Bollum Lise K, Huse Kanutte, Oksvold Morten P, Bai Baoyan, Hilden Vera I, Forfang Lise, Yoon Sun Ok, Wälchli Sébastien, Smeland Erlend B, Myklebust June H
Department of Cancer Immunology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo, Norway.
Center for Cancer Biomedicine, University of Oslo, Oslo, Norway.
PLoS One. 2017 May 10;12(5):e0177188. doi: 10.1371/journal.pone.0177188. eCollection 2017.
Selection and maturation of B cells into plasma cells producing high-affinity antibodies occur in germinal centers (GC). GCs form transiently in secondary lymphoid organs upon antigen challenge, and the GC reaction is a highly regulated process. TGF-β is a potent negative regulator, but the influence of other family members including bone morphogenetic proteins (BMPs) is less known. Studies of human peripheral blood B lymphocytes showed that BMP-6 suppressed plasmablast differentiation, whereas BMP-7 induced apoptosis. Here, we show that human naïve and GC B cells had a strikingly different receptor expression pattern. GC B cells expressed high levels of BMP type I receptor but low levels of type II receptors, whereas naïve B cells had the opposite pattern. Furthermore, GC B cells had elevated levels of downstream signaling components SMAD1 and SMAD5, but reduced levels of the inhibitory SMAD7. Functional assays of GC B cells revealed that BMP-7 suppressed the viability-promoting effect of CD40L and IL-21, but had no effect on CD40L- and IL-21-induced differentiation into plasmablasts. BMP-7-induced apoptosis was counteracted by a selective TGF-β type I receptor (ALK4/5/7) inhibitor, but not by a selective BMP receptor type I inhibitor. Furthermore, overexpression of truncated ALK5 in a B-cell line counteracted BMP-7-induced apoptosis, whereas overexpression of truncated ALK4 had no effect. BMP-7 mRNA and protein was readily detected in tonsillar B cells, indicating a physiological relevance of the study. Altogether, we identified BMP-7 as a negative regulator of GC B-cell survival. The effect was counteracted by truncated ALK5, suggesting greater complexity in regulating BMP-7 signaling than previously believed.
B细胞分化为产生高亲和力抗体的浆细胞的选择和成熟过程发生在生发中心（GC）。抗原刺激后，生发中心在二级淋巴器官中短暂形成，并且生发中心反应是一个高度受调控的过程。转化生长因子-β（TGF-β）是一种有效的负调节因子，但包括骨形态发生蛋白（BMPs）在内的其他家族成员的影响尚鲜为人知。对人外周血B淋巴细胞的研究表明，骨形态发生蛋白-6（BMP-6）抑制浆母细胞分化，而骨形态发生蛋白-7（BMP-7）诱导细胞凋亡。在此，我们表明人类初始B细胞和生发中心B细胞具有明显不同的受体表达模式。生发中心B细胞表达高水平的I型BMP受体，但II型受体水平较低，而初始B细胞则呈现相反的模式。此外，生发中心B细胞下游信号成分SMAD1和SMAD5水平升高，但抑制性SMAD7水平降低。生发中心B细胞的功能分析表明，骨形态发生蛋白-7抑制CD40L和白细胞介素-21的促生存作用，但对CD40L和白细胞介素-21诱导的向浆母细胞分化没有影响。骨形态发生蛋白-7诱导的细胞凋亡被选择性的I型TGF-β受体（ALK4/5/7）抑制剂抵消，但未被选择性的I型BMP受体抑制剂抵消。此外，在B细胞系中截短型ALK5的过表达抵消了骨形态发生蛋白-7诱导的细胞凋亡，而截短型ALK4的过表达则没有影响。在扁桃体B细胞中很容易检测到骨形态发生蛋白-7的mRNA和蛋白，表明该研究具有生理相关性。总之，我们确定骨形态发生蛋白-7为生发中心B细胞存活的负调节因子。截短型ALK5抵消了该作用，表明骨形态发生蛋白-7信号调控比之前认为的更为复杂。
