PRE-B-CELL RECEPTOR-MEDIATED SELECTION OF PRE-B CELLS SYNTHESIZING FUNCTIONAL MU-HEAVY-CHAINS

Ig gene rearrangements could generate V-H-D-J(H) joining sequences tha t interfere with the correct folding of a mu-chain, and thus, its capa bility to pair with IgL chains. Surrogate light (SL) chain might be th e ideal molecule to test the capacity of a mu-chain to pair with a L c hain early in development, in that only pre-B cells that assemble a me mbrane mu-SL complex would be permitted to expand and further differen tiate. We have previously identified two SL chain nonpairing V(H)81X-m u-chains with distinct V-H-D-J(H) joining regions. Here, we show that one of these V(H)81X-mu-chains does not rescue B cell development in J (H) knock-out mice, because flow cytometric analysis of bone marrow ce lls from V(H)81X-mu. transgenic J(H) knock-out mice revealed normal nu mbers of pro-B cells, but essentially no pre-B and surface IgM(+) B ce lls. Immunoprecipitation analysis of transfected pre-B and hybridoma l ines revealed that the same mu-chain fails to pair not only with SL ch ain but also with four distinct kappa L chains. These findings demonst rate that early pre-B cells are selected for maturation on the basis o f the structure of a mu-chain, in particular its V-H-D-J(H) joining or CDR3 sequence, and that one mechanism for this selection is the capac ity of a mu-chain to assemble with SL chain. Therefore, we propose a n ew function of SL chain in early B cell development: SL chain is part of a quality control mechanism that tests a mu-chain for its ability t o pair with conventional L chains.