Cross-presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance.
After ingestion, oral antigens distribute systemically and provoke T cell stimulation outside the gastrointestinal tract. Within the liver, scavenger liver sinusoidal endothelial cells (LSEC) eliminate blood-borne antigens and induce T cell tolerance. Here we investigated whether LSEC contribute to oral tolerance. Oral antigens were efficiently cross-presented on H-2K(b) by LSEC to naive CD8 T cells. Cross-presentation efficiency in LSEC but not dendritic cells was increased by antigen-exposure to heat or low pH. Mechanistically, cross-presentation in LSEC requires endosomal maturation, involves hsc73 and proteasomal degradation. H-2K(b)-restricted cross-presentation of oral antigens by LSEC in vivo induced CD8 T cell priming and led to development of CD8 T cell tolerance in two independent experimental systems. Adoptive transfer of LSEC from mice fed with antigen (ovalbumin) into RAG2-/- knockout mice, previously reconstituted with naive ovalbumin-specific CD8 T cells, prevented development of specific cytotoxicity and expression of IFN-gamma in CD8 T cells. Using a new transgenic mouse line expressing H-2K(b) only on endothelial cells, we have demonstrated that oral antigen administration leads to tolerance in H-2K(b)-restricted CD8 T cells. Collectively, our data demonstrate a participation of the liver, in particular scavenger LSEC, in development of CD8 T cell tolerance towards oral antigens.
Limmer
Andreas
A
Institut für Molekulare Medizin und Experimentelle Immunologie, Bonn, Germany. Andreas.Limmer@ukb.uni-bonn.de
Ohl
Jutta
J
Wingender
Gerhard
G
Berg
Martina
M
Jüngerkes
Frank
F
Schumak
Beatrix
B
Djandji
Dominik
D
Scholz
Kai
K
Klevenz
Alexandra
A
Hegenbarth
Silke
S
Momburg
Frank
F
Hämmerling
Günter J
GJ
Arnold
Bernd
B
Knolle
Percy A
PA
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000941:Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045142:Cross-Priming / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D008099:Liver / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout
D000941:Antigens