title: Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation.
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.
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
authors.forename: Mikyoung
authors.initials: M
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Mako
authors.initials: M
authors.lastname: Nakaya
authors.affiliation: 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.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Chang
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Neurology, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: J William
authors.initials: JW
authors.lastname: Lindsey
authors.affiliation: 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.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dorta-Estremera
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Zal
authors.affiliation: 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.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zal
authors.affiliation: 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.
authors.forename: Shao-Cong
authors.initials: SC
authors.lastname: Sun
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002465:Cell Movement; D002469:Cell Separation; D002490:Central Nervous System / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D009975:Orthomyxoviridae; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; C498588:Tbk1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D058570:TOR Serine-Threonine Kinases