Abstract
IgG-containing B cell antigen receptor (IgG-BCR), the BCR mostly expressed on memory B cells, contains a distinct signaling function from IgM-BCR or IgD-BCR expressed on naïve B cells. Because naïve B cells transgenic for IgG exhibit augmented response to antigens similar to memory B cells, the distinct signaling function of IgG-BCR appears to play a role in augmented antibody responses of memory B cells. However, how IgG-BCR signaling augments B cell responses is not yet well understood. Here we demonstrate that B cells from IgG-transgenic mice are anergic with defect in generation of BCR signaling upon BCR ligation. However, these IgG-transgenic B cells generate markedly augmented antibody response to a T cell-dependent antigen, probably due to hyper-responsiveness to a T cell-derived signal through CD40. Both BCR signaling defect and augmented response to CD40 ligation are partially restored in xid IgG-transgenic mice in which BCR signaling is down-modulated due to a loss-of-function mutation in the tyrosine kinase Btk crucial for BCR signaling. Thus, IgG-BCR induces augmented B cell responses in the absence of antigen-induced BCR signaling probably through high ligand-independent BCR signaling that may “idle” B cells to make them ready to respond to T cell help. This finding strongly suggests a crucial role of ligand-independent signaling in receptor function.
Highlights
The B cell antigen receptor (BCR), composed of the membrane form of immunoglobulin and Iga/Igb, plays a crucial role in both development and homeostasis of B cells as well as their responses to antigen stimulation [1]
We demonstrate that IgG-tg B cells expressing nitrophenyl acetyl (NP)-reactive IgG exhibit reduced BCR expression on the cell surface and BCR signaling defect, both of which are characteristically shown in anergic self-reactive B cells [9,11,36,37]
Other phenotypes found in IgG-tg B cells such as increased number of marginal zone (MZ) B cells [16,17,38], reduced CD23 expression [10] and increased CD44 expression [8,10] are found in anergic self-reactive B cells
Summary
The B cell antigen receptor (BCR), composed of the membrane form of immunoglobulin and Iga/Igb, plays a crucial role in both development and homeostasis of B cells as well as their responses to antigen stimulation [1]. Signal strength of the tonic BCR signaling appears to regulate whether immature B cells differentiate to either one of the two major subsets of conventional B cells, i.e., follicular B cells and marginal zone B cells [1,4]. Continuous BCR signaling generated by interaction with selfantigens during B cell development causes B cell anergy, in which B cells are no longer activated for proliferation and differentiation to plasma cells after antigen stimulation [8]. Ex vivo analysis of anergic B cells has demonstrated that baseline activation of BCR signaling molecules is augmented whereas BCR ligation generates only a weak signaling [8,14], suggesting that ligation-induced BCR signaling is perturbed probably due to continuous BCR signaling in vivo
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