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Adv."],"published-print":{"date-parts":[[2025,12,19]]},"abstract":"<jats:p>\n                    Nonclassical CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells can compensate for classical CD8\n                    <jats:sup>+<\/jats:sup>\n                    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\u2013restricted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells ex vivo, which can be tracked using MCMV peptide\u2013loaded Qa-1 tetramers. Adoptive transfer of predominantly Qa-1 tetramer\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells into RAG-1\u2013deficient mice protects them from mortality, underscoring the critical role of these cells in host defense. Single-cell RNA (scRNA)\/TotalSeq and single-cell T cell receptor sequencing (scTCR-seq) reveal the expansion of unique TCR \u03b1\u03b2 clonotypes, indicating convergent antigen specificity. Together, our findings uncover a conserved and functionally important nonclassical CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell axis mediated by Qa-1\/HLA-E modulating adaptive immunity independent of classical major histocompatibility complex class I (MHC-I) pathways and present previously unidentified opportunities for vaccine development.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aea8707","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T18:58:22Z","timestamp":1766170702000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Unconventional CD8\n                    <sup>+<\/sup>\n                    T cell surveillance of cytomegalovirus via Qa-1\/HLA-E\u2013restricted epitope recognition"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9465-706X","authenticated-orcid":true,"given":"Shanelle P.","family":"Reilly","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02906, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4651-4777","authenticated-orcid":true,"given":"Madison L.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02906, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4960-131X","authenticated-orcid":true,"given":"Samantha M.","family":"Borys","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02906, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Fug\u00e8re","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02906, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia","family":"Demers","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02906, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6244-2993","authenticated-orcid":true,"given":"Michael J.","family":"Hogan","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0990-217X","authenticated-orcid":true,"given":"David","family":"Zemmour","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Chicago, Chicago, IL 60637, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7497-8488","authenticated-orcid":true,"given":"Laurent","family":"Brossay","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02906, 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