title: Systemic antigen cross-presented by liver sinusoidal endothelial cells induces liver-specific CD8 T-cell retention and tolerization.
abstract: Peripheral CD8 T-cell tolerance can be generated outside lymphatic tissue in the liver, but the course of events leading to tolerogenic interaction of hepatic cell populations with circulating T-cells remain largely undefined. Here we demonstrate that preferential uptake of systemically circulating antigen by murine liver sinusoidal endothelial cells (LSECs), and not by other antigen-presenting cells in the liver or spleen, leads to cross-presentation on major histocompatibility complex (MHC) I molecules, which causes rapid antigen-specific naïve CD8 T-cell retention in the liver but not in other organs. Using bone-marrow chimeras and a novel transgenic mouse model (Tie2-H-2K(b) mice) with endothelial cell-specific MHC I expression, we provide evidence that cross-presentation by organ-resident and radiation-resistant LSECs in vivo was both essential and sufficient to cause antigen-specific retention of naïve CD8 T-cells under noninflammatory conditions. This was followed by sustained CD8 T-cell proliferation and expansion in vivo, but ultimately led to the development of T-cell tolerance.
  
  
  CONCLUSIONS
  Our results show that cross-presentation of circulating antigens by LSECs caused antigen-specific retention of naïve CD8 T-cells and identify antigen-specific T-cell adhesion as the first step in the induction of T-cell tolerance.
authors.affiliation: Institute of Molecular Medicine and Experimental Immunology, University Hospital Aachen, Aachen, Germany.
authors.forename: Nanette
authors.initials: N
authors.lastname: von Oppen
authors.forename: Anna
authors.initials: A
authors.lastname: Schurich
authors.forename: Silke
authors.initials: S
authors.lastname: Hegenbarth
authors.forename: Dirk
authors.initials: D
authors.lastname: Stabenow
authors.forename: Rene
authors.initials: R
authors.lastname: Tolba
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
authors.forename: Albert
authors.initials: A
authors.lastname: Geerts
authors.forename: Waldemar
authors.initials: W
authors.lastname: Kolanus
authors.forename: Percy
authors.initials: P
authors.lastname: Knolle
authors.forename: Linda
authors.initials: L
authors.lastname: Diehl
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002464:Cell Migration Inhibition; D002478:Cells, Cultured; D045142:Cross-Priming; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance; D008099:Liver / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology
chemical_list: D000941:Antigens; D010047:Ovalbumin