{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T21:59:15Z","timestamp":1784757555422,"version":"3.55.0"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The cytoplasmic domain of MHC class I (MHC-I) molecules contains a single, highly conserved tyrosine residue (Y320). In previous work, we found that mice expressing a Y320F-mutated form of H-2K<jats:sup>b<\/jats:sup> had reduced capacity to generate K<jats:sup>b<\/jats:sup>-restricted cytotoxic T lymphocyte (CTL) responses following viral infection, due at least in part to defects in endolysosomal trafficking of H-2K<jats:sup>b<\/jats:sup> and antigen cross-presentation by dendritic cells (DCs). In this study, we investigated whether there are additional, post-presentation dependencies on Y320 for T cell priming. We engineered both human- and mouse-derived antigen-presenting cells (APCs) to express either wild-type MHC-I or variants of MHC-I containing Y320F or Y320E mutations. We found that Y320E-mutated HLA-A*0201 elicited enhanced <jats:italic>in vitro<\/jats:italic> priming and expansion of human antigen-specific CD8+ T cells, which showed a unique transcriptional profile compared to T cells primed with APCs expressing either WT or Y320F-mutated A*0201. Furthermore, the Y320E variant of H-2K<jats:sup>b<\/jats:sup> expressed in the context of a murine DC vaccine model induced altered T cell differentiation kinetics while improving both anti-tumor immunity and augmenting the magnitude of memory CD8+ T cell responses <jats:italic>in vivo<\/jats:italic>. These results suggest that Y320 phosphorylation of MHC-I may play a role in determining the fate and function of CD8+ T cells and suggest a novel strategy for improving DC-based cancer immunotherapies.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1572342","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T05:37:41Z","timestamp":1759210661000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Mutation of conserved MHC class I cytoplasmic tyrosine affects CD8+ T cell priming, effector function, and memory response"],"prefix":"10.3389","volume":"16","author":[{"given":"Yimo","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yitao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscilla","family":"Ortiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Nassif Rausseo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Pazdrak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lama","family":"Elzohary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjun","family":"Katailiha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amjad","family":"Talukder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cassian","family":"Yee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard Eric","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Liz\u00e9e","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/ni989","article-title":"Control of dendritic cell cross-presentation by the major histocompatibility complex class I cytoplasmic domain","volume":"4","author":"Lizee","year":"2003","journal-title":"Nat Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2005.01.005","article-title":"Tails of wonder: endocytic-sorting motifs key for exogenous antigen presentation","volume":"26","author":"Lizee","year":"2005","journal-title":"Trends Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1267","article-title":"PhosphoSitePlus, 2014: mutations, PTMs and recalibrations","volume":"43","author":"Hornbeck","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M408794200","article-title":"Misfolding of major histocompatibility complex class I molecules in activated T cells allows cis-interactions with receptors and signaling molecules and is associated with tyrosine phosphorylation","volume":"279","author":"Santos","year":"2004","journal-title":"J Biol Chem"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)47290-5","article-title":"Human and murine class I MHC antigens share conserved serine 335, the site of HLA phosphorylation in vivo","volume":"259","author":"Guild","year":"1984","journal-title":"J Biol Chem"},{"key":"B6","doi-asserted-by":"publisher","first-page":"p","DOI":"10.1042\/bj2560763","article-title":"Phosphorylation of class I histocompatibility antigens in human B lymphocytes. 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