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

doi:10.1038/ni.2210

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

Academic Institute

Research output: Contribution to journal › Article › peer-review

138 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 language	English (US)
Pages (from-to)	300-307
Number of pages	8
Journal	Nature immunology
Volume	13
Issue number	3
DOIs	https://doi.org/10.1038/ni.2210
State	Published - Mar 2012

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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

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.",

author = "Kyoko Ochiai and Mark Maienschein-Cline and Malay Mandal and Triggs, {Joseph R.} and Eric Bertolino and Roger Sciammas and Dinner, {Aaron R.} and Clark, {Marcus R.} and Harinder Singh",

note = "Funding Information: We thank S. Heinz for advice on the preparation of DNA libraries for ChIP-seq; M. Veselitis (University of Chicago) for mouse Blnk cDNA; S.E. Powers for discussions; the Bendelac laboratory for assistance with flow cytometry; R. Duggan, D. Leclerc, M. Olson and J. Cao for assistance with cell sorting; and K. Michelini and J. Zekos for operating the Illumina Genome Analyzer II at the University of Chicago (supported by the Howard Hughes Medical Institute). Supported by Howard Hughes Medical Institute (H.S.), the US National Institutes of Health (GM088847 to M.R.C. and GM081892 to A.R.D.) and the US Department of Energy (DOE) Computational Science Graduate Fellowship Program (M.M.-C.).",

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doi = "10.1038/ni.2210",

language = "English (US)",

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journal = "Nature immunology",

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T1 - A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation

AU - Ochiai, Kyoko

AU - Maienschein-Cline, Mark

AU - Mandal, Malay

AU - Triggs, Joseph R.

AU - Bertolino, Eric

AU - Sciammas, Roger

AU - Dinner, Aaron R.

AU - Clark, Marcus R.

AU - Singh, Harinder

N1 - Funding Information: We thank S. Heinz for advice on the preparation of DNA libraries for ChIP-seq; M. Veselitis (University of Chicago) for mouse Blnk cDNA; S.E. Powers for discussions; the Bendelac laboratory for assistance with flow cytometry; R. Duggan, D. Leclerc, M. Olson and J. Cao for assistance with cell sorting; and K. Michelini and J. Zekos for operating the Illumina Genome Analyzer II at the University of Chicago (supported by the Howard Hughes Medical Institute). Supported by Howard Hughes Medical Institute (H.S.), the US National Institutes of Health (GM088847 to M.R.C. and GM081892 to A.R.D.) and the US Department of Energy (DOE) Computational Science Graduate Fellowship Program (M.M.-C.).

PY - 2012/3

Y1 - 2012/3

N2 - 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.

AB - 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.

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ER -

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

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