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Induction of Germline Transcription in the Human TCR Locus by STAT5¹

Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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 TCR locus, STAT5 proteins activated by the IL-7R interact with consensus motifs in 5' regions of J segments and induce germline transcription. To evaluate the role of STAT5 in controlling the accessibility of the TCR locus, we characterized the germline transcription of human TCR genes and compared it with mouse. We first demonstrated that J-C germline transcripts are induced in a cytokine-dependent human erythroleukemia cell line. STAT consensus motifs are present in 5' regions of J1.1 and J2.1 gene segments, and activated STAT5 binds to these motifs. By using a reporter assay, we showed that the J1.1 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 TCR locus of both mouse and human and suggests the possibility that this mechanism may play an essential role in controlling the TCR locus accessibility. In addition, STAT motifs are conserved among 5' J germline promoters, 3' enhancers, and a locus control region-like element, HsA, in both mouse and human TCR loci, indicating the possibility that IL-7R/STAT5 signaling probably controls the locus-wide accessibility through these elements.

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