Systemic antigen cross-presented by liver sinusoidal endothelial cells induces liver-specific CD8 T-cell retention and tolerization.
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.
von Oppen
Nanette
N
Institute of Molecular Medicine and Experimental Immunology, University Hospital Aachen, Aachen, Germany.
Schurich
Anna
A
Hegenbarth
Silke
S
Stabenow
Dirk
D
Tolba
Rene
R
Weiskirchen
Ralf
R
Geerts
Albert
A
Kolanus
Waldemar
W
Knolle
Percy
P
Diehl
Linda
L
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
D000941:Antigens; D010047:Ovalbumin