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  • 1
    Keywords: CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; Germany ; IN-VIVO ; PATHWAY ; SYSTEM ; SYSTEMS ; liver ; EFFICIENCY ; MICE ; ACTIVATION ; IFN-GAMMA ; INDUCTION ; ANTIGEN ; ANTIGENS ; DENDRITIC CELLS ; T-CELL ; T-CELLS ; TOLERANCE ; BONE-MARROW ; MATURATION ; knockout ; MOUSE ; LINE ; DEGRADATION ; IMMUNITY ; NAIVE ; CYTOTOXICITY ; CROSS-PRESENTATION ; endothelial cells ; PH ; development ; KNOCKOUT MICE ; CYTOKINE PRODUCTION ; CELL TOLERANCE ; dendritic cell ; INDUCE ; T cell tolerance ; KUPFFER CELLS ; ADOPTIVE TRANSFER ; CD8 T cell tolerance ; ENDOTOXIN ; oral tolerance ; scavenger endothelial cells
    Abstract: After ingestion, oral antigens distribute systemically and provoke T cell stimulation outside the gastrointestinal tract. Within the liver, scavenger liver simisoidal 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
    Type of Publication: Journal article published
    PubMed ID: 16163670
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  • 2
    Keywords: RECEPTOR ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; Germany ; IN-VIVO ; VIVO ; liver ; GENE ; GENE-EXPRESSION ; DIFFERENTIATION ; ACTIVATION ; CUTTING EDGE ; INFECTION ; INDUCTION ; DENDRITIC CELLS ; T-CELLS ; TOLERANCE ; bone marrow ; BONE-MARROW ; STIMULATION ; MOUSE ; DELIVERY ; CLONAL EXPANSION ; VIRAL-INFECTION ; CROSS-PRESENTATION ; endothelial cells ; EFFECTOR FUNCTION ; RIG-I ; T cell immunity ; HEPATITIS-B VIRUS ; MURINE CYTOMEGALOVIRUS-INFECTION ; TOLEROGENIC DENDRITIC CELLS
    Abstract: BACKGROUND & AIMS: Dendritic cell activation through ligation of pattern recognition receptors leading to full functional maturation causes induction of CD8(+) T-cell immunity through increased delivery of costimulatory signals instead of tolerance. Here we investigate whether organ-resident antigen-presenting cells, such as liver sinusoidal endothelial cells (LSECs), also switch from tolerogenic to immunogenic CD8(+) T-cell activation upon such stimulation. METHODS: Murine LSECs were isolated by immunomagnetic separation and analyzed for functional maturation upon triggering pattern recognition receptors or viral infection employing gene expression analysis and T cell coculture assays. In vivo relevance of the findings was confirmed with bone-marrow chimeric animals. RESULTS: LSECs expressed numerous pattern recognition receptors that allowed for sentinel function, but ligand-induced activation of these receptors was not sufficient to overcome tolerance induction of CD8(+) T cells. Importantly, viral infection with murine cytomegalovirus caused functional maturation of antigen-presenting LSECs and was sufficient to promote antigen-specific differentiation into effector CD8(+) T cells in the absence of dendritic cells and independent of CD80/86. CONCLUSIONS: These results shed new light on the generation of organ-specific immunity and may contribute to overcoming tolerance in relevant situations, such as cancer
    Type of Publication: Journal article published
    PubMed ID: 19737567
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