A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation

Nat Immunol. 2012 Jan 22;13(3):300-7. doi: 10.1038/ni.2210.

Abstract

The molecular crosstalk between the interleukin 7 receptor (IL-7R) and the precursor to the B cell antigen receptor (pre-BCR) in B lymphopoiesis has not been elucidated. Here we demonstrate that in pre-B cells, the IL-7R but not the pre-BCR was coupled to phosphatidylinositol-3-OH kinase (PI(3)K) and the kinase Akt; signaling by this pathway inhibited expression of recombination-activating gene 1 (Rag1) and Rag2. Attenuation of IL-7 signaling resulted in upregulation of the transcription factors Foxo1 and Pax5, which coactivated many pre-B cell genes, including Rag1, Rag2 and Blnk. Induction of Blnk (which encodes the signaling adaptor BLNK) enabled pre-BCR signaling via the signaling molecule Syk and promoted immunoglobulin light-chain rearrangement. BLNK expression also antagonized Akt activation, thereby augmenting the accumulation of Foxo1 and Pax5. This self-reinforcing molecular circuit seemed to sense limiting concentrations of IL-7 and functioned to constrain the proliferation of pre-B cells and trigger their differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • Cell Differentiation*
  • Cells, Cultured
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / immunology
  • Interleukin-7 / immunology*
  • Mice
  • PAX5 Transcription Factor / immunology
  • Receptors, Antigen, B-Cell / immunology*
  • Receptors, Antigen, B-Cell / metabolism
  • Signal Transduction*

Substances

  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxo1 protein, mouse
  • Interleukin-7
  • PAX5 Transcription Factor
  • Pax5 protein, mouse
  • Receptors, Antigen, B-Cell