The repertoire of mature B cells is positively and negatively selected from the pool of immature B cells. As we will see later, positive selection is well defined in T lymphocytes and is responsible for matching the TCRs on newly generated CD8+ and CD4+ T cells with their ability to recognize self MHC class I and class II molecules, respectively. There is no comparable restriction for B-cell antigen recognition. Nevertheless, positive selection appears to be a general phenomenon primarily geared to preserving lymphocytes that have completed their antigen receptor gene rearrangement program successfully. Only B cells that express functional membrane Ig molecules receive constitutive (tonic) BCR-derived signals, which, as described earlier, are required to keep immature B cells alive.
Immature B cells that recognize self antigens with high avidity in the bone marrow are often induced to change their specificities by a process called receptor editing. Self antigen recognition by immature B cells induces reactivation of RAG genes and the rearrangement and production of a new Ig light chain, allowing the cell to express a different (edited) B-cell receptor that is not self-reactive. The original VκJκ exon encoding the variable domain of an autoreactive light-chain gene is typically deleted and replaced by a new rearrangement involving an upstream Vκ and a downstream Jκ gene segment. If the editing process fails to generate an in-frame productive κ light-chain rearrangement on either chromosome, the activated immature B cell may then go on to rearrange the λ light chain first on one chromosome, and if that is nonproductive, then the λ light chain on the other chromosome. Most B cells expressing λ light chains are likely derived from immature B cells that were self-reactive and have undergone receptor editing.
If receptor editing fails, the immature B cells that express high-affinity receptors for self antigens and encounter these antigens in the bone marrow or the spleen may die by apoptosis. This process is called negative selection. Most negative selection occurs in transitional B cells in the spleen. The anti gens mediating negative selection deliver strong signals to IgM expressing immature B lymphocytes whose receptors happen to be specific for these self antigens. Both receptor editing and deletion are responsible for maintaining B-cell tolerance to self antigens that are present in the bone marrow.
Once the transition is made to the IgM+ IgD+ mature B-cell stage, antigen recognition leads to proliferation and differentiation, not to receptor editing or apoptosis. As a result, mature B cells that recognize antigens with high affinity in peripheral lymphoid tissues are activated, and this process leads to humoral immune responses. Follicular B cells make most of the helper T cell–dependent antibody responses to protein antigens.
