The B cell antigen receptor complex is a hetero-oligomeric structure composed of antigen binding, membrane immunoglobulin, and transducer-transporter substructures. The transducer-transporter substructure is composed of disulfide-linked dimers of immunoglobulin (Ig)-alpha and Ig-beta/gamma subunits that are products of the mb-1(alpha) and B29 (beta/gamma) genes. Although the receptor complex associates with Src family kinases that are activated after receptor ligation, the site of interaction of these and other cytoplasmic effector molecules with receptor subunits is unknown. The cytoplasmic tails of Ig-alpha and Ig-beta chains were found to associate with distinct sets of effector molecules. The Ig-alpha chain cytoplasmic domain bound to the Src family kinases Lyn and Fyn, phosphatidylinositol-3 kinase (PI-3 kinase), and an unidentified 38-kilodalton phosphoprotein; the cytoplasmic tail of Ig-beta bound PI-3 kinase and unidentified 40- and 42-kilodalton phosphoproteins. Binding activity was found to occur within a 26-amino acid sequence of Ig-alpha and Ig-beta that contains a motif [(Asp or Glu)-(any amino acid)7-(Asp or Glu)-Tyr-(any amino acid)3-Leu-(any amino acid)7-Tyr-(any amino acid)2-(Leu or Ile)] previously implicated in signal transduction via other receptors including the Fc epsilon receptor I and the T cell antigen receptor. These findings indicate that the subunits act independently to activate distinct second messenger pathways.
The ability of BCR cross-linking to stimulate receptor editing was analyzed in vitro using bone marrow B cells from immunoglobulin (Ig) transgenic (Tg) and non-Tg mice. In cultured Ig-Tg cells, BCR ligation induced receptor editing as measured by up-regulation of RAG gene expression, light chain gene DNA rearrangements, and expression of lambda-light chain protein in cells that previously expressed kappa. In the culture conditions used, BCR ligation induced light chain rearrangements in most immature IgM+IgD- bone marrow B cells in the absence of significant cell death or cell growth. Receptor editing in non-Tg B cells was also documented in cultures treated with anti-immunoglobulin. These results provide direct evidence for the ability of BCR ligation to stimulate immunoglobulin light chain gene rearrangements in immature B cells.
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.
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