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-c 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.
SummarySince the identi®cation of the ®rst plant MYB-like protein, the Zea mays factor C1, the number of MYBrelated genes described has greatly increased. All of the more than 150 plant MYB-like proteins known so far contain either two or only one sequence-related helix-turn-helix motif in their DNA-binding domain. Animal c-MYB genes contain three such helix-turn-helix motif-encoding repeats (R1R2R3 class genes). It has therefore been concluded that R2R3-MYB genes are the plant equivalents of c-MYB and that there are signi®cant differences in the basic structure of MYB genes of plants and animals. Here, we describe expressed R1R2R3-MYB genes from Physcomitrella patens and Arabidopsis thaliana, designated PpMYB3R-1 and AtMYB3R-1. The amino acid sequences of their DNA-binding domains show high similarity to those of animal MYB factors, and less similarity to R2R3-MYB proteins from plants. In addition, R1R2R3-MYB genes were identi®ed in different plant evolutionary lineages including mosses, ferns and monocots. Our data show that a DNA-binding domain consisting of three MYB repeats existed before the divergence of the animal and plant lineages. R1R2R3-MYB genes may have a conserved function in eukaryotes, and R2R3-MYB genes may predominantly regulate plant-speci®c processes which evolved during plant speciation.
Inactivated orf virus (ORFV, parapoxvirus ovis) induces antiviral activity in animal models of acute and chronic viral infections and exerts strong effects on human immune cells. ORFV activates antigen presenting cells (APC) via CD14 and, probably, Toll-like receptor signalling, and triggers the release of IFN-c that has been identified as the key mediator of the antiviral activity. After delineating virus proteins as being the most likely active constituent, we aimed to characterize the ORFV proteins responsible for the therapeutic effect. By using a vaccinia virus/ORFV expression library we identified several multi-gene DNA fragments with strong immunomodulatory activity. Together these fragments contain 27 ORFs. The encoded proteins are related to virion structure and transcription but are otherwise unrelated. Two proteins were separately expressed and purified, and demonstrated immunostimulatory activity. Gene expression profiles induced by ORFV and the identified fragments were investigated by microarray analysis. Interestingly, all active fragments induced a similar gene-expression pattern, differing only in quantitative aspects. Obviously, several proteins of ORFV activate similar cellular pathways, modulating APC to generate a strong T-helper 1-dominated immune response. This was balanced by additional induction of immune dampening mechanisms, suggesting regulatory differences compared to single cytokine therapies. We conclude that ORFV may have the potential to enrich the armamentarium of antiviral therapies.
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