IMMUNOBIOLOGY Differential expression of CD21 identifies developmentally and functionally

The transitional stage of B-cell develop-ment 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 transi-tional B cells have focused on a single subset defined as CD24hiCD38hi B cells. Here, we have identified 2 subsets of human transitional B cells based on the differential expression of CD21. CD21hi transitional cells displayed higher expres-sion of CD23, CD44, and IgD, and exhib-ited greater proliferation and Ig secretion in vitro than CD21lo transitional B cells. In contrast, the CD21lo subset expressed elevated levels of LEF1, a transcription factor highly expressed by immature lym-phocytes, and produced higher amounts of autoreactive Ab. These phenotypic, functional, and molecular features sug-gest that CD21lo transitional B cells are less mature than the CD21hi subset. This was confirmed by analyzing X-linked agammaglobulinemia patients and the ki-netics of B-cell reconstitution after stem cell transplantation, which revealed that the development of CD21lo transitional B cells preceded that of CD21hi transi-tional cells. These findings provide impor-tant insights into the process of human B-cell development and have implica-tions for understanding the processes underlying perturbed B-cell maturation in autoimmune and immunodeficient condi-tions. (Blood. 2010;115:519-529