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

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96 Scopus citations

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 (US)
Pages (from-to)300-307
Number of pages8
JournalNature Immunology
Volume13
Issue number3
DOIs
StatePublished - Mar 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology

Cite this

Ochiai, K., Maienschein-Cline, M., Mandal, M., Triggs, J. R., Bertolino, E., Sciammas, R., Dinner, A. R., Clark, M. R., & Singh, H. (2012). A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation. Nature Immunology, 13(3), 300-307. https://doi.org/10.1038/ni.2210