Sites of B Lymphocyte Selection, Activation, and Tolerance in Spleen

T he immune system appears to be rigid, restricting one lymphocyte to make one antibody (1) and the peripheral B cell pool to a constant number (10 8 in mice) (2– 4). To make a rapid immune response to an unlimited number of antigens at any anatomical site, it has developed at least three major strategies: (a) continuous production of 2 ϫ 10 7 lymphocytes/d from bone marrow (mice; 5), displaying a part of the 10 11 potential immunoglobulin repertoire (6); (b) the establishment of a long-lived B cell pool (10 8), under the influence of environmental antigens (7) or an idiotypic network (8, 9); and (c) the ability of long-lived B cells to migrate between different lymphoid tissues (10, 11), thus monitoring sites of antigen invasion. Since the 10 8 peripheral B cells have an average life span of months, Ͻ 10% of the 2 ϫ 10 7 B cells produced every day are expected to be recruited into the long-lived peripheral B cell pool (2–4). The question is: where and how does this selection take place? Splenic Outer Periarteriolar Lymphoid Sheath, the Site of Heavy Chain of the Valuable Region of Ig Gene (IgVH) Re-gion–targeted Selection of Newly Produced B Cells into the Long-lived Peripheral B Cell Pool. Most newly produced B cells from bone marrow first migrate into the spleen through the terminal branches of central arterioles, arriving in the marginal zone blood sinusoids (Fig. 1 A). Both newly produced B cells and long-lived recirculating B cells can penetrate the marginal zone sinus, reaching the outer zone of the pe-riarteriolar lymphocytic sheath (outer periarteriolar lym-phoid sheath [PALS]). Although the long-lived recirculat-ing B cells migrate further into the follicle, the majority of newly produced B cells appear to die within the outer PALS (2, 12). Thus, outer PALS may represent the site where a small proportion of the newly produced B cells are recruited into the long-lived pool. The selection signal has the following features: (a) it selects B cells according to heavy chain of the valuable region of Ig gene (IgVH) expression (7); (b) it may respond to environmental antigen at a low dose (7) or an idiotypic element such as serum Ig (8); (c) it appears to positively select cells (7); and (d) it does not induce somatic hypermutation and isotype switch (7, 13). Three aspects of this ligand selection process are unclear: (a) Does the …