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

Nature volume 391, pages 904–907 (1998)Cite this article

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.

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Figure 1: Normal (D)J h recombination in IL-7Rα−/− mice.
Figure 2: Impaired targeting of recombination to 5′ V h segments.
Figure 3: Specific defect in recombination substrates rather than the recombinase machinery.
Figure 4: Expression and activity of Pax-5 are diminished in the absence of IL-7Rα.

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Acknowledgements

We thank J. Peschon and J. Sims (Immunex) for the IL-7R−/− mouse strain; S. Davies and Neuberger for µMT bone marrow; C. Rada and C. Napper for DNA sequencing; and D. Fearon, M.Neuberger and K. J. Patel for critically reviewing this manuscript. A.E.C. is a Fellow of the Kay Kendall Leukaemia Research Fund. Work in A.R.V.'s laboratory is funded by the MRC.

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  1. Medical Research Council Laboratory of Molecular Biology, CB2 2QH, Cambridge, UK

    Anne E. Corcoran, Andrew Riddell, Danielle Krooshoop & Ashok R. Venkitaraman

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  1. Anne E. Corcoran
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Correspondence to Ashok R. Venkitaraman.

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Corcoran, A., Riddell, A., Krooshoop, D. et al. Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor. Nature 391, 904–907 (1998). https://doi.org/10.1038/36122

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