Transient IL-7/IL-7R signaling provides a mechanism for feedback inhibition of immunoglobulin heavy chain gene rearrangements

Production of immunoglobulin heavy chain (IgH) protein feeds back to terminate further V_H gene recombination, a phenomenon also referred to as allelic exclusion. Here we provide evidence to support the proposition that allelic exclusion is the consequence of terminating signals that activate V_H genes for recombination. For the largest V_HJ558 family of genes, this occurs by attenuating IL-7/IL-7R signals in pre-B cells. Loss of these signals reverts the V_H locus to a chromatin state that is associated with hypoacetylated histones and is less accessible to nucleases. Furthermore, hyperacetylation and accessibility of unrearranged V_H genes can be restored in allelically excluded splenic B cells by activating this pathway. Thus, transient signals mediate V_H gene activation and inactivation during development.