{"id":72508,"date":"2026-08-08T00:49:34","date_gmt":"2026-08-07T22:49:34","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2026\/08\/08\/enforcing-mtorc1-activity-in-therapeutic-cd4-t-cells-promotes-persistence-but-eventual-immune-exhaustion\/"},"modified":"2026-08-08T00:49:34","modified_gmt":"2026-08-07T22:49:34","slug":"enforcing-mtorc1-activity-in-therapeutic-cd4-t-cells-promotes-persistence-but-eventual-immune-exhaustion","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2026\/08\/08\/enforcing-mtorc1-activity-in-therapeutic-cd4-t-cells-promotes-persistence-but-eventual-immune-exhaustion\/","title":{"rendered":"Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion"},"content":{"rendered":"<div>\n<p><b>J Immunol<\/b>. 2026 Aug 4;215(8):vkag206. doi: 10.1093\/jimmun\/vkag206.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>There is substantial interest in developing novel engineering strategies to promote the sustained metabolic fitness of therapeutic T cells. We previously showed that overexpression of RAS homologue enriched in brain (RHEB), a positive regulator of mammalian target of rapamycin complex 1 (mTORC1), promotes aerobic glycolysis and increases the anti-tumor functions of effector CD8+ T cells. To address whether these effects are conserved in CD4+ T cells, we have now examined how enforced activation of mTORC1 activity affects CD4+ T cell differentiation and function. Rheb overexpression induced a more balanced metabolic shift in CD4+ T cells than in CD8+ T cells, with increases in both oxidative phosphorylation and aerobic glycolysis. Although Rheb overexpression initially increased CD4+ T cell activation and proliferation in vitro, the underlying population architecture was complex, involving a shift to both more proliferative, cytotoxic-like cell states as well as more quiescent cell clusters characterised by counter-regulation of mTORC1 activity. Following adoptive transfer, tumor antigen-specific Rheb-transduced CD4+ T cells showed greater persistence but were less efficient than controls in eliminating tumor. This functional deficiency could be explained by a greater propensity of persisting Rheb-transduced CD4+ T cells to develop features of immune exhaustion, as evidenced by expression of multiple co-inhibitory receptors and impaired proliferation upon tumor rechallenge. Together, these data demonstrate the dynamic population response to tuning of T cell mTORC1 and the need to separately appraise cellular outputs of therapeutic CD4+ versus CD8+ T cells when metabolic pathways are manipulated by the same method.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/42566506\/?utm_source=SimplePie&amp;utm_medium=rss&amp;utm_content=2985117R&amp;ff=20260807184933&amp;v=2.20.1\">42566506<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1093\/jimmun\/vkag206\">10.1093\/jimmun\/vkag206<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>J Immunol. 2026 Aug 4;215(8):vkag206. doi: 10.1093\/jimmun\/vkag206. ABSTRACT There is substantial interest in developing novel engineering strategies to promote the sustained metabolic fitness of therapeutic T cells. We previously showed that overexpression of RAS homologue enriched in brain (RHEB), a positive regulator of mammalian target of rapamycin complex 1 (mTORC1), promotes aerobic glycolysis and increases &#8230; <a title=\"Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2026\/08\/08\/enforcing-mtorc1-activity-in-therapeutic-cd4-t-cells-promotes-persistence-but-eventual-immune-exhaustion\/\" aria-label=\"Read more about Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion\">Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[42,71],"tags":[],"class_list":["post-72508","post","type-post","status-publish","format-standard","hentry","category-publicaciones","category-the-journal-of-immunology"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/72508","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=72508"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/72508\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=72508"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=72508"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=72508"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}