After activation, IgM+ B cells migrate to the secondary lymphoid organs where they undergo antigen-driven maturation. This involves CSR — in which Cμ, the constant region of the immunoglobulin heavy chain, is exchanged for an alternative immunoglobulin heavy-chain constant region such that B cells produce antibodies of the same specificity but with distinct effector functions — and SHM, in which point mutations introduced into the variable region of immunoglobulin heavy and light chains enable the selection of B cells that generate antibodies of higher affinity for antigen.
Immunohistochemical analysis of transcription-factor expression revealed that BACH2 is expressed by IgM+ cells within the lymphoid follicles of the spleen — the site of CSR and SHM. By contrast, no BACH2 was detected in IgM+ marginal-zone B cells. To determine whether this pattern of expression reflected a role for BACH2 in the antibody response, Muto et al. generated BACH2-deficient mice. Normal numbers of B220+IgM+IgD− naive B cells were observed in the spleens of Bach2−/− animals; however, these mice had markedly fewer B220hiIgMlowIgD+ mature B cells. Consistent with this, when compared with control animals, BACH2-deficient mice had higher levels of IgM and lower levels of other immunoglobulin isotypes (such as IgG1 and IgG2a) in the serum. Furthermore, BACH2-deficient mice failed to mount antigen-specific IgG3 and IgG1 antibody responses after immunization with a T-cell-independent antigen or a T-cell-dependent antigen, respectively. By contrast, antigen-specific IgM production and differentiation of IgM plasma cells was normal, implicating BACH2 as a regulator of CSR. A role for BACH2 in SHM was also indicated by the observation that the frequency of mutations in the immunoglobulin regions that are crucial for antigen binding was decreased in Bach2−/− mice immunized with a T-cell-dependent antigen.
This is a preview of subscription content, access via your institution
