Repertoire-based selection into the marginal zone compartment during B cell development

Marginal zone (MZ) B cells resemble fetally derived B1 B cells in their innate-like rapid responses to bacterial pathogens, but the basis for this is unknown. We report that the MZ is enriched in “fetal-type” B cell receptors lacking N regions (N(−)). Mixed bone marrow (BM) chimeras, made with adult terminal deoxynucleotidyl transferase (TdT)(+/+) and TdT(−/−) donor cells, demonstrate preferential repertoire-based selection of N(−) B cells into the MZ. Reconstitution of irradiated mice with adult TdT(+/+) BM reveals that the MZ can replenish N(−) B cells in adult life via repertoire-based selection and suggest the possibility of a TdT-deficient precursor population in the adult BM. The mixed chimera data also suggest repertoire-based bifurcations into distinct BM and splenic maturation pathways, with mature “recirculating” BM B cells showing a very strong preference for N(+) complementarity-determining region (CDR) 3 compared with follicular B cells. Because the T1 and MZ compartments are both the most enriched for N(−) H-CDR3, we propose a novel direct T1→MZ pathway and identify a potential T1–MZ precursor intermediate. We demonstrate progressive but discontinuous repertoire-based selection throughout B cell development supporting multiple branchpoints and pathways in B cell development. Multiple differentiation routes leading to MZ development may contribute to the reported functional heterogeneity of the MZ compartment.