{"id":67802,"date":"2026-06-18T10:35:32","date_gmt":"2026-06-18T08:35:32","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2026\/06\/18\/t-cell-exhaustion-as-a-regulated-differentiation-programme-valuemarc-veldhoen-cristina-ferreira\/"},"modified":"2026-06-18T10:35:32","modified_gmt":"2026-06-18T08:35:32","slug":"t-cell-exhaustion-as-a-regulated-differentiation-programme-valuemarc-veldhoen-cristina-ferreira","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2026\/06\/18\/t-cell-exhaustion-as-a-regulated-differentiation-programme-valuemarc-veldhoen-cristina-ferreira\/","title":{"rendered":"T Cell Exhaustion as a Regulated Differentiation Programme. [[{&#8220;value&#8221;:&#8221;Marc Veldhoen, \nCristina Ferreira&#8221;}]]"},"content":{"rendered":"<p><img decoding=\"async\" src=\"https:\/\/onlinelibrary.wiley.com\/cms\/asset\/8be2db73-0e6d-4f26-90a5-91ce09fd5e70\/eji70205-gra-0001-m.png\" alt=\"T Cell Exhaustion as a Regulated Differentiation Programme\" \/><\/p>\n<p>This review highlights T cell exhaustion as an adaptive differentiation trajectory, not dysfunction, showing how precursor, intermediate, and terminal exhausted states maintain antigen recognition while limiting tissue damage in chronic immune activation.<\/p>\n<p><\/p>\n<h2>ABSTRACT<\/h2>\n<p>T cell exhaustion is now recognised as a structured, antigen-driven differentiation programme rather than a state of cellular fatigue. Under sustained antigen exposure, CD8<sup>+<\/sup> T cells progress through distinct, hierarchically organised differentiation states, initiated by progenitor exhausted cells (T<sub>PEX<\/sub>), which retain self-renewal, multipotency, and responsiveness to immune checkpoint blockade. Continued stimulation drives differentiation into intermediate (T<sub>EXint<\/sub>) and terminally exhausted (T<sub>EX term<\/sub>) states, with T<sub>EXint<\/sub> retaining greater effector capacity than T<sub>EXterm<\/sub> despite both exhibiting restraint relative to functional effector T cells, alongside increasingly consolidated epigenetic architecture. Rather than reflecting immunological failure, exhaustion preserves long-term antigen surveillance while limiting tissue damage. Convergence between exhaustion-associated transcriptional modules and tissue-resident memory (T<sub>RM<\/sub>) programmes highlights shared mechanisms of adaptation to restrictive microenvironments. Yet T<sub>RM<\/sub> and T<sub>EX<\/sub> arise in distinct contexts and are not interchangeable. Recognising exhaustion as a context-dependent differentiation process reframes therapeutic strategies, in line with current evidence indicating that immune checkpoint blockade primarily acts by expanding and redirecting the T<sub>PEX<\/sub> pool rather than reversing terminal exhaustion. This framework integrates insights from chronic infection, tumour immunology, and tissue adaptation.<\/p>","protected":false},"excerpt":{"rendered":"<p>This review highlights T cell exhaustion as an adaptive differentiation trajectory, not dysfunction, showing how precursor, intermediate, and terminal exhausted states maintain antigen recognition while limiting tissue damage in chronic immune activation. ABSTRACT T cell exhaustion is now recognised as a structured, antigen-driven differentiation programme rather than a state of cellular fatigue. Under sustained antigen &#8230; <a title=\"T Cell Exhaustion as a Regulated Differentiation Programme. [[{&#8220;value&#8221;:&#8221;Marc Veldhoen, \nCristina Ferreira&#8221;}]]\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2026\/06\/18\/t-cell-exhaustion-as-a-regulated-differentiation-programme-valuemarc-veldhoen-cristina-ferreira\/\" aria-label=\"Read more about T Cell Exhaustion as a Regulated Differentiation Programme. [[{&#8220;value&#8221;:&#8221;Marc Veldhoen, \nCristina Ferreira&#8221;}]]\">Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[112,42],"tags":[],"class_list":["post-67802","post","type-post","status-publish","format-standard","hentry","category-european-journal-of-immunology","category-publicaciones"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/67802","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=67802"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/67802\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=67802"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=67802"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=67802"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}