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Expression of CD226 Antagonizes Apoptotic Cell Death in Murine Thymocytes¹

Liang Fang^2,*, Xinhai Zhang^2,*,¶, Jun Miao, Fang Zhao, Kun Yang^*, Ran Zhuang^*, Hermann Bujard, Yanzhang Wei^¶, Angang Yang^*, Lihua Chen^3,* and Boquan Jin^3,*

^* Department of Immunology, Department of Etiology, and Department of Occupational and Environmental Health, Fourth Military Medical University, Xi’an, People’s Republic of China; Zentrum fuer Molekulare Biologie der Universitaet Heidelberg, Heidelberg, Germany; and ^¶ Oncology Research Institute and Cancer Treatment Center, Greenville Hospital System, Greenville, SC 29605

CD226 is known to be expressed on many types of peripheral lymphoid cells and involved in T cell differentiation, activation, and cytotoxicity. In this study, we report that CD226 is also expressed on mouse thymocytes at varying developmental stages, and its expression is associated with resistance of thymocytes to apoptosis. The levels of CD226 expression appeared to be closely coupled with thymocyte development, in that it was preferentially expressed on CD4⁺CD8^– and CD4^–CD8⁺ thymocytes at all stages during mouse development, and was markedly increased on the cells in neonatal mice. Of the CD4⁺CD8⁺ population, CD226 was predominantly expressed by the cells also positive for CD69, suggesting that CD226 expression may be induced in thymocyte-positive selection. Inhibition of CD226 by short hairpin RNA in a fetal thymus organ culture model led to reduced thymus cellularity, which was associated with enhanced apoptotic cell death. In contrast, CD226-transgenic mice displayed enlarged thymus lobes resulting from increased thymus cellularity. CD226 on thymocytes seemed to play a role in regulating the expression of survivin, as inhibition of CD226 down-regulated survivin, but overexpression of CD226 rescued thymocytes from apoptosis through up-regulation of survivin. In addition, overexpression of CD226 reduced sensitivity of EL-4 thymoma cells to apoptosis by up-regulating the expression of survivin. Taken together, these results indicate that CD226 is an antiapoptotic molecule and may play an important role in murine thymocyte development.

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 the National Natural Science Foundation of China (Grants 30030130, 30570268, and 30672370).

² L.F. and X.Z. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Boquan Jin, and Dr. Lihua Chen, Department of Immunology, the Fourth Military Medical University, Xi’an 710032, China. E-mail addresses: immu_jin{at}fmmu.edu.cn and chenlh{at}fmmu.edu.cn

⁴ Abbreviations used in this paper: siRNA, short interfering RNA; shRNA, short hairpin RNA; DP, double positive; DN, double negative; FTOC, fetal thymus organ culture; MFI, mean fluorescence intensity; MOI, multiplicity of infection; SP, single positive; E15, embryonic day 15; TG, transgenic; E18, embryonic day 18.

⁵ The online version of this article contains supplemental material.