T-cell mediated control of Epstein-Barr virus infection : viral mechanisms of immune escape

Detta är en avhandling från Stockholm : Karolinska Institutet, Microbiology and Tumor Biology Center (MTC)

Sammanfattning: Mechanisms regulating the immunogenicity of Epstein-Barr Virus (EBV)-encoded CTL peptide epitopes and their contribution to the escape of virus infected cells from CTL-mediated immunosurveillance were the subject of these studies. It was demonstrated that two HLA A11-restricted CTL epitopes of EBV nuclear antigen (EBNA)-4 (designated IVT and AVF) possessed different immunogenicity that appeared to be due to a rapid surface turnover of All molecules containing the AVF peptide. This difference in persistence of IVT and AVF-containing complexes is likely to determine the representation of individual class I-restricted CTL epitopes within the cell surface pool of molecules and may be an important factor contributing to their immunogenicity. EBV isolates from human populations with a high frequency of HLA A11 evade recognition by CTLs specific for the IVT epitope. The epitope variants containing the substitutions in the anchor residues were able to bind to HLA A11 but formed complexes of significantly lower stability in comparison to the immunogenic epitope. In spite of the efficient production by endogenous processing and efficient association with All-molecules these complexes failed to accumulate at the cell surface, which suggests that complexes containing the non-immunogenic epitope variants are formed but are then destroyed intracellulary. Thus, a specialised sorting mechanism seems to contribute to shaping the repertoire of peptides presented to T-lymphocytes. EBV infected B-lymphocytes persist for life in healthy virus carriers. These infected cells express the EBV encoded nuclear antigen (EBNA)l but down-regulate other highly immunogenic viral products. We have shown that the glycine-alanine domain of EBNA1 generate a cis-acting inhibitory signal which interferes with antigen processing and MHC class I restricted presentation. In vitro processing assays suggest that the repeat may affect MHC class I-restricted responses by inhibiting antigen processing via the ubiquitin/ proteasome pathway. Presense of the Gly-Ala repeat was also shown to prolong half-life of EBNAl in vivo.

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