Differential expression of CD21 identifies developmentally and functionally distinct subsets of human transitional B cells

The transitional stage of B-cell development represents an important step where autoreactive cells are deleted, allowing the generation of a mature functional B-cell repertoire. In mice, 3 subsets of transitional B cells have been identified. In contrast, most studies of human transitional B cells have focused on a single subset defined as CD24(hl)CD38(hl) B cells. Here, we have identified 2 subsets of human transitional B cells based on the differential expression of CD21. CD21(hl) transitional cells displayed higher expression of CD23, CD44, and IgD, and exhibited greater proliferation and Ig secretion in vitro than CD21(lo) transitional B cells. In contrast, the CD21(lo) subset expressed elevated levels of LEF1, a transcription factor highly expressed by immature lymphocytes, and produced higher amounts of autoreactive Ab. These phenotypic, functional, and molecular features suggest that CD21(lo) transitional B cells are less mature than the CD21(hl) subset. This was confirmed by analyzing X-linked agammaglobulinemia patients and the kinetics of B-cell reconstitution after stem cell transplantation, which revealed that the development of CD21(lo) transitional B cells preceded that of CD21(hl) transitional cells. These findings provide important insights into the process of human B-cell development and have implications for understanding the processes underlying perturbed B-cell maturation in autoimmune and immunodeficient conditions. (Blood. 2010; 115: 519-529)