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Collectively, these findings suggest that MZ B cells have unique signaling and subsequent differentiative capabilities that permit them to react much more vigorously than the majority of splenic B cells (FO) in the earliest stages of an in vivo immune response. This is particularly evident with limiting T cell help, low concentration of thymus-independent mitogens or low amounts of particulate blood-borne antigen in the spleen (Fig. 4). They are uniquely situated adjacent to the marginal sinuses and a rich array of antigen trapping macrophages. Because of this location the MZ B cells are ideally positioned for immediate exposure to blood-borne antigens. In contrast, the FO B cells are in juxtaposition to the PALS which may expedite the interactions of FO B cells with T cells and antigen presenting cells. Collectively these properties point to a role for FO B cells in antibody responses to T dependent antigens generated in germinal centers. These responses occur temporally later in immune responses and may be involved principally in the response to protein antigens. [figure: see text].