Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling.
Productive rearrangement of the immunoglobulin heavy-chain locus triggers a major developmental checkpoint that promotes limited clonal expansion of pre-B cells, thereby culminating in cell-cycle arrest and rearrangement of light-chain loci. By using Irf4-/-Irf8-/- pre-B cells, we demonstrated that two pathways converge to synergistically drive light-chain rearrangement, but not simply as a consequence of cell-cycle exit. One pathway was directly dependent on transcription factor IRF-4, whose expression was elevated by pre-B cell receptor signaling. IRF-4 targeted the immunoglobulin 3'Ekappa and Elambda enhancers and positioned a kappa allele away from pericentromeric heterochromatin. The other pathway was triggered by attenuation of IL-7 signaling and activated the iEkappa enhancer via binding of the transcription factor E2A. IRF-4 also regulated expression of chemokine receptor Cxcr4 and promoted migration of pre-B cells in response to the chemokine ligand CXCL12. We propose that IRF-4 coordinates the two pathways regulating light-chain recombination by positioning pre-B cells away from IL-7-expressing stromal cells.
Johnson
Kristen
K
Department of Molecular Genetics and Cell Biology, University of Chicago, 929 East 57(th) Street, GCIS W522, Chicago, IL 60637, USA.
Hashimshony
Tamar
T
Sawai
Catherine M
CM
Pongubala
Jagan M R
JM
Skok
Jane A
JA
Aifantis
Iannis
I
Singh
Harinder
H
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain / Q000276:immunology*; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D050835:Interferon Regulatory Factors / Q000276:immunology* / Q000378:metabolism; D015851:Interleukin-7 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D000099218:Interferon Regulatory Factor-4
D050835:Interferon Regulatory Factors; D015851:Interleukin-7; D000099218:Interferon Regulatory Factor-4