The skewed heavy-chain repertoire in peritoneal B-1 cells is predetermined by the selection via pre-B cell receptor during B cell ontogeny in the fetal liver

As many as 5-15% of B-1 cells in the peritoneal cavity of adult mice produce antibodies reactive to phosphatidylcholine (PtC) and the vast majority of them express B cell receptors (BCRs) composed of V(H)11-muH chains utilizing the J(H)1 segment and Vkappa9-L chains. This extremely skewed repertoire of PtC-reactive B-1 cells is traditionally attributed to the expansion of particular clones in response to self or exogenous antigens. Here, we show that the strong bias toward the J(H)1 usage among V(H)11-muH chains is already established prior to the BCR assembly, namely at the transition from the large to the small pre-B cell stage during B cell ontogeny in the fetal liver. Among V(H)11-muH clones isolated from large pre-B cells where the J(H)1 skewing was not established yet, the J(H)1 users showed the highest ability to form pre-B cell receptor (pre-BCR) and to induce cellular proliferation and differentiation when expressed in fetal liver pro-B cells. Thus, the J(H)1 users were positively selected and amplified at the pre-BCR checkpoint. When co-expressed with Vkappa9-L chains to form BCR, the J(H)1 users almost exclusively conferred the PtC reactivity on BCR even though other J(H) users could also form BCR on the cell surface. Therefore, the pre-BCR-mediated positive selection of the J(H)1 users among V(H)11-muH chains appears to be beneficial to the efficient generation of 'innate-type' PtC-reactive B cells during the fetal B cell development, even before the self-renewal or the antigen-driven clonal expansion of B-1 cells takes place in the peritoneal cavity.