Immunoglobulin heavy chain enhancer's (Eμ) role in cell selection at the pre-B to immature B cell transition (109.7)

Abstract

Abstract We have recently described a second check-point for allelic exclusion that operates at the pre-B to immature B cell transition and is dependent upon the IgH intronic enhancer Eμ. We suggest that Eμ’s function at this transition is to ensure that IgH chains are made at levels sufficient to signal positive selection, regardless of light chain sequences and despite mono-allelic expression of the heavy chain. Evidence leading to this hypothesis includes our findings that B cells expressing an Eμ-deficient allele undergo heightened light-chain editing (suggesting that only some light-chain partners can circumvent the effects of lower BCR levels), or express a second IgH allele (“double-producing” cells to achieve higher BCR levels). We now show that B cells expressing an Eμ-deficient IgH allele, consistent with inefficient positive selection, remain longer at the pre-B cell stage, resulting in a significantly diminished immature B cell compartment. To determine whether escape from this developmental stall is dependent upon light chain, we limited the available light chain repertoire in these animals by pre-assembled VL insertion. The result was an effect on both B cell development and the emergence of double-producing cells. Together with our earlier findings, these new results suggest that IgH levels at the pre-B to immature B transition have an important impact on the breadth of the BCR repertoire as well as on the maintenance of allelic exclusion.