Role of immunoglobulin heavy chain intronic enhancer Eμ in cell selection at the pre-B to immature B cell transition (P1437)

Abstract

Abstract We previously described an Eμ-dependent checkpoint for allelic exclusion, operating at the pre-B to immature B cell transition. We now show that Eμ functions at this transition to ensure that Igμ levels, and consequently B cell receptor (BCR) levels, reach a threshold required for positive selection into the immature B cell pool. We find that Ig-mediated signalling is reduced in pre-B cells expressing an Eμ-deficient IgH allele, as is the size of the emerging immature B cell compartment. Some Eμ-deficient B cells break the rules of allelic exclusion as “double-producers” to achieve higher BCR levels. We previously showed that B cells expressing only the Eμ-deficient allele underwent heightened light-chain editing, consistent with the hypothesis that deficient BCR signals were driving further light chain gene rearrangements in search of an IgH/IgL combination with superior signalling properties. In the current study, we tested this by providing Eμ-deficient mice with a pre-assembled VL gene. As predicted, both heavy chain allelic exclusion and the size of the immature B cell pool were affected. In addition, we found that the double-producers in allelic exclusion-defective mice include a subpopulation in which the BCR generated from the Eμ-deficient allele is autoreactive. These results demonstrate that Igμ levels in developing B cells have an important impact on the breadth of the BCR repertoire, the maintenance of allelic exclusion, and the emergence of autoimmune B cells.