V(D)J recombinase induction in splenic B lymphocytes is inhibited by antigen-receptor signalling.
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 editing. 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 proteins or by stimulation in vitro with interleukin-4 and lipopolysaccharides. 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.
National Jewish Medical and Research Center, Division of Basic Sciences, Department of Pediatrics, Denver, Colorado 80206, USA.
M
M
Hertz
V
V
Kouskoff
T
T
Nakamura
D
D
Nemazee
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D002455:Cell Division; D002478:Cells, Cultured; D004254:DNA Nucleotidyltransferases / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D007108:Immune Tolerance; D007146:Immunoglobulin lambda-Chains / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D045567:VDJ Recombinases
D007146:Immunoglobulin lambda-Chains; D008070:Lipopolysaccharides; D011947:Receptors, Antigen, B-Cell; D015847:Interleukin-4; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases