Transcriptional Regulation of CD4 Gene Expression by T Cell Factor-1/beta-Catenin Pathway

• Published in: Journal of Immunology Vol. 176; no. 8; pp. 4880 - 4887
• Main Authors: Huang, Zhaofeng, Xie, Huimin, Ioannidis, Vassilio, Held, Werner, Clevers, Hans, Sadim, Maureen S, Sun, Zuoming
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.04.2006
• Subjects: Animals; Base Sequence; beta Catenin - genetics; beta Catenin - metabolism; Binding Sites - genetics; CD4 Antigens - genetics; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; DNA - genetics; DNA - metabolism; Enhancer Elements, Genetic; Gene Expression Regulation; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; RNA, Messenger - genetics; RNA, Messenger - metabolism; T Cell Transcription Factor 1 - deficiency; T Cell Transcription Factor 1 - genetics; T Cell Transcription Factor 1 - metabolism; Transcription, Genetic
• DOI: 10.4049/jimmunol.176.8.4880
• ISSN: 0022-1767

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/beta-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/beta-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 beta-catenin. Furthermore, forced expression of a stabilized beta-catenin, a coactivator of TCF-1, resulted in up-regulation of CD4. TCF-1 or stabilized beta-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 beta-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/beta-catenin pathway enhances CD4 expression in vivo by recruiting TCF-1 to stimulate CD4 enhancer activity.