Modulation of MHC class I antigen presentation by the adenovirus E3-19K protein.

摘要

CTL-mediated immunity is one important mechanism the immune system has adapted to cope with viral infections. The MHC class I antigen presentation pathway is central to CTL-mediated immunity. The E3-19K protein from human adenoviruses (Ads) retains MHC class I molecules in the endoplasmic reticulum (ER). As a consequence, the cell surface expression of class I molecules is suppressed, allowing Ads to evade immune surveillance. In this study, the ER-lumenal domain of the Ad2 E3-19K of subgroup C was characterized biochemically and structurally. We found that a delicate structural interplay between the variable and conserved regions is required for E3-19K to associate with MHC class I molecules. The recombinant Ad2 E3-19K comprising the N-terminal 1-93 residues associates with high-affinity to HLA-A*1101. Tyr93 in the conserved region of Ad2 E3-19K is critical for this interaction.;Ad2 E3-19K associates with MHC class I molecules in an allele- and locus- specific manner. Among the alleles of the HLA-A locus examined, HLA-A*3101 associates less avidly with E3-19K. E3-19K associates with HLA-A and -B molecules, and no interaction with HLA-C molecules could be detected. We also show that Ad37 E3-19K of subgroup D displays weaker affinities for class I molecules relative to Ad2 E3-19K but retains the same locus specificity. Overall, our data imply that a link may exist between host genetic factors and the susceptibility of individuals to Ad infections.;We demonstrated that MHC residues 56 and 177 are critical for modulating interactions with E3-19K. These two residues are positioned on opposite alpha-helices at the N-terminal end of the peptide-binding groove. We propose a model of interaction in which E3-19K "cap" the N-terminal end of the class I groove by interacting with MHC residues 56 and 177.;To determine the high-resolution structure of E3-19K/class I complex, we construct a homogeneously glycosylated form and a fully deglycosylated form of Ad2 E3-19K protein. These proteins may be good candidates for the crystallization of E3-19K/class I complex.;In conclusion, this study has greatly enriched our knowledge about the molecular basis of the immunomodulatory function of E3-19K, this knowledge is relevant for better understanding of Ad persistent infections.