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

Kyoko Ochiai, Mark Maienschein-Cline, Malay Mandal, Joseph R. Triggs, Eric Bertolino, Roger Sciammas, Aaron R. Dinner, Marcus R. Clark, Harinder Singh

Research output: Contribution to journalArticlepeer-review

107 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)300-307
Number of pages8
JournalNature Immunology
Volume13
Issue number3
DOIs
Publication statusPublished - 2012 Mar
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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