{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:56:14Z","timestamp":1786125374153,"version":"build-2736575974"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":6,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C34276\/A11995"],"award-info":[{"award-number":["C34276\/A11995"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P019072\/1"],"award-info":[{"award-number":["MR\/P019072\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/S000135\/2"],"award-info":[{"award-number":["MR\/S000135\/2"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats: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.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag206","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:54:31Z","timestamp":1786121671000},"source":"Crossref","is-referenced-by-count":0,"title":["Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion"],"prefix":"10.1093","volume":"215","author":[{"given":"Francesca","family":"Sillito","sequence":"first","affiliation":[{"name":"Cancer Institute, University College London , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Armbrecht","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford , Oxford,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aideen T","family":"O\u2019Neill","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford , Oxford,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"McIntyre","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford , Oxford,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melville","family":"Nyatondo","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford , Oxford,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Holler","sequence":"additional","affiliation":[{"name":"Institute of Immunity and Transplantation, University College London , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren A","family":"Callender","sequence":"additional","affiliation":[{"name":"Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sian M","family":"Henson","sequence":"additional","affiliation":[{"name":"Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Stauss","sequence":"additional","affiliation":[{"name":"Institute of Immunity and Transplantation, University College London , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2301-2664","authenticated-orcid":false,"given":"Ronjon","family":"Chakraverty","sequence":"additional","affiliation":[{"name":"Weatherall Institute of Molecular Medicine, University of Oxford , Oxford,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"2026080712542814500_vkag206-B1","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/s41577-020-0306-5","article-title":"A guide to cancer immunotherapy: from T cell basic science to clinical practice","volume":"20","author":"Waldman","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"2026080712542814500_vkag206-B2","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.chembiol.2024.02.001","article-title":"Metabolic rewiring and communication in cancer immunity","volume":"31","author":"Chapman","year":"2024","journal-title":"Cell Chem Biol"},{"key":"2026080712542814500_vkag206-B3","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/s42255-024-00976-2","article-title":"Metabolic engineering for optimized CAR-T cell therapy","volume":"6","author":"McPhedran","year":"2024","journal-title":"Nat Metab"},{"key":"2026080712542814500_vkag206-B4","doi-asserted-by":"crossref","first-page":"596","DOI":"10.3390\/cancers13040596","article-title":"CD4+ T cells: multitasking cells in the duty of cancer immunotherapy","volume":"13","author":"Richardson","year":"2021","journal-title":"Cancers"},{"key":"2026080712542814500_vkag206-B5","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/s43018-023-00521-2","article-title":"CD4(+) T cells in cancer","volume":"4","author":"Speiser","year":"2023","journal-title":"Nat Cancer"},{"key":"2026080712542814500_vkag206-B6","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/s41586-021-04390-6","article-title":"Decade-long leukaemia remissions with persistence of CD4(+) CAR T cells","volume":"602","author":"Melenhorst","year":"2022","journal-title":"Nature"},{"key":"2026080712542814500_vkag206-B7","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/s41586-024-07762-w","article-title":"Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission","volume":"634","author":"Bai","year":"2024","journal-title":"Nature"},{"key":"2026080712542814500_vkag206-B8","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S0140-6736(20)31366-0","article-title":"Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study","volume":"396","author":"Abramson","year":"2020","journal-title":"Lancet"},{"key":"2026080712542814500_vkag206-B9","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1146\/annurev-immunol-042617-053019","article-title":"Unraveling the complex interplay between T cell metabolism and function","volume":"36","author":"Geltink","year":"2018","journal-title":"Annu Rev Immunol"},{"key":"2026080712542814500_vkag206-B10","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1016\/j.immuni.2025.06.010","article-title":"More TOR: The expanding role of mTOR in regulating immune responses","volume":"58","author":"Patel","year":"2025","journal-title":"Immunity"},{"key":"2026080712542814500_vkag206-B11","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1038\/s41590-019-0495-x","article-title":"Quantitative analysis of T cell proteomes and environmental sensors during T cell differentiation","volume":"20","author":"Howden","year":"2019","journal-title":"Nat Immunol"},{"key":"2026080712542814500_vkag206-B12","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.cmet.2018.08.009","article-title":"The translational machinery of human CD4(+) T cells is poised for activation and controls the switch from quiescence to metabolic remodeling","volume":"28","author":"Ricciardi","year":"2018","journal-title":"Cell Metab"},{"key":"2026080712542814500_vkag206-B13","doi-asserted-by":"crossref","first-page":"eadi8753","DOI":"10.1126\/scisignal.adi8753","article-title":"Reciprocal regulation of mTORC1 signaling and ribosomal biosynthesis determines cell cycle progression in activated T cells","volume":"17","author":"Rosenlehner","year":"2024","journal-title":"Sci Signal"},{"key":"2026080712542814500_vkag206-B14","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.immuni.2009.04.014","article-title":"The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment","volume":"30","author":"Delgoffe","year":"2009","journal-title":"Immunity"},{"key":"2026080712542814500_vkag206-B15","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/ni.2005","article-title":"The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2","volume":"12","author":"Delgoffe","year":"2011","journal-title":"Nat Immunol"},{"key":"2026080712542814500_vkag206-B16","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41586-018-0806-7","article-title":"Metabolic heterogeneity underlies reciprocal fates of T(H)17 cell stemness and plasticity","volume":"565","author":"Karmaus","year":"2019","journal-title":"Nature"},{"key":"2026080712542814500_vkag206-B17","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/nature12297","article-title":"mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function","volume":"499","author":"Zeng","year":"2013","journal-title":"Nature"},{"key":"2026080712542814500_vkag206-B18","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/s41568-018-0074-8","article-title":"mTOR signalling and cellular metabolism are mutual determinants in cancer","volume":"18","author":"Mossmann","year":"2018","journal-title":"Nat Rev Cancer"},{"key":"2026080712542814500_vkag206-B19","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1158\/0008-5472.CAN-14-3283","article-title":"Genetic regulation of fate decisions in therapeutic T cells to enhance tumor protection and memory formation","volume":"75","author":"Velica","year":"2015","journal-title":"Cancer Res"},{"key":"2026080712542814500_vkag206-B20","doi-asserted-by":"crossref","first-page":"14858","DOI":"10.1073\/pnas.1404264111","article-title":"Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs","volume":"111","author":"Shrestha","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026080712542814500_vkag206-B21","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nature08155","article-title":"mTOR regulates memory CD8 T-cell differentiation","volume":"460","author":"Araki","year":"2009","journal-title":"Nature"},{"key":"2026080712542814500_vkag206-B22","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/ni.3438","article-title":"Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation","volume":"17","author":"Pollizzi","year":"2016","journal-title":"Nat Immunol"},{"key":"2026080712542814500_vkag206-B23","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nature17442","article-title":"Metabolic maintenance of cell asymmetry following division in activated T lymphocytes","volume":"532","author":"Verbist","year":"2016","journal-title":"Nature"},{"key":"2026080712542814500_vkag206-B24","doi-asserted-by":"crossref","first-page":"e160025","DOI":"10.1172\/JCI160025","article-title":"mTOR regulates T cell exhaustion and PD-1-targeted immunotherapy response during chronic viral infection","volume":"133","author":"Ando","year":"2023","journal-title":"J Clin Invest"},{"key":"2026080712542814500_vkag206-B25","doi-asserted-by":"crossref","first-page":"6858","DOI":"10.1038\/s41467-023-42634-3","article-title":"Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1alpha-mediated glycolytic reprogramming","volume":"14","author":"Wu","year":"2023","journal-title":"Nat Commun"},{"key":"2026080712542814500_vkag206-B26","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1182\/blood-2007-11-120998","article-title":"Tumor-specific Th17-polarized cells eradicate large established melanoma","volume":"112","author":"Muranski","year":"2008","journal-title":"Blood"},{"key":"2026080712542814500_vkag206-B27","doi-asserted-by":"crossref","first-page":"3796","DOI":"10.1016\/j.csbj.2021.06.043","article-title":"UCell: robust and scalable single-cell gene signature scoring","volume":"19","author":"Andreatta","year":"2021","journal-title":"Comput Struct Biotechnol J"},{"key":"2026080712542814500_vkag206-B28","doi-asserted-by":"crossref","first-page":"e13067","DOI":"10.1111\/acel.13067","article-title":"Mitochondrial mass governs the extent of human T cell senescence","volume":"19","author":"Callender","year":"2020","journal-title":"Aging Cell"},{"key":"2026080712542814500_vkag206-B29","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/978-1-4939-3801-8_20","article-title":"Metabolomics analyses of cancer cells in controlled microenvironments","volume":"1458","author":"Gravel","year":"2016","journal-title":"Methods Mol Biol"},{"key":"2026080712542814500_vkag206-B30","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1101\/gad.995802","article-title":"Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1\/eIF4E","volume":"16","author":"Fingar","year":"2002","journal-title":"Genes Dev"},{"key":"2026080712542814500_vkag206-B31","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.it.2014.12.005","article-title":"Fatty acid metabolism in the regulation of T cell function","volume":"36","author":"Lochner","year":"2015","journal-title":"Trends Immunol"},{"key":"2026080712542814500_vkag206-B32","doi-asserted-by":"crossref","first-page":"762","DOI":"10.3390\/cells10040762","article-title":"The metabolic fates of pyruvate in normal and neoplastic cells","volume":"10","author":"Prochownik","year":"2021","journal-title":"Cells"},{"key":"2026080712542814500_vkag206-B33","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1093\/bib\/bbv090","article-title":"Transcriptomic and metabolomic data integration","volume":"17","author":"Cavill","year":"2016","journal-title":"Brief Bioinform"},{"key":"2026080712542814500_vkag206-B34","doi-asserted-by":"crossref","first-page":"4168","DOI":"10.1016\/j.cell.2021.05.045","article-title":"Metabolic modeling of single Th17 cells reveals regulators of autoimmunity","volume":"184","author":"Wagner","year":"2021","journal-title":"Cell"},{"key":"2026080712542814500_vkag206-B35","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1084\/jem.20091918","article-title":"Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts","volume":"207","author":"Quezada","year":"2010","journal-title":"J Exp Med"},{"key":"2026080712542814500_vkag206-B36","doi-asserted-by":"crossref","first-page":"5165","DOI":"10.1172\/JCI69751","article-title":"TSC1 regulates the balance between effector and regulatory T cells","volume":"123","author":"Park","year":"2013","journal-title":"J Clin Invest"},{"key":"2026080712542814500_vkag206-B37","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1038\/ni.2068","article-title":"The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function","volume":"12","author":"Yang","year":"2011","journal-title":"Nat Immunol"},{"key":"2026080712542814500_vkag206-B38","doi-asserted-by":"crossref","first-page":"eabg0791","DOI":"10.1126\/sciimmunol.abg0791","article-title":"Activation of mTORC1 at late endosomes misdirects T cell fate decision in older individuals","volume":"6","author":"Jin","year":"2021","journal-title":"Sci Immunol"},{"key":"2026080712542814500_vkag206-B39","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.semcdb.2023.01.008","article-title":"Epigenetics in T-cell driven inflammation and cancer","volume":"154","author":"Falkowski","year":"2024","journal-title":"Semin Cell Dev Biol"},{"key":"2026080712542814500_vkag206-B40","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.it.2023.02.006","article-title":"Exhausted CD8(+) T cells face a developmental fork in the road","volume":"44","author":"Zander","year":"2023","journal-title":"Trends Immunol"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/215\/8\/vkag206\/70531718\/vkag206.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/215\/8\/vkag206\/70531718\/vkag206.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:54:36Z","timestamp":1786121676000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/doi\/10.1093\/jimmun\/vkag206\/8754166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":40,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8,4]]}},"URL":"https:\/\/doi.org\/10.1093\/jimmun\/vkag206","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,8]]},"published":{"date-parts":[[2026,8]]},"article-number":"vkag206"}}