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To determine whether HCMV encodes additional, nonconserved inhibitors of unconventional T cell priming, we inserted 41 HCMV-specific ORFs into a chemokine-deficient strain (68-1 RhCMV). Monitoring of epitope recognition revealed that HCMV UL18 prevented unconventional T cell priming, resulting in MHC-Ia\u2013targeted responses. UL18 is homologous to MHC-I but does not engage T cell receptors and, instead, binds with high affinity to inhibitory leukocyte immunoglobulin-like receptor\u20131 (LIR-1). UL18 lacking LIR-1 binding no longer interfered with MHC-E\u2013restricted T cell stimulation by RhCMV-infected cells or the induction of unconventionally restricted T cells. Thus, LIR-1 binding needs to be deleted from UL18 of HCMV\/HIV vaccines to allow for the induction of protective MHC-E\u2013restricted T cells.\n                  <\/jats:p>","DOI":"10.1126\/sciimmunol.adp5216","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T13:58:29Z","timestamp":1728655109000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":10,"title":["Human cytomegalovirus UL18 prevents priming of MHC-E\u2013 and MHC-II\u2013restricted CD8\n                    <sup>+<\/sup>\n                    T cells"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1287-7283","authenticated-orcid":true,"given":"Daniel","family":"Malouli","sequence":"first","affiliation":[{"name":"Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health &amp; Science University, Beaverton, OR, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Husam","family":"Taher","sequence":"additional","affiliation":[{"name":"Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health &amp; 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