Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor

Anne E. Corcoran, Andrew Riddell, Danielle Krooshoop and Ashok R. Venkitaraman ()
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Anne E. Corcoran: Medical Research Council Laboratory of Molecular Biology
Andrew Riddell: Medical Research Council Laboratory of Molecular Biology
Danielle Krooshoop: Medical Research Council Laboratory of Molecular Biology
Ashok R. Venkitaraman: Medical Research Council Laboratory of Molecular Biology

Nature, 1998, vol. 391, issue 6670, 904-907

Abstract: Abstract 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 α-chain of the receptor for interleukin-7, a cytokine that stimulates B-cell lymphopoiesis1. D–J joining occurs normally in immature B lymphocytes from mice lacking the α-chain of the interleukin-7 receptor (IL-7Rα). 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.

Date: 1998
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DOI: 10.1038/36122

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