| Marginal zone (MZ) B cells are key mediators of the immune response against blood-borne pathogens. The cellular pathways and selective pressures involved in MZ B cell development, however, are poorly characterized. Selection of newly formed B cells into the follicular or marginal zone compartments is thought to occur via proliferative intermediates expressing high levels of CD21/35 and CD23. However, I show that CD21/35high CD23 + splenocytes are not enriched for proliferative cells and do not significantly contribute to the generation of follicular B cells. Instead, these cells serve primarily as precursors for MZ B cells. This precursor-product relationship is supported by ontogenic relationships, steady-state kinetic labeling studies, and adoptive transfer experiments. Also, CD21/35 high CD23+ splenocytes share several key characteristics with MZ B cells, including their capacity to trap T-independent antigen and their heightened proliferative response to LPS.; Furthermore, B-cell deficiency promotes development of MZ B cells from multiple splenic subsets, including follicular B cells. I show that highly purified follicular B cells transferred into lymphopenic hosts differentiate via a stepwise process into marginal zone (MZ) B cells as judged by surface phenotype, anatomical localization, and functional criteria. The extent of lymphopenia in the B cell compartment of the host dictates the degree of this homeostatic response. Notch signaling, which is dispensable for the development and function of follicular B cells, is required for homeostatic proliferation and generation of MZ B cells from follicular B cells and is mitogenic for mature B cells ex vivo. Overall, my observations challenge previous models of peripheral intermediates Furthermore MZ B cells can be generated from follicular B cells in B cell maturation and suggest that MZ B cells develop via CD21/35high CD23 + lymphopenic environments by a Notch-dependent mechanism. |
