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1.
J Gen Virol ; 92(Pt 7): 1571-1584, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21346027

RESUMEN

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-γ 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.


Asunto(s)
Ectima Contagioso/inmunología , Virus del Orf/inmunología , Proteínas Virales/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Bovinos , Línea Celular , Ectima Contagioso/virología , Femenino , Humanos , Ratones , Virus del Orf/genética , Proteínas Virales/genética
2.
Gastroenterology ; 138(1): 336-46, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19737567

RESUMEN

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.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Infecciones por Herpesviridae/inmunología , Tolerancia Inmunológica/inmunología , Hígado/virología , Muromegalovirus , Traslado Adoptivo , Animales , Médula Ósea , Linfocitos T CD8-positivos/citología , Diferenciación Celular/inmunología , Células Cultivadas , Quimera , Células Endoteliales/citología , Células Endoteliales/virología , Ligandos , Hígado/citología , Hígado/inmunología , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Especificidad de Órganos , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/inmunología , Receptores de Reconocimiento de Patrones/metabolismo
3.
Eur J Immunol ; 38(4): 957-67, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18383043

RESUMEN

The liver is known to induce tolerance rather than immunity through tolerogenic antigen presentation or elimination of effector T cells. In particular, hepatic dendritic cells (DC) are known to be little immunogenic for CD8 T cells. Here, we investigated whether this peculiar phenotype resulted from interaction with resident hepatic cell populations. Contact of DC with liver sinusoidal endothelial cells (LSEC) but not hepatocytes or B cells vetoed antigen-presenting DC to fully activate naive CD8 T cells. This MHC-independent regulatory effect of LSEC on DC function was not connected to soluble mediators but required physical contact. Because interaction with third-party LSEC still allowed antigen-presenting DC to stimulate expression of initial activation markers on naive CD8 T cells and to stimulate activated CD8 T cells, we hypothesize that LSEC controlled the DC costimulatory function. Indeed, contact with LSEC led to reduced DC expression levels of CD80/86 or IL-12, but supplementation of these signals failed to rescue the ability to prime naive CD8 T cells, indicating involvement of further molecules. Taken together, our results reveal a novel principle operative in hepatic tolerance induction, in which LSEC not only tolerize T cells themselves but also suppress neighboring APC normally capable of inducing T cell immunity.


Asunto(s)
Presentación de Antígeno/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Células Endoteliales/inmunología , Hígado/irrigación sanguínea , Hígado/inmunología , Activación de Linfocitos/inmunología , Animales , Linfocitos T CD8-positivos/citología , Comunicación Celular/inmunología , Proliferación Celular , Células Cultivadas , Técnicas de Cocultivo , Inmunidad Innata/inmunología , Ratones , Sensibilidad y Especificidad
4.
Eur J Immunol ; 35(10): 2970-81, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16163670

RESUMEN

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.


Asunto(s)
Antígenos/inmunología , Linfocitos T CD8-positivos/inmunología , Reactividad Cruzada/inmunología , Células Endoteliales/inmunología , Tolerancia Inmunológica/inmunología , Traslado Adoptivo , Animales , Presentación de Antígeno/inmunología , Hígado/citología , Ratones , Ratones Noqueados
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