Control of B Cell Responsiveness by Isotype and Structural Elements of the Antigen Receptor

Expression of a functional B cell antigen receptor (BCR) plays a central role in regulating B cell development, maturation, and effector functions. Although IgM is solely expressed in immature B cell stages, the presence of both IgM- and IgD-BCR isotypes on mature naïve B cells raises the question of whether IgD has a unique role in B cell activation and function. While earlier studies suggested a broad functional redundancy between IgM and IgD, recent data point to an important immune regulatory role of IgD. Herein, we review these findings and discuss how the structural flexibility, mode of antigen binding, and co-receptor interactions, enable the IgD-BCR to act as a ‘rheostat’, regulating the activation and function of mature naïve B cells.

TrendsWhile immunoglobulin (Ig)M and IgD may largely substitute for each other, IgD-deficient B cells are defective in affinity maturation, whereas the development of innate-like B cells is impaired in IgM-deficient mice.The response of IgM and IgD receptors bearing the same antigen (Ag) specificity to different forms of Ag is distinct. Treatment with multivalent Ags results in comparable activation of both receptors; however, these B cell Ag receptors (BCRs) respond to treatment with low-valence Ags only when expressed as IgM, rather than as IgD-BCR.Similar to normal mature B cells, anergic B cells from mice transgenic for autoreactive BCR and cognate soluble autoantigen are defined by low IgM and high IgD expression. Anergic B cells efficiently respond to treatment with polyvalent Ag, suggesting that, contrary to the initial postulation, these cells are functionally responsive.The hinge region in the heavy chain (HC) of IgD is the essential element underlying the difference between IgM and IgD activation.