V(D)J RECOMBINASE INDUCTION IN SPLENIC B-LYMPHOCYTES IS INHIBITED BY ANTIGEN-RECEPTOR SIGNALING

In lymphocytes, DNA recombinations that generate the antigen-receptor genes can sometimes be reinduced in receptor-bearing cells in a proces s called receptor editing, which modifies the specificity of the recep tor for antigen. In immature B lymphocytes, B-cell antigen receptor (B CR) signalling stimulates immune tolerance by receptor editing(1-5). M ore mature splenic B cells can also be induced to undergo V(D)J recomb ination, which generates diversity in the immune system, either by imm unization with foreign proteins(6-9) or by stimulation in vitro with i nterleukin-4 and lipopolysaccharides(8-10). Here we show that immune t olerance is unlikely to induce V(D)J recombination in mature B cells, because BCR ligation actively inhibits V(D)J recombination induced by interleukin-ii and lipopolysaccharide. Furthermore, immunization of im munoglobulin transgenic mice with ligands of varying avidities for the BCR showed that low-avidity antigen could induce strong V(D)J recombi nation, whereas non-binding or high-avidity ligands could not. These d ata suggest that V(D)J recombination induced during the immune respons e modifies the antigen receptors of B cells with weak, but not strong, reactivity to antigen, potentially rescuing cells with improved recep tor affinity and promoting their contribution to the immune response. Thus BCR signalling regulates V(D)J recombination in both tolerance an d immunity, but in strikingly different ways.