MOLECULAR CONTROL OF B-LYMPHOCYTE GROWTH AND DIFFERENTIATION

During antigen driven immune responses, antigen-specific naive B lymphocytes undergo a cascade of events including activation, expansion, mutations, isotype switch, selections and differentiation into either antibody secreting plasma cells or memory B cells. These antigen-dependent events, which we propose to call immunopoiesis, occur in different areas of secondary lymphoid organs, as well as other nonlymphoid organs. B cells interact with antigens and numerous cell types (T cells, dendritic cells, follicular dendritic cells and macrophages) through numerous cell surface molecules and cytokines. B cells costimulated through their antigen receptor and cytokines such as interleukin 2 (IL-2), IL-4 and IL-10 undergo limited proliferation and differentiation into immunoglobulin (Ig) secreting cells. In contrast, crosslinking of the B cell CD40 antigen, a member of the tumor necrosis factor (TNF) receptor family, results in major cellular activation further modulated by cytokines. In particular, IL-4 and IL-13 permit establishment of long-term factor-dependent B cell lines, as well as isotype switch towards the production of IgE and IgG4. Addition of IL-10 to CD40-activated B cells results in limited proliferation and remarkable differentiation into plasma cells. IL-10 also participates in isotype switch towards IgG1, IgG3 and IgA. The ligand for CD40, a member of the TNF family, is transiently expressed on activated T cells, and interrupted CD40/CD40-L interactions result in profoundly altered humoral immune responses.