Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor.
To generate the full diversity of antibody heavy-chain genes, hundreds of dispersed germline V segments must undergo recombination following D-J segment joining. Here we report that this process is regulated by the alpha-chain of the receptor for interleukin-7, a cytokine that stimulates B-cell lymphopoiesis. D-J joining occurs normally in immature B lymphocytes from mice lacking the alpha-chain of the interleukin-7 receptor (IL-7Ralpha). But recombination of V segments is progressively impaired as their distance increases upstream of D/J, causing infrequent rearrangement of most V segments, which markedly reduces diversity. This is not simply due to defective cell proliferation or impaired recombinase expression. Rather, germline transcripts from distal, unrearranged V segments, a marker of chromatin changes that precede recombination, are specifically silenced. So too is expression of Pax-5, which binds to heavy-chain locus control elements and normally stimulates recombination, suggesting a mechanism for these effects. Thus ligands of the interleukin-7 receptor deliver an extrinsic signal that targets V segment recombination in the heavy-chain locus by altering the accessibility of DNA substrates to the recombinase. This mechanism augments the recombinational diversity of the primary antibody repertoire.
Corcoran
A E
AE
Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
Riddell
A
A
Krooshoop
D
D
Venkitaraman
A R
AR
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology; D001854:Bone Marrow Cells / Q000378:metabolism; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000502:physiology*; D015851:Interleukin-7 / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000096:biosynthesis; D051757:PAX5 Transcription Factor; D016133:Polymerase Chain Reaction; D018123:Receptors, Interleukin / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D020395:Receptors, Interleukin-7; D011995:Recombination, Genetic; D014157:Transcription Factors; D045567:VDJ Recombinases
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D015851:Interleukin-7; D009687:Nuclear Proteins; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D018123:Receptors, Interleukin; D020395:Receptors, Interleukin-7; D014157:Transcription Factors; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases