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Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor
A E Corcoran1, A Riddell, D Krooshoop
1Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
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.
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.