{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T06:29:56Z","timestamp":1786688996478,"version":"build-2736575974"},"reference-count":26,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":24,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100008662","name":"Joachim Herz Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008662","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["885539"],"award-info":[{"award-number":["885539"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The possibility of enhancing T cell function by deleting specific genes represents a long\u2010sought goal in preclinical studies and ultimately for clinical applications. Using CRISPR\/Cas9 genome editing, we report that, in human cytotoxic CD8 T cell clones, the cell cycle checkpoint gene\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    , encoding p16\n                    <jats:sup>INK4A<\/jats:sup>\n                    , plays a nonredundant role in controlling T cell receptor (TCR)\u2010dependent and independent cell expansion. Deletion of\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    dramatically enhanced antigen\u2010driven and homeostatic proliferation, while preserving effector functions. In contrast, the deletion of other cell cycle inhibitors (\n                    <jats:italic>CDKN1B<\/jats:italic>\n                    ,\n                    <jats:italic>CDKN2C<\/jats:italic>\n                    , and\n                    <jats:italic>CDKN2D<\/jats:italic>\n                    ), alone or in combination, had no impact on T cell proliferation. We also report that mediator complex subunit 12 (MED12) and the E3 ubiquitin ligase CBL\u2010B deletions did not affect proliferative capacity of CD8 T cell clones. Interestingly, deletion of the negative regulator of Ras signaling, RASA2, increased antigen sensitivity and cytotoxic activity, while not improving in vitro expansion. Collectively, these findings reveal a unique and critical nonredundant role for p16\n                    <jats:sup>INK4A<\/jats:sup>\n                    in regulating CD8 T cells. Deletion of\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    offers a promising strategy to enhance CD8 T cell expansion ex vivo, thereby improving TCR discovery pipelines and, potentially, therapeutic applications.\n                  <\/jats:p>","DOI":"10.1002\/eji.70224","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T12:17:53Z","timestamp":1782389873000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CRISPR\/Cas9\u2010Mediated Gene Knockout Reveals a Nonredundant Role for p16\n                    <sup>INK4A<\/sup>\n                    in Controlling TCR\u2010Dependent and Independent CD8 T Cell Expansion"],"prefix":"10.1002","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7858-4395","authenticated-orcid":false,"given":"Silvia","family":"Fiori","sequence":"first","affiliation":[{"name":"National Institute of Molecular Genetics  Milan Italy"},{"name":"Department for Clinical Sciences and Community Health (DISCCO) (DoE 2023\u20132027) University of Milan  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2924-6641","authenticated-orcid":false,"given":"Cecilia","family":"Adragna","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics  Milan Italy"},{"name":"Institute for Research in Biomedicine  Bellinzona Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2286-8954","authenticated-orcid":false,"given":"Emilia","family":"Malvicini","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Basini","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0889-0362","authenticated-orcid":false,"given":"Donatella","family":"Galgano","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5886-6929","authenticated-orcid":false,"given":"Edoardo","family":"Scarpa","sequence":"additional","affiliation":[{"name":"National Institute of Molecular Genetics  Milan Italy"},{"name":"Department of Pharmaceutical Sciences University of Milan  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Jovic","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine  Bellinzona Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3998-1139","authenticated-orcid":false,"given":"Niklas A.","family":"Schmacke","sequence":"additional","affiliation":[{"name":"Gene Center and Department of Biochemistry Ludwig\u2010Maximilians\u2010Universit\u00e4t M\u00fcnchen  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4150-194X","authenticated-orcid":false,"given":"Veit","family":"Hornung","sequence":"additional","affiliation":[{"name":"Gene Center and Department of Biochemistry Ludwig\u2010Maximilians\u2010Universit\u00e4t M\u00fcnchen  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3750-2752","authenticated-orcid":false,"given":"Federica","family":"Sallusto","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine  Bellinzona Switzerland"},{"name":"Institute of Microbiology ETH Zurich  Zurich 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