on the GC response. Global B cell aCARD11 expression led to a modest increase in splenic B cells and a severe reduction in B1 B cell numbers, respectively. Following T cell-dependent immunization, aCARD11 cells exhibited increased rates of GC formation, resolution, and differentiation. Restriction of aCARD11 to GC B cells similarly altered the GC response and B cell differentiation. In this model, aCARD11 promoted dark zone skewing along with increased cycling, AID levels, and class switch recombination. Furthermore, aCard11 GC B cells displayed increased biomass and mTORC1 signaling, suggesting a novel strategy for targeting aCARD11-driven DLBCL. While aCARD11 potently impacts GC responses, the rapid GC contraction suggests it requires collaboration with events that limit terminal differentiation to promote lymphoma.
与弥漫性大 B 细胞淋巴瘤（DLBCLs）相关的衔接蛋白 CARD11 的激活突变预计在生发中心（GC）反应中产生，导致 NF-κB 信号的异常激活。在这里，我们模拟了 CARD11（aCARD11）中的 L251P 激活突变对 GC 反应的内在 B 细胞影响。全局 B 细胞 aCARD11 表达分别导致脾脏 B 细胞适度增加和 B1 B 细胞数量严重减少。在 T 细胞依赖性免疫接种后，aCARD11 细胞表现出 GC 形成、解决和分化的增加率。将 aCARD11 限制在 GC B 细胞中同样改变了 GC 反应和 B 细胞分化。在该模型中，aCARD11 促进暗区偏斜，同时增加循环、AID 水平和类别转换重组。此外，aCard11 GC B 细胞显示出增加的生物量和 mTORC1 信号，表明针对 aCARD11 驱动的 DLBCL 的一种新策略。虽然 aCARD11 强烈影响 GC 反应，但快速的 GC 收缩表明它需要与限制终末分化以促进淋巴瘤的事件协作。
