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 V-H gene recombination. This phenomenon is referred to as allelic exclusion. The chromatin structure of the V-H genes regulates their recombination potential, hence alterations in chromatin are a key factor in allelic exclusion. In pro-B cells, IL-7/lL-7R signaling induces histone hyperacetylation and nuclease accessibility of the largest family Of V-H genes (J558) and potentially activates these genes for recombination. Loss of these signals in the later stages of B-cell development reverts the V(H)J558 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 V-H gene families. D-proximal V-H genes, however, appear to be less susceptible to feedback inhibition.