Signal thresholds and modular synergy during expression of costimulatory molecules in B lymphocytes
Signal thresholds and modular synergy during expression of costimulatory molecules in B lymphocytes
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DOI：
10.4049/jimmunol.167.1.114
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发表时间：
2001-07-01
影响因子：
4.4
通讯作者：
Rao, KVS
中科院分区：
文献类型：
--
作者：
Natarajan, K;Sahoo, NC;Rao, KVS
我们分析了通过连接Ag受体和粘附分子CD54激活的B细胞中调节CD80和CD86表面密度的细胞内通路。B细胞Ag受体（BCR）单独交联可刺激CD86的表达增加，而CD80的上调则需要抗igm和抗cd54的双重刺激。BCR信号对CD80和CD86诱导的主要下游成分是通过容性内流募集的游离细胞质Ca2+浓度升高。仅这一点就足以产生CD86水平的增加。然而，CD80增强需要细胞内Ca2+浓度和cd54启动途径的协同作用。在CD80调控的背景下，抗igm和抗cd54刺激之间的联系被确定为涉及顺序协同的自传播过程。第一步涉及细胞内cAMP的扩增积累，这是bcr动员的Ca2+和cd54衍生信号之间的串扰的结果。这促进了Ca2+和cAMP之间的第二次协同相互作用，最终导致CD80的表达。我们发现不同的信号换能器需求，加上串扰的附加后果，为响应不同生理刺激的共刺激分子表达的可变调节提供了解释。重要的是，这些结果还揭示了如何通过信号模块的建设性收敛来克服个体第二信使招募的集中阈值障碍。
We analyzed intracellular pathways modulating surface densities of CD80 and CD86 in B cells activated through ligation of the Ag receptor, and the adhesion molecule CD54. Whereas B cell Ag receptor (BCR) cross-linking alone stimulated increased expression of CD86, up-regulation of CD80 required dual stimulation with anti-IgM and anti-CD54. The principal downstream component contributed by BCR signaling, toward both CD80 and CD86 induction, was the elevated concentration of free cytoplasmic Ca2+, recruited by way of capacitative influx. This alone was sufficient to generate an increase in CD86 levels. However, CD80 enhancement required the concerted action of both intracellular Ca2+ concentration and CD54-initiated pathways. The nexus between anti-IgM and anti-CD54 stimulation, in the context of CD80 regulation, was identified to involve a self-propagating process of sequential synergy. The first step involved amplified accumulation of intracellular cAMP, as a result of cross-talk between BCR-mobilized Ca2+ and CD54-derived signals. This then facilitated a second synergistic interaction between Ca2+ and cAMP, culminating in CD80 expression. Our findings of distinct signal transducer requirements, with the added consequences of cross-talk, offers an explanation for variable modulation of costimulatory molecule expression in response to diverse physiological stimuli. Importantly, these results also reveal how concentration threshold barriers for recruitment of individual second messengers can be overcome by constructive convergence of signaling modules.