T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation

Nat Immunol. 2017 Oct;18(10):1117-1127. doi: 10.1038/ni.3816. Epub 2017 Aug 14.

Abstract

The transcription factor T-bet has been associated with increased susceptibility to systemic and organ-specific autoimmunity, but the mechanism by which T-bet expression promotes neuroinflammation remains unknown. In this study, we demonstrate a cardinal role of T-bet-dependent NKp46+ innate lymphoid cells (ILCs) in the initiation of CD4+ TH17-mediated neuroinflammation. Loss of T-bet specifically in NKp46+ ILCs profoundly impaired the ability of myelin-reactive TH17 cells to invade central nervous system (CNS) tissue and protected the mice from autoimmunity. T-bet-dependent NKp46+ ILCs localized in the meninges and acted as chief coordinators of meningeal inflammation by inducing the expression of proinflammatory cytokines, chemokines and matrix metalloproteinases, which together facilitated T cell entry into CNS parenchyma. Our findings uncover a detrimental role of T-bet-dependent NKp46+ ILCs in the development of CNS autoimmune disease.

MeSH terms

  • Animals
  • Biomarkers
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Gene Expression
  • Immunity, Innate*
  • Immunophenotyping
  • Lymphocyte Subsets / immunology*
  • Lymphocyte Subsets / metabolism*
  • Mice
  • Mice, Knockout
  • Myelin Sheath / immunology
  • Natural Cytotoxicity Triggering Receptor 1 / genetics
  • Natural Cytotoxicity Triggering Receptor 1 / metabolism*
  • T-Box Domain Proteins
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism*

Substances

  • Biomarkers
  • Natural Cytotoxicity Triggering Receptor 1
  • T-Box Domain Proteins
  • T-box transcription factor TBX21