Positive selection and lineage commitment during peripheral B-lymphocyte development

Although it is appreciated that the antigen receptor on B cells is required for peripheral B-lymphocyte development and survival, it has been unclear whether this receptor interacts with self-antigens during development or if it signals constitutively in an antigen-independent fashion. The analysis of mutant mice in which antigen receptor signaling in B cells is either attenuated or enhanced has revealed the existence of a follicular versus marginal zone B-lymphocyte cell-fate decision. These analyses indicate that weak antigen receptor-derived signals favor marginal zone B-cell generation, and relatively strong signals favor the development of mature follicular B cells. Even stronger signals derived from the antigen receptor favor the generation of B1 B cells. This signal strength model for B-cell development supports the notion that self-antigens of varying affinity may mediate positive selection and lineage commitment. Direct evidence supporting such a view has been obtained from the analysis of antigen receptor knockin mice. Specific antigen receptors guide B cells to develop into specific lineages. Although Notch-2, nuclear factor-kappaBp50, and other genes are essential for marginal zone B-cell development, instructive signals delivered by the antigen receptor represent the primary force driving positive selection and lineage commitment in B lymphocytes.