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Krüppel-Like Transcription Factor 13 Regulates T Lymphocyte Survival In Vivo¹

Meixia Zhou^*, Lisa McPherson^*, Dongdong Feng^*, An Song, Chen Dong^*, Shu-Chen Lyu^*, Lu Zhou^*, Xiaoyan Shi^*, Yong-Tae Ahn^*, Demin Wang, Carol Clayberger^* and Alan M. Krensky^2,*

^* Department of Pediatrics, Stanford University, Palo Alto, CA 94305; Genentech, South San Francisco, CA 94080; and Blood Research Institute, Blood Center of Wisconsin and Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226

Krüppel-like transcription factor (KLF)13, previously shown to regulate RANTES expression in vitro, is a member of the Krüppel- like family of transcription factors that controls many growth and developmental processes. To ascertain the function of KLF13 in vivo, Klf13-deficient mice were generated by gene targeting. As expected, activated T lymphocytes from Klf13^–/– mice show decreased RANTES expression. However, these mice also exhibit enlarged thymi and spleens. TUNEL, as well as spontaneous and activation-induced death assays, demonstrated that prolonged survival of Klf13^–/– thymocytes was due to decreased apoptosis. Microarray analysis suggests that protection from apoptosis-inducing stimuli in Klf13^–/– thymocytes is due in part to increased expression of BCL-X_L, a potent antiapoptotic factor. This finding was confirmed in splenocytes and total thymocytes by real-time quantitative PCR and Western blot as well as in CD4⁺CD8^– single-positive thymocytes by real-time quantitative PCR. Furthermore, EMSA and luciferase reporter assays demonstrated that KLF13 binds to multiple sites within the Bcl-X_L promoter and results in decreased Bcl-X_L promoter activity, making KLF13 a negative regulator of BCL-X_L.

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 a grant from the National Institutes of Health (DK35008). A.M.K. is the Shelagh Galligan Professor of Pediatrics.

² Address correspondence and reprint requests to Dr. Alan M. Krensky, Department of Pediatrics, Stanford University, 300 Pasteur Drive, Stanford, CA 94305. E-mail address: krensky{at}stanford.edu

³ Abbreviations used in this paper: KLF, Krüppel-like transcription factor; RFLAT, RANTES factors of late-activated T lymphocyte; ES, embryonic stem; RT, room temperature; rt-qPCR, real-time quantitative PCR; Ct, cycle threshold; SP, single positive.

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