Crystal structures of H-2Db in complex with the LCMV-derived peptides GP92 and GP392 explain pleiotropic effects of glycosylation on antigen presentation and immunogenicity

Abstract

Post-translational modifications significantly broaden the epitope repertoire for major histocompatibility class I complexes (MHC-I) and may allow viruses to escape immune recognition. Lymphocytic choriomeningitis virus (LCMV) infection of H-2b mice generates CD8+ CTL responses directed towards several MHC-I-restricted epitopes including the peptides GP92 (CSANNSHHYI) and GP392 (WLVTNGSYL), both with a N-glycosylation site. Interestingly, glycosylation has different effects on the immunogenicity and association capacity of these two epitopes to H-2Db. To assess the structural bases underlying these functional results, we determined the crystal structures of H-2Db in complex with GP92 (CSANNSHHYI) and GP392 (WLVTNGSYL) to 2.4 and 2.5 Å resolution, respectively. The structures reveal that while glycosylation of GP392 most probably impairs binding, the glycosylation of the asparagine residue in GP92, which protrudes towards the solvent, possibly allows for immune escape and/or forms a neo-epitope that may select for a different set of CD8 T cells. Altogether, the presented results provide a structural platform underlying the effects of post-translational modifications on epitope binding and/or immunogenicity, resulting in viral immune escape.

Can Glycosylation Mask the Detection of MHC Expressing p53 Peptides by T Cell Receptors?

“…However, the role of glycosylation remains complex. Glycosylation of epitopes in a virus has been shown to prevent T cell recognition and, hence, immune escape of a virus epitope [56]. On the other hand, GlcNAc modified peptides can create new epitopes and have been shown to elicit glycopeptide specific immune responses in mice [14].…”

Structural aspects of chemical modifications in the MHC-restricted immunopeptidome; Implications for immune recognition

“…As already stated above, all the hitherto described immunopeptidomes include glycosylated peptides ( Mommen et al, 2014 ; Marino et al, 2015 ; Malaker et al, 2017b ). Moreover, T cell responses to MHC-restricted glycoepitopes have been described in tuberculosis ( Harriff et al, 2017 ), for several viruses ( Hafstrand et al, 2017 ; Bagdonaite and Wandall 2018 ), including HIV ( Olvera et al, 2020 ), and in tumors ( Bennun et al, 2013 ; Peixoto et al, 2019 ). Reprograming of cancer cells has a strong impact on their glycosylation system, leading not only to overexpression of common glycoproteins, but also to expression of cancer-specific glycoproteins.…”

“…This is exemplified by the crystal structures of the LCMV epitopes GP92 and GP392 in complex with H-2D b . While glycosylation of the asparagine residue at peptide position 4 in GP92 (5JWE.pdb, in green) may impair TCR recognition, glycosylation of the main anchor asparagine residue at p5 in GP392 (5JWD.pdb, in green) may reduce significantly pMHC stability ( Hafstrand et al, 2017 ).…”

Does Antigen Glycosylation Impact the HIV-Specific T Cell Immunity?

“…Indeed, crystal structure analyses of MHC/glyco-peptide/ TCR complexes indicate that MHC binding is mediated by the peptide backbone, while the glycan moieties interact with the TCR variable sites (17,25,37,38). In a report by Avci et al (39,40), a carbohydrate CD4+ T cell epitope derived from a streptococcal glyco-conjugate was found to significantly increase vaccine-induced T cell responses.…”

“…There are many types of PTM, we will focus herein on the most abundant, glycosylation, and the existence of HIV-specific T cell responses to glycosylated epitopes ("glyco-epitopes"). T cell responses to such glycoepitopes have been described in tumors (10)(11)(12)(13)(14), tuberculosis (15) and other viruses (16)(17)(18), but to our knowledge only in two studies for HIV (19)(20)(21).…”