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

Nat Commun. 2015 Jan 21;6:6074. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / immunology
  • CD4-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / cytology
  • Cell Movement
  • Cell Separation
  • Central Nervous System / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Female
  • Gene Expression Regulation*
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation / immunology*
  • Macrophages / metabolism
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / metabolism
  • Orthomyxoviridae
  • Phenotype
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • T-Lymphocytes / cytology*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Multiprotein Complexes
  • Tbk1 protein, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human