2. Academic Validation
  3. Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation

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

  • Nat Commun. 2015 Jan 21;6:6074. doi: 10.1038/ncomms7074.
Jiayi Yu 1,  Xiaofei Zhou 1,  Mikyoung Chang 1,  Mako Nakaya 2,  Jae-Hoon Chang 3,  Yichuan Xiao 1,  J William Lindsey 4,  Stephanie Dorta-Estremera 5,  Wei Cao 5,  Anna Zal 1,  Tomasz Zal 6,  Shao-Cong Sun 6
Affiliations

Affiliations

  • 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.
PMID: 25606824 DOI: 10.1038/ncomms7074
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.

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