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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 ; EXPRESSION ; Germany ; MICE ; ACTIVATION ; RESPONSES ; DNA ; INDUCTION ; LYMPH-NODES ; oligonucleotides ; TOLL-LIKE RECEPTORS ; IMMUNE SUPPRESSION ; CATABOLISM ; LYMPH-NODE ; INDOLEAMINE 2,3-DIOXYGENASE ; BACTERIAL-DNA ; EXPANSION ; indoleamine 2,3-dioxygenase (IDO) ; local and systemic immunity ; MURINE DENDRITIC CELLS ; TRYPTOPHAN DEGRADATION
    Abstract: CpG-rich oligonucleotides (CpG-ODN) bind to Toll-like receptor 9 (TLR9) and are used as powerful adjuvants for vaccination. Here we report that CpG-ODN not only act as immune stimulatory agents but can also induce strong immune suppression depending on the anatomical location of application. In agreement with the adjuvant effect, subcutaneous application of antigen plus CpG-ODN resulted in antigen-specific T cell activation in local lymph nodes. In contrast, systemic application of CpG-ODN resulted in suppression of T cell expansion and CTL activity in the spleen. The suppressive effect was mediated by indoleamine 2,3-dioxygenase (IDO) as indicated by the observation that CpG-ODN induced IDO in the spleen and that T cell suppression could be abrogated by 1-methyl-tryptophan (1-MT), an inhibitor of IDO. No expression of IDO was observed in lymph nodes after injection of CpG-ODN, explaining why suppression was restricted to the spleen. Studies with a set of knockout mice demonstrated that the CpG-ODN-induced immune suppression is dependent on TLR9 stimulation and independent of type I and type II interferons. The present study shows that for the use of CpG-ODN as an adjuvant in vaccines, the route of application is crucial and needs to be considered. In addition, the results indicate that down-modulation of immune responses by CpG-ODN may be possible in certain pathological conditions
    Type of Publication: Journal article published
    PubMed ID: 16323249
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  • 3
    Keywords: APOPTOSIS ; CELLS ; ENDOTHELIAL-CELLS ; tumor ; TUMOR-CELLS ; CELL ; Germany ; IN-VIVO ; VIVO ; SYSTEM ; liver ; MICE ; MECHANISM ; INDUCTION ; ANTIGEN ; ANTIGENS ; DENDRITIC CELLS ; T cell ; T cells ; T-CELLS ; TOLERANCE ; BONE-MARROW ; CANCER-CELLS ; NATURAL-KILLER-CELLS ; FRAGMENTS ; FAILURE ; ADAPTIVE IMMUNITY ; TUMOR CELLS ; ELIMINATION ; IMMUNE ESCAPE ; IMMUNE-SYSTEM ; ESCAPE ; CYTOKINE PRODUCTION ; TUMOR-CELL ; KUPFFER CELLS ; in vivo ; FRAGMENT ; CD8(+) T cell ; COLON-CARCINOMA CELLS ; liver sinusoidal endothelial cells ; NKT CELLS ; PERFORIN/GRANZYME PATHWAY ; sinusoidal endothelial cells
    Abstract: Development of tumor-specific T cell tolerance contributes to the failure of the immune system to eliminate tumor cells. Here we report that hematogenous dissemination of tumor cells followed by their elimination and local removal of apoptotic tumor cells in the liver leads to subsequent development of T cell tolerance towards antigens associated with apoptotic tumor cells. We provide evidence that liver sinusoidal. endothelial cells (LSEC) remove apoptotic cell fragments generated by induction of tumor cell apoptosis through hepatic NK1.1(+) cells. Antigen associated with apoptotic cell material is processed and cross-presented by LSEC to CD8(+) T cells, leading to induction of CD8(+) T cell tolerance. Adoptive transfer of LSEC isolated from mice challenged previously with tumor cells promotes development of CD8(+) T cell tolerance towards tumor-associated antigen in vivo. Our results indicate that hematogenous dissemination of tumor cells, followed by hepatic tumor cell elimination and local cross-presentation of apoptotic tumor cells by LSEC and subsequent CD8(+) T cell tolerance induction, represents a novel mechanism operative in tumor immune escape
    Type of Publication: Journal article published
    PubMed ID: 17039564
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