Gamma-aminobutyric acid transporter 1 negatively regulates T cell activation and survival through protein kinase C-dependent signaling pathways.

Gamma-aminobutyric acid transporter 1 (GAT-1), as the major regulator in maintaining a gamma-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-kappaB through induction of translocation and phosphorylation of protein kinase C (PKC) theta. 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.