A V(H)12 transgenic mouse exhibits defects in pre-B cell development and is unable to make IgM(+) B cells

V(H)12 B cells undergo stringent selection at multiple checkpoints to favor development of B-1 cells that bind phosphatidylcholine. Selection begins w ith the V-H third complementarity-determining region (CDR3) at the pre-B ce ll stage, in which most V(H)12 pre-B cells are selectively eliminated, enri ching for those with V(H)CDR3s of 10 aa and a fourth position Gly (designat ed 10/G4). To understand this selection, we compared B cell differentiation in mice of two V(H)12 transgenic lines, one with the favored 10/G4 V(H)CDR 3 and one with a non-10/G4 V(H)CDR3 of 8 aa and no Gly (8/G0). Both H chain s drive B cell differentiation to the small pre-BII cell stage, and induce allelic exclusion and L chain gene rearrangement. However, unlike 10/G4 pre -B cells, 8/G0 pre-B cells are deficient in cell division and unable to dif ferentiate to B cells. We suggest that this is due to poor 8/G0 pre-B cell receptor expression and to an inability to form an 8/G0 B cell receptor. Ou r findings also suggest that V(H)12 H chains have evolved such that associa tion with surrogate and conventional L chains is most efficient with a 10/G 4 CDR3. Thus, selection for phosphatidylcholine-binding B-1 cells is most l ikely the underlying evolutionary basis for the loss of non-10/G4 pre-B cel ls.