Induction of metabolic quiescence defines the transitional to follicular B cell switch
Induction of metabolic quiescence defines the transitional to follicular B cell switch
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DOI：
10.1126/scisignal.aaw5573
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发表时间：
2019-10-22
影响因子：
7.3
通讯作者：
Pillai, Shiv
中科院分区：
文献类型：
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作者：
Farmer, Jocelyn R.;Allard-Chamard, Hugues;Pillai, Shiv
过渡性B细胞必须主动接受自我耐受的选择，才能成熟为其静息的滤泡B细胞继代细胞。我们发现，在人类和小鼠的卵泡B细胞期，代谢都处于停滞状态。在滤泡B细胞中，与核糖体生物发生、有氧呼吸和哺乳动物靶标雷帕霉素复合体1(MTORC1)信号转导相关的基因的表达与过渡性B细胞相比降低。人类B细胞的功能代谢研究、全细胞代谢物图谱和细胞表面蛋白分析表明，这种转变也与细胞外腺苷回收增加有关。滤泡B细胞增加细胞表面ECT酶CD73的丰度，这与腺苷单磷酸活化蛋白激酶(AMPK)的激活相一致。体外向滤泡B细胞期的分化与人移行B细胞表面CD73的获得相关，并被AMPK激动剂AICAR增强。功能增益PIK3CD(PI3K.)突变和pS6激活增加显示几乎没有循环滤泡B细胞。综上所述，我们的数据表明mTORC1的衰减对于人类滤泡B细胞的发育可能是必要的。这些数据确定了人类B细胞发育过程中一个明显的代谢开关，其特征是诱导细胞外腺苷回收，AMPK激活，并获得代谢停滞。
Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis, aerobic respiration, and mammalian target of rapamycin complex 1 (mTORC1) signaling was reduced when compared to that in transitional B cells. Functional metabolism studies, profiling of whole-cell metabolites, and analysis of cell surface proteins in human B cells suggested that this transition was also associated with increased extracellular adenosine salvage. Follicular B cells increased the abundance of the cell surface ectonucleotidase CD73, which coincided with adenosine 5'-monophosphate-activated protein kinase (AMPK) activation. Differentiation to the follicular B cell stage in vitro correlated with surface acquisition of CD73 on human transitional B cells and was augmented with the AMPK agonist, AICAR. Last, individuals with gain-of-function PIK3CD (PI3K.) mutations and increased pS6 activation exhibited a near absence of circulating follicular B cells. Together, our data suggest that mTORC1 attenuation may be necessary for human follicular B cell development. These data identify a distinct metabolic switch during human B cell development at the transitional to follicular stages, which is characterized by an induction of extracellular adenosine salvage, AMPK activation, and the acquisition of metabolic quiescence.