Neue Mechanismen der Immunintervention durch das Hepatitis C-Virus Core-Protein
Auch gedruckt in der BibliothekZ: J-H 11.882; W: W-H 11.370
Ressourcen- / MedientypDissertation, Text
Datum der Freischaltung2008-06-20
To characterize the effects of the Hepatitis C virus (HCV) core protein (HCVc) on innate and adaptive immune responses the impact of HCVc on the acute phase response (APR) and on priming of antigen-specific T cell responses was investigated. The lipopolysaccharide (LPS)-induced APR was analyzed in C57BL/6 wild type mice and HCV transgenic mice that express HCVc in the liver. Livers but not spleens of transgenic mice showed reduced activation of the transcription factors Nuclear Factor kappa-B (NFkappaB) and Interferon Stimulated Gene Factor 3 (ISGF3) and reduced expression of interleukin (IL)-6, IL-10 and interferon (IFN)-gamma mRNAs. In these mice serum concentrations of IL-6, IFN-gamma and the type II acute phase protein (APP) fibrinogen were decreased. Expression of Tumor Necrosis Factor (TNF)-alpha mRNA and serum concentrations of IL-10, TNF-alpha and the type I APP Serum Amyloid A were comparable to controls. In conclusion, liver-specific expression of HCVc caused significant disturbance of the APR. Priming of antigen-specific T cell responses by myeloid dendritic cells (mDC) and hepatocytes was investigated using the OT-I and OT-II systems. HCVc, either in the culture medium or expressed by antigen-presenting cells (APCs), led to decreased activation, reduced production of IFN-gamma and IL-2 and reduced proliferation of CD4+ and CD8+ T cells. Furthermore, more T cells produced IL-10. APCs expressed reduced levels of MHC molecules as well as CD80, CD86 and Programmed Death Ligand 1 (PD-L1) regarding mDC. Also, mDC secreted less IL-6 and IL-12 in the presence of HCVc. Modulated T cell activation did not depend on binding of HCVc to Toll-like Receptor 2 (TLR2) on mDC or C1q receptor on T cells. The induction of IL-10 in CD4+ and CD8+ T cells suggests that HCVc cannot only suppress T cell responses but facilitate the development of regulatory T cells. As a potential mechanism for modified T cell activation phenotypic alteration of APCs could be identified.
LizenzStandard (Fassung vom 03.05.2003)
MHC Klasse I
MHC Klasse II