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

Nat Commun. 2017 Nov 13;8(1):1457. doi: 10.1038/s41467-017-01388-5.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Female
  • Interleukin-7 / immunology*
  • Lymphopoiesis / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phospholipase C gamma / deficiency*
  • Phospholipase C gamma / genetics
  • Phospholipase C gamma / immunology*
  • Precursor Cells, B-Lymphoid / cytology*
  • Precursor Cells, B-Lymphoid / immunology
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / immunology
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Interleukin-7
  • STAT5 Transcription Factor
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Phospholipase C gamma