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Stabilized β-Catenin Potentiates Fas-Mediated T Cell Apoptosis¹

Zhaofeng Huang^*, Ruiqing Wang^*, Huimin Xie^*, Weirong Shang, Santhakumar Manicassamy^* and Zuoming Sun^2,

^* Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, IL 60612; Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA 30308; and Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010

In response to Ag stimulation, Ag-specific T cells proliferate and accumulate in the peripheral lymphoid tissues. To avoid excessive T cell accumulation, the immune system has developed mechanisms to delete clonally expanded T cells. Fas/FasL-mediated apoptosis plays a critical role in the deletion of activated peripheral T cells, which is clearly demonstrated by superantigen (staphylococcal enterotoxin B)-induced deletion of Vβ8⁺ T cells. Using transgenic mice expressing a stabilized β-catenin (β-cat^Tg), we show here that β-catenin was able to enhance apoptosis of activated T cells by up-regulating Fas. In response to staphylococcal enterotoxin B stimulation, β-cat^Tg mice exhibited accelerated deletion of CD4⁺Vβ8⁺ T cells compared with wild type mice. Surface Fas levels were significantly higher on activated T cells obtained from β-cat^Tg mice than that from wild type mice. Additionally, T cells from β-cat^Tg mice were more sensitive to apoptosis induced by crosslinking Fas, activation-induced cell death, and to apoptosis induced by cytokine withdrawal. Lastly, β-catenin bound to and stimulated the Fas promoter. Therefore, our data demonstrated that the β-catenin pathway was able to promote the apoptosis of activated T cells in part via up-regulation of Fas.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01-AI053147.

² Address correspondence and reprint requests to Dr. Zuoming Sun, Division of Immunology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010. E-mail address: zsun{at}coh.org

³ Abbreviations used in this paper: AICD, activation-induced cell death; SEB, staphylococcal enterotoxin B; WT, wild type; TOP, Topflash; FOP, fopflash; ChIP, chromatin immunoprecipitation; MFI, mean fluorescence intensity; TCF, T cell factor.