Interleukin 7 receptor control of T cell receptor gamma gene rearrangement: Role of receptor-associated chains and locus accessibility

VDJ recombination of T cell receptor and immunoglobulin loci occurs in imma ture lymphoid cells. Although the molecular mechanisms of DNA cleavage and ligation have become more clear, it is not understood what controls which t arget loci undergo rearrangement. In interleukin 7 receptor (IL-7R)alpha(-/ -) murine thymocytes, it has been shown that rearrangement of the T cell re ceptor (TCR)-gamma locus is virtually abrogated, whereas other rearranging loci are less severely affected. By examining different strains of mice wit h targeted mutations, we now observe that the signaling pathway leading fro m IL-7R alpha to rearrangement of the TCR-gamma locus requires the gamma(c) receptor chain and the gamma(c)-associated Janus kinase Jak3. Production o f sterile transcripts from the TCR-gamma locus, a process that generally pr ecedes rearrangement of a locus, was greatly repressed in IL-7R alpha(-/-) thymocytes. The repressed transcription was not due to a lack in transcript ion factors since the three transcription factors known to regulate this lo cus were readily detected in IL-7R alpha(-/-) thymocytes. Instead, the TCR- gamma locus was shown to be methylated in IL-7R alpha(-/-) thymocytes. Trea tment of IL-7R alpha(-/-) precursor T cells with the specific histone deace tylase inhibitor trichostatin A released the block of TCR-gamma gene rearra ngement. This data supports the model that IL-7R promotes TCR-gamma gene re arrangement by regulating accessibility of the locus via demethylation and histone acetylation of the locus.