Regulation of B-cell fate by antigen-receptor signals

B cells are instructed continuously by B-cell receptor (BCR) signals to make crucial cell-fate decisions at several checkpoints during their development. Protein tyrosine kinases, such as LYN, SYK and BTK, and effector enzymes, such as phosphatidylinositol 3-kinase (PI3K) and phospholipase Cγ2, have crucial roles in the BCR-induced activation of transcription factors, including nuclear factor-κB (NF-κB) and nuclear factor of activated T cells, that are important for B-cell fate decisions. Moreover, BCR signalling is integrated by adaptors in B cells and fine-tuned by co-receptors on B cells. The BCR induces the signals that are required for survival and proliferation of B cells. These include activation of PI3K-regulated AKT, RAS–RAF–ERK (extracellular signal-regulated kinase) and NF-κB pathways. Immature B cells are eliminated by negative selection (BCR-induced cell death) or inactivated (anergy), or they revise the specificity of their BCRs (receptor editing). Transitional B cells can be divided into two subsets — transitional type 1 (T1) and T2. The T1 to T2 transition is a crucial event in the spleen; BCR signals facilitate T2-cell generation, and signals through the BCR and B-cell activating factor of the tumour-necrosis-factor family (BAFF) maintain the survival of T2 cells by, for example, enhancing NF-κB activation. Different strengths of BCR signalling are required for the development of the three mature B-cell subsets; peritoneal B cells require the strongest BCR signal, follicular B cells require an intermediate BCR signal, and marginal-zone B cells require a weaker BCR signal. B-cell fate is determined by the balance between survival and death signals initiated through the BCR.