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/IL-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_HJ558 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.