Cross‐presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance

• Published in: European Journal of Immunology 2005-10, Vol.35 (10), p.2970-2981
• Main Authors: Limmer, Andreas, Ohl, Jutta, Wingender, Gerhard, Berg, Martina, Jüngerkes, Frank, Schumak, Beatrix, Djandji, Dominik, Scholz, Kai, Klevenz, Alexandra, Hegenbarth, Silke, Momburg, Frank, Hämmerling, Günter J., Arnold, Bernd, Knolle, Percy A.
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antigen Presentation - immunology; Antigens - immunology; CD8 T cell tolerance; CD8-Positive T-Lymphocytes - immunology; Cross-Priming - immunology; Endothelial Cells - immunology; Immune Tolerance - immunology; Liver - cytology; Mice; Mice, Knockout; Oral tolerance; Scavenger endothelial cells
• ISSN: 0014-2980; 1521-4141; 1365-2567
• DOI: 10.1002/eji.200526034

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‐2Kb 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‐2Kb‐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‐γ in CD8 T cells. Using a new transgenic mouse line expressing H‐2Kb only on endothelial cells, we have demonstrated that oral antigen administration leads to tolerance in H‐2Kb‐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.