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V(D)J recombinase induction in splenic B lymphocytes is inhibited by antigen-receptor signalling

Abstract

In lymphocytes, DNA recombinations that generate the antigen-receptor genes can sometimes be reinduced in receptor-bearing cells in a process called receptor editing, which modifies the specificity of the receptor for antigen. In immature B lymphocytes, B-cell antigen receptor (BCR) signalling stimulates immune tolerance by receptor editing1,2,3,4,5. More mature splenic B cells can also be induced to undergo V(D)J recombination, which generates diversity in the immune system, either by immunization with foreign proteins6,7,8,9 or by stimulation in vitro with interleukin-4 and lipopolysaccharide8,9,10. Here we show that immune tolerance is unlikely to induce V(D)J recombination in mature B cells, because BCR ligation actively inhibits V(D)J recombination induced by interleukin-4 and lipopolysaccharide. Furthermore, immunization of immunoglobulin transgenic mice with ligands of varying avidities for the BCR showed that low-avidity antigen could induce strong V(D)J recombination, whereas non-binding or high-avidity ligands could not. These data suggest that V(D)J recombination induced during the immune response modifies the antigen receptors of B cells with weak, but not strong, reactivity to antigen, potentially rescuing cells with improved receptor affinity and promoting their contribution to the immune response. Thus BCR signalling regulates V(D)J recombination in both tolerance and immunity, but in strikingly different ways.

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Figure 1: IL-4/LPS treatment of isolated 3-83 μδ transgenic splenic B cells induces an increased percentage and number of λ+ B cells; this effect can be inhibited by BCR ligation.
Figure 2: CFSE cell-division analysis of cultured B220+ and λ+ 3-83 μδ transgenic splenic B cells.
Figure 3: BCR ligation blocks secondary L-chain gene rearrangements induced in purified 3-83 μδ transgenic splenic B cells by IL-4/LPS treatment in vitro.
Figure 4: Immunization of 3-83 μδ transgenic mice with phage bearing a low-avidity 3-83 peptide ligand induces secondary immunoglobulin L-chain gene rearrangements in vivo.

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Acknowledgements

We thank L. Wysocki and T. Rolink for reagents and discussion, and members of D.N.'s lab for critical review of the manuscript and discussion. V. Kouskoff was supported by an EMBO fellowship. This work was supported by grants from the NIH and the Arthritis Foundation.

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Correspondence to David Nemazee.

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Hertz, M., Kouskoff, V., Nakamura, T. et al. V(D)J recombinase induction in splenic B lymphocytes is inhibited by antigen-receptor signalling. Nature 394, 292–295 (1998). https://doi.org/10.1038/28419

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