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-Aminobutyric Acid Transporter 1 Negatively Regulates T Cell Activation and Survival through Protein Kinase C-Dependent Signaling Pathways¹

Ying Wang^*,,, Qingqiong Luo, Yan Xu, Dechun Feng, Jian Fei, Qi Cheng^2,* and Lingyun Xu^2,

^* Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Health Sciences, Shanghai Jiaotong University School of Medicine/Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai, China; and School of Life Science and Technology, Tong Ji University, Shanghai, China

-aminobutyric acid transporter 1 (GAT-1), as the major regulator in maintaining a -aminobutyric acid reservoir in the CNS, plays negative roles in experimental autoimmune encephalomyelitis pathogenesis. Our previous study has revealed that, besides its wide expression in the CNS, GAT-1 expression can be induced on activated T cells triggered by Ag. However, the function of GAT-1 in T cell activation is unclear. In this study, we show that GAT-1 deficiency induces more vigorous cell cycle entry and less cell apoptosis in T cells, thus leading to enhanced cell proliferation. GAT-1 deficiency promotes T cell division and survival by down-regulating cyclin dependent kinase inhibitor p27^kip1, differentially regulating the pro- and anti-apoptotic proteins Bcl-2, Bcl-xl, and Bad and activating transcription factor NF-B through induction of translocation and phosphorylation of protein kinase C (PKC) . In addition, our data reveal that GAT-1 expression on T cells is modulated by PKC activation. Taken together, the data show that GAT-1 negatively regulates T cell activation and survival through PKC-dependent signaling pathways.

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 grants from the National Natural Science Foundation of China (30570706, 30671994, 30872179), the Knowledge Innovation Program of the Chinese Academy of Sciences (J0171-1905) and New Century Excellent Talents in University (NCET-06-0407).

² Address correspondence and reprint requests to Dr. Lingyun Xu, Room 308 Building I, 225 South Chongqing Road, Shanghai, China or Dr. Qi Cheng, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. E-mail addresses: lyxu{at}sibs.ac.cn or qicheng8{at}yahoo.com.cn

³ Abbreviations used in this paper: GABA, -aminobutyric acid; GAT-1, GABA transporter 1; EAE, experimental autoimmune encephalomyelitis; CDK, cyclin dependent kinase; AICD, activation induced cell death; PKC, protein kinase C; Ct, cycle threshold; MNC, mononuclear cell; WT, wild type; Bis VIII, Bisindolylmaleimide VIII; IS, immunological synapse.