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-Aminobutyric Acid Transporter 1 Negatively Regulates T Cell-Mediated Immune Responses and Ameliorates Autoimmune Inflammation in the CNS1
* 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;
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; and
School of Life Science and Technology, Tong Ji University, Shanghai, China
-aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the CNS, and GABA transporter 1 (GAT-1) is critical in maintaining a GABA reservoir and associated functions. The wide expression of GAT-1 in the CNS prompted us to explore its role in neuroimmunological disorders. In mice induced with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, we found that the expression levels of GAT-1 mRNA and protein in spinal cord were greatly suppressed as compared with those in naive mice and irrelevant Ag-immunized mice. Therefore, we induced EAE in GAT-1–/– mice and found that the disease was significantly aggravated and was accompanied by some nonclassic EAE signs. Mononuclear cells from GAT-1–/– mice with EAE showed much higher Ag-specific proliferative responses. Proinflammatory cytokine production in these mice was also greatly up-regulated. Further studies revealed that GAT-1 deficiency induced vigorous immune responses by enhancing I
B kinase phosphorylation and NF-B-DNA binding activity, as well as strengthening the T-bet-STAT1 circuit signaling pathway. Finally, we found that GAT-1 was expressed only on activated T cells primed with Ags, but not on B cells or macrophages. These findings indicate that GAT-1 is a critical modulator in T cell-mediated immune responses and in EAE pathogenesis.
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) and the Knowledge Innovation Program of the Chinese Academy of Sciences (J0171-1905).
2 Address correspondence and reprint requests to Dr. Lingyun Xu, Room 308 Building I, 225 South Chongqing Road, Shanghai 200025, China. E-mail address: lyxu{at}sibs.ac.cn or Dr. Jian Fei, School of Life Science and Technology, Tong Ji University, Shanghai 200092, China. E-mail address: jfei{at}mail.tongji.edu.cn
3 Abbreviations used in this paper: MS, multiple sclerosis; DTH, delayed-type hypersensitivity; EAE, experimental autoimmune encephalomyelitis; GABA, -aminobutyric acid; GAD, glutamate decarboxylase; GAT-1, GABA transporter 1; IKK, IB kinase; MNC, mononuclear cell; MOG, myelin oligodendrocyte glycoprotein; p.i., postimmunization; WT, wild type.
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  Y. Wang, Q. Luo, Y. Xu, D. Feng, J. Fei, Q. Cheng, and L. Xu {gamma}-Aminobutyric Acid Transporter 1 Negatively Regulates T Cell Activation and Survival through Protein Kinase C-Dependent Signaling Pathways J. Immunol., September 1, 2009; 183(5): 3488 - 3495. [Abstract] [Full Text] [PDF]
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