PLCγ-dependent mTOR signalling controls IL-7-mediated early B cell development

Mei Yu, Yuhong Chen, Hu Zeng, Yongwei Zheng, Guoping Fu, Wen Zhu, Ulrich Broeckel, Praful Aggarwal, Amy Turner, Geoffrey Neale, Cliff Guy, Nan Zhu, Hongbo Chi, Renren Wen and Demin Wang ()
Additional contact information
Mei Yu: Blood Research Institute, Blood Center of Wisconsin
Yuhong Chen: Blood Research Institute, Blood Center of Wisconsin
Hu Zeng: St. Jude Children’s Research Hospital
Yongwei Zheng: Blood Research Institute, Blood Center of Wisconsin
Guoping Fu: Blood Research Institute, Blood Center of Wisconsin
Wen Zhu: Blood Research Institute, Blood Center of Wisconsin
Ulrich Broeckel: Medical College of Wisconsin
Praful Aggarwal: Medical College of Wisconsin
Amy Turner: Medical College of Wisconsin
Geoffrey Neale: Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children’s Research Hospital
Cliff Guy: St. Jude Children’s Research Hospital
Nan Zhu: Blood Research Institute, Blood Center of Wisconsin
Hongbo Chi: St. Jude Children’s Research Hospital
Renren Wen: Blood Research Institute, Blood Center of Wisconsin
Demin Wang: Blood Research Institute, Blood Center of Wisconsin

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01388-5

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