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

• Published in: Nature communications 2017-11, Vol.8 (1), p.1457-18, Article 1457
• Main Authors: Yu, Mei, Chen, Yuhong, Zeng, Hu, Zheng, Yongwei, Fu, Guoping, Zhu, Wen, Broeckel, Ulrich, Aggarwal, Praful, Turner, Amy, Neale, Geoffrey, Guy, Cliff, Zhu, Nan, Chi, Hongbo, Wen, Renren, Wang, Demin
• Format: Article
• Language: English
• Subjects: 631/136/232/2058; 631/250/1619/40/1907; AKT protein; Animals; Cell activation; Cell cycle; Cell lineage; Female; Gene expression; Humanities and Social Sciences; Inhibition; Interleukin 7; Interleukin-7 - immunology; Kinases; Lymphocyte receptors; Lymphocytes B; Lymphopoiesis; Lymphopoiesis - immunology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Phospholipase C gamma - deficiency; Phospholipase C gamma - genetics; Phospholipase C gamma - immunology; Precursor Cells, B-Lymphoid - cytology; Precursor Cells, B-Lymphoid - immunology; Protein kinase C; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - immunology; Signaling; Stat5 protein; STAT5 Transcription Factor - metabolism; TOR protein; TOR Serine-Threonine Kinases - metabolism
• ISSN: 2041-1723; 2041-1723
• 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. IL-7R activation drives early B cell development, but the signalling is unclear. Here the authors show PLCγ is involved in IL-7R-induced mTOR activation via a DAG/PKC-dependent pathway, and that double deficiency of the two PLCγ isoforms arrests B cell development at the pre-pro-B stage in mice.