| First Author | Tani-Ichi S | Year | 2011 |
| Journal | Int Immunol | Volume | 23 |
| Issue | 9 | Pages | 553-63 |
| PubMed ID | 21750145 | Mgi Jnum | J:176159 |
| Mgi Id | MGI:5288561 | Doi | 10.1093/intimm/dxr055 |
| Citation | Tani-Ichi S, et al. (2011) The pre-TCR signal induces transcriptional silencing of the TCRgamma locus by reducing the recruitment of STAT5 and Runx to transcriptional enhancers. Int Immunol 23(9):553-63 |
| abstractText | The mouse TCRgamma locus is positively regulated by the transcription factors STAT5 and Runx. While the locus undergoes frequent rearrangements in T lymphocytes, TCRgamma transcription is repressed in alphabeta T cells. This phenomenon, known as TCRgamma silencing, depends on pre-TCR-induced thymocyte proliferation. The molecular basis for TCRgamma silencing, however, is largely unknown. Here, we show that pre-TCR signaling reduces transcription and histone acetylation of the TCRgamma locus irrespective of V-J rearrangements. We also demonstrate that Runx is recruited to Egamma and HsA enhancer elements of the TCRgamma locus, primarily at the CD4(-)CD8(-) double-negative stage and that Runx binding to these elements decreases at later stages of thymocyte development. Importantly, anti-CD3 antibody treatment decreased IL-7R expression levels, STAT5 phosphorylation and recruitment of STAT5 and Runx to Egamma and HsA elements in RAG2-deficient thymocytes, suggesting that pre-TCR signaling triggers reduced binding of STAT5 and Runx to the enhancer elements. Furthermore, we observed that misexpression of STAT5 or Runx in the CD4(+)CD8(+) double-positive cell line DPK induces TCRgamma gene transcription. Finally, we showed that TCRgamma transcription is induced in alphabeta T cells from Runx3 transgenic mice, suggesting that Runx3 counteracts TCRgamma silencing in alphabeta T cells in vivo. Our results suggest that pre-TCR signaling indirectly inactivates TCRgamma enhancers by reducing recruitment of STAT5 and Runx and imply that this effect is an important step for TCRgamma silencing in alphabeta T cells. |
