Transfer of MHC-class-I Molecules Among Liver Sinusoidal Cells Facilitates Hepatic Immune Surveillance

J Hepatol. 2014 Sep;61(3):600-8. doi: 10.1016/j.jhep.2014.04.028. Epub 2014 May 4.

Abstract

Background & aims: In the liver, antigen-presenting cell populations such as Kupffer cells, liver dendritic cells, and liver sinusoidal endothelial cells (LSECs) participate through cross-presentation to CD8 T cells (CTLs) in hepatic immune-regulation and immune-surveillance. The participation of hepatic stellate cells (HSCs) in immune regulation is controversial. Here we studied HSC's contribution to antiviral CTL immunity.

Methods: Flow cytometric analysis of MHC-I molecules at the cell surface of liver cells from mice with cell-type restricted MHC-I expression. Mice with HSC-restricted MHC-I expression were infected with a hepatotropic virus and analyzed for development of viral hepatitis after CTL transfer.

Results: HSCs transferred MHC-I molecules to LSECs and these molecules were employed for LSEC cross-presentation to CTLs. Such transfer of MHC-I molecules was sufficient to support in vivo LSEC cross-presentation of soluble antigens to CTLs. Importantly, this transfer of MHC-I molecules contributed to anti-viral CTL immunity leading to development of immune-mediated hepatitis.

Conclusions: Our findings demonstrate transfer of MHC-I molecules among sinusoidal liver cell populations as a potent mechanism to increase anti-viral CTL effector function. The transfer of MHC-I molecules from HSCs supplies LSECs with additional MHC-I molecules for their own cell-intrinsic cross-presentation. Such cross-allocation of MHC-I molecules in liver cell populations is distinct from cross-dressing that occurs among immune cell populations in lymphoid tissues where peptide-loaded MHC-I molecules are transferred. Our findings thus reveal a novel mechanism that increases local cross-presentation and CTL effector function in the liver, which may be instrumental for immune-surveillance during viral infection of antigen-presenting liver cells.

Keywords: Cross-presentation; HSC; LSEC; MHC-I.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Gene Expression Regulation / genetics*
  • Gene Transfer Techniques
  • Genes, MHC Class I / genetics*
  • Hepatic Stellate Cells / immunology*
  • Hepatic Stellate Cells / pathology
  • Immunologic Surveillance / genetics*
  • Liver / immunology*
  • Liver / pathology
  • Lymphocyte Activation
  • Mice
  • Mice, Transgenic
  • Models, Animal