Induction of germline transcription in the human TCR gamma locus by STAT5

TCR and Ig genes are assembled by V(D)J recombination during lymphocyte development. The enhancer and the germline promoter control the accessibility of each locus for the common recombinase activity. In the mouse TCRgamma locus, STAT5 proteins activated by the IL-7R interact with consensus motifs in 5' regions of Jgamma segments and induce germline transcription. To evaluate the role of STAT5 in controlling the accessibility of the TCRgamma locus, we characterized the germline transcription of human TCRgamma genes and compared it with mouse. We first demonstrated that Jgamma-Cgamma germline transcripts are induced in a cytokine-dependent human erythroleukemia cell line. STAT consensus motifs are present in 5' regions of Jgamma1.1 and Jgamma2.1 gene segments, and activated STAT5 binds to these motifs. By using a reporter assay, we showed that the Jgamma1.1 germline promoter is transactivated by STAT5 and that mutations in any of the two STAT motifs abrogate this activity. Thus, this study demonstrates that STAT5 induces germline transcription in the TCRgamma locus of both mouse and human and suggests the possibility that this mechanism may play an essential role in controlling the TCRgamma locus accessibility. In addition, STAT motifs are conserved among 5' Jgamma germline promoters, 3' enhancers, and a locus control region-like element, HsA, in both mouse and human TCRgamma loci, indicating the possibility that IL-7R/STAT5 signaling probably controls the locus-wide accessibility through these elements.