The unique region of surrogate light chain component λ5 is a heavy chain-specific regulator of precursor B cell receptor signaling

Signals transduced by precursor-BCRs (pre-BCRs) composed of Ig mu heavy chains (HCs) and the surrogate L chain components lambda 5 and VpreB are critical for B cell development. A conserved unique region (UR) of lambda 5 was shown to activate pre-BCR complexes in transformed cells and to engage putative ligands, but its contribution to pre-B cell development is not known. It is also not clear why the lambda-like sequences in lambda 5 are used to select HCs that will associate mainly with kappa L chains. In this study, we show that, in transformed and primary mouse B cell progenitors, receptors containing full-length HCs and lacking the lambda 5UR were expressed at higher surface levels, but exhibited reduced activity compared with normal pre-BCRs in supporting developmental changes that accompany the progenitor to pre-B cell transition in primary cell culture systems and in the bone marrow in vivo. In contrast, deletion of the lambda 5UR did not change net signaling output by the D mu-pre-BCR, a developmentally defective receptor that exhibited impaired activity in the primary cell culture system. Moreover, the lambda-like sequences in lambda 5 were more accommodating than K in supporting surface expression and signaling by the different HCs. These results show that the lambda 5UR is important, although not essential, for surrogate L chain-dependent receptor signaling in primary cells, and furthermore may help allow discrimination of signaling competency between normal and D mu-pre-BCRs. That the lambda-like portion of lambda 5 in the absence of the UR was nondiscriminatory suggests that the lambda 5UR focuses pre-BCR-dependent selection on the HC V region.