Transcriptional regulation of CD4 gene expression by T cell factor-1/β-catenin pathway

Zhaofeng Huang, Huimin Xie, Vassilio Ioannidis, Werner Held, Hans Clevers, Maureen S. Sadim, Zuoming Sun

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

36 Citaten (Scopus)


By interacting with MHC class II molecules, CD4 facilitates lineage development as well as activation of Th cells. Expression of physiological levels of CD4 requires a proximal CD4 enhancer to stimulate basic CD4 promoter activity. T cell factor (TCF)-1/ β-catenin pathway has previously been shown to regulate thymocyte survival via up-regulating antiapoptotic molecule Bcl-XL. By both loss and gain of function studies, in this study we show additional function of TCF-1/β-catenin pathway in the regulation of CD4 expression in vivo. Mice deficient in TCF-1 displayed significantly reduced protein and mRNA levels of CD4 in CD4+CD8+ double-positive (DP) thymocytes. A transgene encoding Bcl-2 restored survival but not CD4 levels of TCF-1-/- DP cells. Thus, TCF-1-regulated survival and CD4 expression are two separate events. In contrast, CD4 levels were restored on DP TCF-1-/- cells by transgenic expression of a wild-type TCF-1, but not a truncated TCF-1 that lacks a domain required for interacting with β-catenin. Furthermore, forced expression of a stabilized β-catenin, a coactivator of TCF-1, resulted in up-regulation of CD4. TCF-1 or stabilized β-catenin greatly stimulated activity of a CD4 reporter gene driven by a basic CD4 promoter and the CD4 enhancer. However, mutation of a potential TCF binding site located within the enhancer abrogated TCF-1 and β-catenin-mediated activation of CD4 reporter. Finally, recruitment of TCF-1 to CD4 enhancer was detected in wild-type but not TCF-1 null mice by chromatin-immunoprecipitation analysis. Thus, our results demonstrated that TCF/β-catenin pathway enhances CD4 expression in vivo by recruiting TCF-1 to stimulate CD4 enhancer activity.

Originele taal-2Engels
Pagina's (van-tot)4880-4887
Aantal pagina's8
TijdschriftJournal of Immunology
Nummer van het tijdschrift8
StatusGepubliceerd - 15 apr. 2006
Extern gepubliceerdJa


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