Tuning B cell responsiveness by antigen receptor isotype

The expression of functional B cell antigen receptors (BCRs) is essential for development, survival and activation of B cells. During early developmental stages, immature B cells exclusively express IgM. Cells that pass the immature B cell stage and leave the bone marrow coexpress BCRs of IgM and IgD isotypes, which differ in the usage of the heavy chain (HC) µ versus δ that are generated by alternative poly-adenylation and splicing. It is currently unclear how the prevalent expression of the µHC over δHC at the early stages of B-cell development is reverted in mature B cells, where IgD becomes the dominant antigen receptor. The reason for this tightly regulated expression and the individual function of IgD versus IgM are poorly understood. Another remarkable difference is that µHC can be found both as membrane-associated BCR and soluble antibody, whereas IgD antibodies are barely detectable in the serum and δHC is predominantly part of membrane-associated IgD BCR. This points to a cell-associated signaling specific function of IgD, which is supported by experiments suggesting that activation IgD as compared with IgM BCR leads to specific kinetics of phosphorylation of intracellular proteins in vitro [1]. The role of IgM and IgD was studied in vivo by selective expression or deletion of either µHC or δHC in transgenic animal models. This showed that, while IgM and IgD may largely substitute for each other, the development of innate-like B cells was impaired in IgM knockout mice whereas IgD knockout B cells show defects in affinity maturation [2-3]. Continuous exposure to soluble neo-self-antigen in transgenic mice expressing hen-egg-lysozyme (HEL) and the cognate BCR (IgHEL) manifests with downregulation of surface IgM while IgD expression is unaffected [4]. Peripheral B cells from these mice are resistant to activation by soluble HEL and exemplify the original description of B-cell anergy. Remarkably, selective downmodulation or removal of IgM is characteristic for normal mature B cells or human B cells expressing autoreactive receptors [5-6]. While these data suggest a role for IgD in regulating the activation of mature B cells, the underlying molecular mechanism remained unclear. Using an in vitro reconstitution system, model BCRs including the IgHEL were investigated as IgM and IgD receptors bearing the same antigen specificity. Surprisingly, the tested BCRs responded to treatment with low-valence antigens, such as soluble HEL, only when expressed as IgM but not when expressed as IgD BCR. Treatment with multivalent antigens however resulted in …