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Nat Commun. 2015 Jan 21;6:6074. doi: 10.1038/ncomms7074.

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

Author information

1
Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
2
1] Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA [2] Division of Pharmacology, School of Medicine, University of Fukui, Fukui 910-8507, Japan.
3
1] Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA [2] College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
4
Department of Neurology, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
5
1] Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA [2] The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA.
6
1] Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA [2] The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 77030, USA [3] Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.

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.

PMID:
25606824
PMCID:
PMC4302769
DOI:
10.1038/ncomms7074
[Indexed for MEDLINE]
Free PMC Article

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