Meyer-Bahlburg Almut, Bandaranayake Ashok D, Andrews Sarah F, Rawlings David J
Seattle Children's Research Institute, WA 98101, USA.
J Immunol. 2009 Apr 1;182(7):4065-75. doi: 10.4049/jimmunol.0802961.
The splenic B cell compartment is comprised of two major, functionally distinct, mature B cell subsets, i.e., follicular mature (FM) and marginal zone (MZ) B cells. Whereas MZ B cells exhibit a robust proliferative response following stimulation with the TLR4 ligand LPS, FM B cells display markedly delayed and reduced levels of proliferation to the identical stimulus. The current study was designed to identify a potential mechanism(s) accounting for this differential responsiveness. In contrast to the delay in cell cycle entry, FM and MZ B cells exhibited nearly identical LPS-driven alterations in the expression level of cell surface activation markers. Furthermore, both the NF-kappaB and mTOR signaling cascades were similarly activated by LPS stimulation in FM vs MZ B cells, while inducible activation of ERK and AKT were nearly absent in both subsets. MZ B cells, however, exhibited higher basal levels of phospho-AKT and pS6, consistent with a preactivated status. Importantly, both basal and LPS activation-induced c-myc expression was markedly reduced in FM vs MZ B cells and enforced c-myc expression fully restored the defective proliferative response in FM B cells. These data support a model wherein TLR responses in FM B cells are tightly regulated by limiting c-myc levels, thereby providing an important checkpoint to control nonspecific FM B cell activation in the absence of cognate Ag.
脾脏B细胞区室由两个主要的、功能不同的成熟B细胞亚群组成，即滤泡成熟（FM）B细胞和边缘区（MZ）B细胞。MZ B细胞在用Toll样受体4（TLR4）配体脂多糖（LPS）刺激后表现出强烈的增殖反应，而FM B细胞对相同刺激的增殖水平则明显延迟且降低。本研究旨在确定导致这种差异反应性的潜在机制。与细胞周期进入延迟相反，FM和MZ B细胞在细胞表面激活标志物表达水平上表现出几乎相同的LPS驱动的变化。此外，在FM与MZ B细胞中，LPS刺激同样激活了核因子κB（NF-κB）和哺乳动物雷帕霉素靶蛋白（mTOR）信号级联反应，而在这两个亚群中几乎都不存在细胞外信号调节激酶（ERK）和蛋白激酶B（AKT）的诱导性激活。然而，MZ B细胞表现出更高的磷酸化AKT和磷酸化核糖体蛋白S6（pS6）基础水平，这与预激活状态一致。重要的是，与MZ B细胞相比，FM B细胞中基础和LPS激活诱导的原癌基因c-myc表达明显降低，而强制表达c-myc可完全恢复FM B细胞中缺陷的增殖反应。这些数据支持了一种模型，即FM B细胞中的TLR反应通过限制c-myc水平受到严格调控，从而在缺乏同源抗原的情况下提供一个重要的检查点来控制非特异性FM B细胞激活。
