T Cells Infiltrating Diseased Liver Express Ligands for the NKG2D Stress Surveillance System

J Immunol. 2017 Feb 1;198(3):1172-1182. doi: 10.4049/jimmunol.1601313. Epub 2016 Dec 28.

Abstract

NK cells, which are highly enriched in the liver, are potent regulators of antiviral T cells and immunopathology in persistent viral infection. We investigated the role of the NKG2D axis in T cell/NK cell interactions in hepatitis B. Activated and hepatitis B virus (HBV)-specific T cells, particularly the CD4 fraction, expressed NKG2D ligands (NKG2DL), which were not found on T cells from healthy controls (p < 0.001). NKG2DL-expressing T cells were strikingly enriched within HBV-infected livers compared with the periphery or to healthy livers (p < 0.001). NKG2D+NK cells were also increased and preferentially activated in the HBV-infected liver (p < 0.001), in direct proportion to the percentage of MICA/B-expressing CD4 T cells colocated within freshly isolated liver tissue (p < 0.001). This suggests that NKG2DL induced on T cells within a diseased organ can calibrate NKG2D-dependent activation of local NK cells; furthermore, NKG2D blockade could rescue HBV-specific and MICA/B-expressing T cells from HBV-infected livers. To our knowledge, this is the first ex vivo demonstration that non-virally infected human T cells can express NKG2DL, with implications for stress surveillance by the large number of NKG2D-expressing NK cells sequestered in the liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Communication
  • Cells, Cultured
  • Female
  • Hepatitis B, Chronic / immunology*
  • Humans
  • Killer Cells, Natural / immunology*
  • Ligands
  • Liver / immunology*
  • Liver / virology
  • Lymphocyte Activation
  • Male
  • NK Cell Lectin-Like Receptor Subfamily K / antagonists & inhibitors
  • NK Cell Lectin-Like Receptor Subfamily K / physiology*

Substances

  • KLRK1 protein, human
  • Ligands
  • NK Cell Lectin-Like Receptor Subfamily K