Altadill, MireiaÁlvarez, IñakiAtaya Fernández, Michelle, 1993-Heredia, GemmaAlari-Pahissa, ElisendaMuntasell i Castellví, Aura, 1972-Llano, ManuelFuchs, JonasVilches, CarlosHengel, HartmutHalenius, AnneLópez-Botet, M. (Miguel)2025-06-102025-06-102025Altadill M, Álvarez I, Ataya M, Heredia G, Alari-Pahissa E, Muntasell A, et al. Human cytomegalovirus antigen presentation by HLA-G in infected cells. HLA. 2025 May;105(5):e70089. DOI: 10.1111/tan.700892059-2302http://hdl.handle.net/10230/70643HLA-E and -G class Ib molecules were considered unrelated to viral antigen presentation. HLA-E binds nonamers from the leader sequences of other HLA-I molecules and the human cytomegalovirus (HCMV) UL40 protein, interacting with CD94/NKG2 NK cell receptors. Yet, evidence that HLA-E may present some pathogen-derived peptides to CD8+ T lymphocytes has been reported. By contrast, HLA-G binds a broad spectrum of endogenous sequences but its role in antigen presentation is unknown. An experimental approach was set up to search for HCMV antigens displayed by HLA-G in infected cells. Among the analysed peptidome, 22 sequences corresponding to 16 HCMV molecules were identified; 17 peptides were confirmed to interact in vitro with HLA-G of which 10 displayed characteristic anchor residues. As compared to the response in short-term (6 h) assays to immunodominant IE-1 and pp65 antigens, none of the HLA-G-binding peptides stimulated cytokine production by CD8+ T cells from HCMV-seropositive blood donors (n = 15). Following a 14-day peptide stimulation of PBMC and expansion with IL-2, CD8+ T cells specifically responding to a subset of these viral antigens were detected in some individuals, yet were not restricted by HLA-G in functional assays. A subset of viral peptides did bind to both HLA-G and -E but were not recognised by CD94/NKG2 NK cell receptors. Our results provide the first evidence that HLA-G may display potentially immunogenic viral peptides in HCMV-infected cells, yet do not support their ability to promote HLA-G-restricted CD8+ T cell responses nor to modulate NK cell functions.application/pdfeng© 2025 The Author(s). HLA: Immune Response Genetics published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1111/tan.70089HLA‐EHLA‐GNK cellT lymphocyteCytomegalovirusinfo:eu-repo/semantics/openAccess