Mechanisms for feedback inhibition of the immunoglobulin heavy chain locus

The production of immunoglobulin heavy chain (IgH) protein in pro-B cells provides feedback to terminate further VH gene recombination. This phenomenon is referred to as allelic exclusion. The chromatin structure of the VH genes regulates their recombination potential, hence alterations in chromatin are a key factor in allelic exclusion. In pro-B cells, IL-7/IL-7R signaling induces histone hyperacetylation and nuclease accessibility of the largest family of VH genes (J558) and potentially activates these genes for recombination. Loss of these signals in the later stages of B-cell development reverts the VHJ558 gene segments to a less accessible state, making them recombinationally refractive. This provides a molecular mechanism for allelic exclusion of these genes. Similar transient signals may be responsible for enforcing allelic exclusion in other VH gene families. D-proximal VH genes, however, appear to be less susceptible to feedback inhibition.