{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:48:58Z","timestamp":1791582538942,"version":"4.3.4"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":16,"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"}],"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                    T cell exhaustion is now recognised as a structured, antigen\u2010driven differentiation programme rather than a state of cellular fatigue. Under sustained antigen exposure, CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells progress through distinct, hierarchically organised differentiation states, initiated by progenitor exhausted cells (T\n                    <jats:sub>PEX<\/jats:sub>\n                    ), which retain self\u2010renewal, multipotency, and responsiveness to immune checkpoint blockade. Continued stimulation drives differentiation into intermediate (T\n                    <jats:sub>EXint<\/jats:sub>\n                    ) and terminally exhausted (T\n                    <jats:sub>EX term<\/jats:sub>\n                    ) states, with T\n                    <jats:sub>EXint<\/jats:sub>\n                    retaining greater effector capacity than T\n                    <jats:sub>EXterm<\/jats:sub>\n                    despite both exhibiting restraint relative to functional effector T cells, alongside increasingly consolidated epigenetic architecture. Rather than reflecting immunological failure, exhaustion preserves long\u2010term antigen surveillance while limiting tissue damage. Convergence between exhaustion\u2010associated transcriptional modules and tissue\u2010resident memory (T\n                    <jats:sub>RM<\/jats:sub>\n                    ) programmes highlights shared mechanisms of adaptation to restrictive microenvironments. Yet T\n                    <jats:sub>RM<\/jats:sub>\n                    and T\n                    <jats:sub>EX<\/jats:sub>\n                    arise in distinct contexts and are not interchangeable. Recognising exhaustion as a context\u2010dependent differentiation process reframes therapeutic strategies, in line with current evidence indicating that immune checkpoint blockade primarily acts by expanding and redirecting the T\n                    <jats:sub>PEX<\/jats:sub>\n                    pool rather than reversing terminal exhaustion. This framework integrates insights from chronic infection, tumour immunology, and tissue adaptation.\n                  <\/jats:p>","DOI":"10.1002\/eji.70205","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T11:21:53Z","timestamp":1781695313000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["T Cell Exhaustion as a Regulated Differentiation Programme"],"prefix":"10.1002","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1478-9562","authenticated-orcid":false,"given":"Marc","family":"Veldhoen","sequence":"first","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine  Lisbon Portugal"},{"name":"Faculdade de Medicina da Universidade de Lisboa  Lisbon Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine  Lisbon 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