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( Mako Nakaya ),( Yichuan Xiao ),( Xiaofei Zhou ),( Jae Hoon Chang ),( Mikyong Chang ),( Xuhong Cheng ),( Marzenna Blonska ),( Xin Lin ),( Shao Cong Sun ) 영남대학교 약품개발연구소 2014 영남대학교 약품개발연구소 연구업적집 Vol.24 No.0
Glutamine has been implicated as an immunomodulatory nutrient, but how glutamine uptake is mediated during T cell activation is poorly understood. We have shown that naive T cell activation is coupled with rapid glutamine uptake, which depended on the amino acid transporter ASCT2. ASCT2 deficiency impaired the induction of T helper 1 (Th1) and Th17 cells and attenuated inflammatory T cell responses in mouse models of immunity and autoimmunity. Mechanistically, ASCT2 was required for T cell receptor (TCR)-stimulated activation of the metabolic kinase mTORC1. We have further shown that TCR-stimulated glutamine uptake and mTORC1 activation also required a TCR signaling complex composed of the scaffold protein CARMA1, the adaptor molecule BCL10, and the paracaspase MALT1. This function was independent of IKK kinase, a major downstream target of the CARMA1 complex. These findings highlight a mechanism of T cell activation involving ASCT2-dependent integration of the TCR signal and a metabolic signaling pathway.
( Jia Yi Yu ),( Xiao Fei Zhou ),( Mi Kyoung Chang ),( Mako Nakaya ),( Jae Hoon Chang ),( Yi Chuan Xiao ),( J. William Lindsey ),( Stephanie Dorta Estremera ),( Wei Cao ),( Anna Zal ),( Tomasz Zal ),( 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-
Development of an immune or autoimmune response involves T-cell activation in lymphoid organs and subsequent migration to peripheral tissues. Here we show that T-cell-specific ablation of the kinase TBK1 promotes T-cell activation but causes retention of effector T cells in the draininglumph node in a neuroinflammatory autoimmunity model,experimental autoimmune encephalomyelitis (EAE).Atolder ager,the T-cell-conditional TBK1-knockout mice also spontaneously accumulate T cells with activated phenotype.TBK1 contrlos the activation of AKT and its downsream kinase m TIORC1 by a mechanism involving TBK1-stimulated AKT ubiquitination and degradation. The deregulated AKT-mTORC1 signalling in turn contributes to enhanced T-cell activation and impaired effector T-cell egress from draining lymph nodes. Treatment of mice with a small-molecule inhibitor fo TBK1 inhibits EAE induction. These results suggest a role for TBK1 in regulating T-cell migration and establish TBK1 as a regulator of the AKT-mTORC1 signalling axis.