Gamma-aminobutyric acid transporter 1 negatively regulates T cell-mediated immune responses and ameliorates autoimmune inflammation in the CNS.
gamma-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 IkappaB kinase phosphorylation and NF-kappaB-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.
Wang
Ying
Y
Institute of Health Sciences, Shanghai Jiaotong University School of Medicine, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Feng
Dechun
D
Liu
Guoxiang
G
Luo
Qingqiong
Q
Xu
Yan
Y
Lin
Shuting
S
Fei
Jian
J
Xu
Lingyun
L
D000595:Amino Acid Sequence; D000818:Animals; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D050485:GABA Plasma Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
D018984:Epitopes, T-Lymphocyte; D050485:GABA Plasma Membrane Transport Proteins; C493414:Slc6a1 protein, mouse