Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI, 53226, USA.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Nat Commun. 2017 Nov 13;8(1):1457. doi: 10.1038/s41467-017-01388-5.
The precise molecular mechanism underlying the regulation of early B cell lymphopoiesis is unclear. The PLCγ signaling pathway is critical for antigen receptor-mediated lymphocyte activation, but its function in cytokine signaling is unknown. Here we show that PLCγ1/PLCγ2 double deficiency in mice blocks early B cell development at the pre-pro-B cell stage and renders B cell progenitors unresponsive to IL-7. PLCγ pathway inhibition blocks IL-7-induced activation of mTOR, but not Stat5. The PLCγ pathway activates mTOR through the DAG/PKC signaling branch, independent of the conventional Akt/TSC/Rheb signaling axis. Inhibition of PLCγ/PKC-induced mTOR activation impairs IL-7-mediated B cell development. PLCγ1/PLCγ2 double-deficient B cell progenitors have reduced expression of genes related to B cell lineage, IL-7 signaling, and cell cycle. Thus, IL-7 receptor controls early B lymphopoiesis through activation of mTOR via PLCγ/DAG/PKC signaling, not via Akt/Rheb signaling.
PLCγ 信号通路在抗原受体介导的淋巴细胞激活中至关重要，但它在细胞因子信号中的功能尚不清楚。在这里，我们表明 PLCγ1/PLCγ2 双缺失会阻止小鼠早期 B 细胞发育到前 B 细胞阶段，并使 B 细胞祖细胞对 IL-7 无反应。PLCγ 通路抑制会阻断 IL-7 诱导的 mTOR 激活，但不会阻断 Stat5。PLCγ 通路通过 DAG/ PKC 信号分支激活 mTOR，而不依赖于传统的 Akt/TSC/Rheb 信号轴。抑制 PLCγ/ PKC 诱导的 mTOR 激活会损害 IL-7 介导的 B 细胞发育。PLCγ1/PLCγ2 双缺失的 B 细胞祖细胞中与 B 细胞谱系、IL-7 信号和细胞周期相关的基因表达减少。因此，IL-7 受体通过 PLCγ/ DAG/ PKC 信号而不是 Akt/ Rheb 信号激活 mTOR 来控制早期 B 淋巴细胞的发生。
