Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation.

Jiayi Yu, Xiaofei Zhou, Mikyoung Chang, Mako Nakaya, Jae-Hoon Chang, Yichuan Xiao, J William Lindsey, Stephanie Dorta-Estremera, Wei Cao, Anna Zal, Tomasz Zal, Shao-Cong Sun

Index: Nat. Commun. 6 , 6074, (2015)

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Abstract

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 draining lymph node in a neuroinflammatory autoimmunity model, experimental autoimmune encephalomyelitis (EAE). At older ages, the T-cell-conditional TBK1-knockout mice also spontaneously accumulate T cells with activated phenotype. TBK1 controls the activation of AKT and its downstream kinase mTORC1 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 of 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.