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* Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Institute for Neuroscience and Biophysics 1, Research Center Juelich, Juelich, Germany; and
Laboratory of Tolerance and Autoimmunity, German Rheumatism Research Center, Berlin, Germany
The persistence of CD4 expression is a key event distinguishing the differentiation of MHC class II-restricted thymocytes into CD4 T cells from that of MHC class I-restricted thymocytes into CD8 T cells. The zinc finger transcription factor Zbtb7b (or cKrox or Thpok) is normally expressed in MHC class II-restricted thymocytes and promotes CD4 lineage choice. When expressed in MHC class I-restricted cells, Zbtb7b redirects these cells from their normal CD8 fate to CD4 differentiation, implying that it promotes, directly or not, sustained CD4 expression; the present study has investigated the mechanism of this effect. We demonstrate that, although Zbtb7b does not enhance CD4 expression on its own, it antagonizes the CD4 repression mediated by the transcription factor Runx3, which is normally up-regulated during CD8 differentiation and promotes CD4 silencing. Zbtb7b also antagonizes CD4 repression by the related protein Runx1, which is expressed in CD4 lineage cells. This antagonism is observed both in vitro and in vivo, is transcriptional, and requires domains of Zbtb7b that are essential to its ability to promote CD4 differentiation in vivo. Furthermore, Zbtb7b fails to antagonize Runx in cells treated with histone deacetylase inhibitors, suggesting that Zbtb7b acts by reducing the expression of thus far unknown factors that cooperate with Runx molecules to repress CD4. These findings demonstrate that the transcription factor Zbtb7b promotes CD4 expression by antagonizing Runx-mediated CD4 repression.
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1 This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. M.E. is supported by the Claussen-Simon-Stiftung, Germany, and was a recipient of a fellowship award from the Eileen Ludwig Foundation.
2 Current address: Department of Immunology, Communicable Diseases & Immunology, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910.
3 Address correspondence and reprint requests to Dr. Rémy Bosselut, Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Building 37, Room 3015, 37 Convent Drive, Bethesda, MD 20892-4259. E-mail address: remy{at}helix.nih.gov
4 Abbreviations used in this paper: MHC-II, MHC class II; MHC-I, MHC class I; HDAC, histone deacetylase; TsA, trichostatin A; DP, double positive; DN, double negative; SP, single positive; ISP, immature SP; FSC, forward light scatter.
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  R. Setoguchi, M. Tachibana, Y. Naoe, S. Muroi, K. Akiyama, C. Tezuka, T. Okuda, and I. Taniuchi Repression of the Transcription Factor Th-POK by Runx Complexes in Cytotoxic T Cell Development Science, February 8, 2008; 319(5864): 822 - 825. [Abstract] [Full Text] [PDF]
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