Immature B cells in the spleen proceed through two distinct transitional stages, called T1 and T2, defined by the absence or presence of the B-cell co-receptor component CD21 (complement receptor 2) (see Section 2-13 and Section 7-20). In mice lacking BAFF, immature B cells progress to the T1 stage in the spleen but fail to express CD21, and the mice lack mature B cells. Signaling through the B-cell receptor is also required for immature B cells in the spleen to progress through the T1 and T2 stages and enter the long-lived peripheral B-cell pool. In this case, the B-cell receptor signals do not arise from high-affinity interactions between the sIgM of the B-cell receptor with an antigen, which would induce strong signals; instead, these B-cell receptor signals are thought to be weak, constitutive signals that are developmentally programmed into the maturing B cells, although the mechanism responsible for this constitutive signaling is not known. These weak B-cell receptor signals together with the BAFF-R signals are essential to promote the final stages of B-cell maturation in the periphery. Disregulation of the appropriate balance between B-cell receptor and BAFF-R signaling occurs in individuals who overexpress BAFF, and has been linked to the development of autoimmune diseases, such as Sjögren’s syndrome, that result from a failure to purge auto-reactive B cells.
The majority of peripheral B cells that reside in the spleen and other secondary lymphoid organs are known as follicular B cells, often referred to as B-2 B cells. A second, minor population of B cells found in the spleen consists of marginal zone B cells, named for their predominance at the marginal zones that lie at the white pulp/red pulp junctions (see Fig. 8.12). Follicular and marginal zone B cells both derive from a common lineage that develops in the bone marrow and bifurcates during the final stage of B-cell maturation in the splenic follicles. Experiments reconstituting the signals promoting peripheral B-cell maturation in cell culture, starting from immature B-cell precursors, indicate that follicular versus marginal zone B-cell lineages diverge at the transitional T2 stage, as cells transition to the fully mature stage. Like follicular B cells, marginal zone B cells are dependent on BAFF signals, and are missing in mice lacking BAFF expression. Marginal zone B cells can be identified by their expression of very high levels of the complement receptor CD21. Studies using rearranged immunoglobulin gene knock-in mice that express a single B-cell receptor specificity on all developing B cells have demonstrated that some B-cell receptors predominantly generate follicular B cells whereas others generate marginal zone B cells. These findings indicate that the specificity of the B-cell receptor is a major factor in determining the final commitment of transitional B cells to the follicular versus the marginal zone lineage; however, the details of this process are still not fully understood. Due to their location, marginal zone B cells are poised to make rapid responses to antigens or pathogens filtered from the blood. Therefore, it is thought that marginal zone B cells represent an early line of defense for blood-borne pathogens.
Peripheral B cells also include memory B cells, which are generated in addition to antibody-producing plasma cells from mature B cells after their first encounter with antigen; we will return to B-cell memory in Chapter 11. Competition for follicular entry favors mature B cells that are already established in the relatively long-lived and stable peripheral B-cell pool. Mature B cells have undergone phenotypic changes that might make their access to the follicles easier; for example, they express CXCR5, the receptor for CXCL13, which is expressed by FDCs (see Section 10-3). They also have increased expression of CD21 compared with immature newly developed B cells, which enhances the signaling capacity of the B cell.