Pre-B Cell Receptor-Mediated Selection of Pre-B Cells Synthesizing Functional μ Heavy Chains

Abstract

Ig gene rearrangements could generate VH-D-JH joining sequences that interfere with the correct folding of a μ-chain, and thus, its capability to pair with IgL chains. Surrogate light (SL) chain might be the ideal molecule to test the capacity of a μ-chain to pair with a L chain early in development, in that only pre-B cells that assemble a membrane μ-SL complex would be permitted to expand and further differentiate. We have previously identified two SL chain nonpairing VH81X-μ-chains with distinct VH-D-JH joining regions. Here, we show that one of these VH81X-μ-chains does not rescue B cell development in JH knock-out mice, because flow cytometric analysis of bone marrow cells from VH81X-μ transgenic JH knock-out mice revealed normal numbers of pro-B cells, but essentially no pre-B and surface IgM+ B cells. Immunoprecipitation analysis of transfected pre-B and hybridoma lines revealed that the same μ-chain fails to pair not only with SL chain but also with four distinct κ L chains. These findings demonstrate that early pre-B cells are selected for maturation on the basis of the structure of a μ-chain, in particular its VH-D-JH joining or CDR3 sequence, and that one mechanism for this selection is the capacity of a μ-chain to assemble with SL chain. Therefore, we propose a new function of SL chain in early B cell development: SL chain is part of a quality control mechanism that tests a μ-chain for its ability to pair with conventional L chains.