biostudies-literatureReilly SPNational Institutes of Healtheaea8707https://www.ebi.ac.uk/biostudies/studies/S-EPMC12716397biostudies-literatureUnknown11(51)Nonclassical CD8⁺ T cells can compensate for classical CD8⁺ T cell effector responses during murine cytomegalovirus (MCMV) infection. Through a combination of motif-based discovery, predictive algorithms, AlphaFold3 structural modeling, and biological assays, we identified multiple MCMV and human cytomegalovirus (HCMV) peptides that bind to Qa-1 and HLA-E, respectively. In the mouse system, we demonstrated that these virally encoded antigens stimulate Qa-1-restricted CD8⁺ T cells ex vivo, which can be tracked using MCMV peptide-loaded Qa-1 tetramers. Adoptive transfer of predominantly Qa-1 tetramer⁺ CD8⁺ T cells into RAG-1-deficient mice protects them from mortality, underscoring the critical role of these cells in host defense. SingleScience advancesUnconventional CD8<sup>+</sup> T cell surveillance of cytomegalovirus via Qa-1/HLA-E-restricted epitope recognition.PMC12716397T32HL134625R01AI173163F31DE032593R24AI072073R01AI0467093R01AI046709-19S1Fugere CSmith MLDemers DHogan MJZemmour DBorys SMBrossay LReilly SPfalseUnconventional CD8<sup>+</sup> T cell surveillance of cytomegalovirus via Qa-1/HLA-E-restricted epitope recognition.Nonclassical CD8⁺ T cells can compensate for classical CD8⁺ T cell effector responses during murine cytomegalovirus (MCMV) infection. Through a combination of motif-based discovery, predictive algorithms, AlphaFold3 structural modeling, and biological assays, we identified multiple MCMV and human cytomegalovirus (HCMV) peptides that bind to Qa-1 and HLA-E, respectively. In the mouse system, we demonstrated that these virally encoded antigens stimulate Qa-1-restricted CD8⁺ T cells ex vivo, which can be tracked using MCMV peptide-loaded Qa-1 tetramers. Adoptive transfer of predominantly Qa-1 tetramer⁺ CD8⁺ T cells into RAG-1-deficient mice protects them from mortality, underscoring the critical role of these cells in host defense. Single2025-01-01T00:00:00Z2025 Dec2026-06-08T05:32:44.336Z2026-06-08T03:09:03.32ZS-EPMC127163974141789910.1126/sciadv.aea8707