Insights into B‐cell ontogeny inferred from human immunology

Abstract Due to ontogenetic changes in B‐cell developmental lineages, the mature B‐cell compartment constitutes by functionally different B‐cell subsets that emerged from prenatal, early postnatal or adult precursors. While negative selection processes operate primarily within the framework of B‐cell tolerance checkpoints during B‐cell development, further differentiation into distinct B‐cell subsets is additionally induced by positive selection. In addition to endogenous antigens, contact with microbial antigens is also involved in this selection process, with intestinal commensals having a significant influence on the development of a large layer within the B‐cell compartment. The decisive threshold that triggers negative selection seems to be relaxed during fetal B‐cell development, thereby allowing recruitment of polyreactive and also autoreactive B‐cell clones into the mature naïve B‐cell compartment. Almost all of the concepts on B‐cell ontogeny are based on observations in laboratory mice that not only differ from humans in their developmental timeline but also in their composition of commensal microorganisms or rather a lack of exposure to these. In this review, we summarize conceptual findings on B‐cell ontogeny and particularly describe key insights into the developing human B‐cell compartment and immunoglobulin repertoire formation.