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Aminobisphosphonate drugs, such as zoledronate, are commonly used to expand V\u03b42 T cells. Yet, such in\u00a0vitro generated cells have limited efficacy in the clinic. We found that despite inducing excessive proliferation of V\u03b42 T cells, zoledronate impaired their effector function and caused the upregulation of the inhibitory receptor TIM3. This effect was due to the inhibition of mevalonate metabolism and dysregulation of downstream biological processes such as protein prenylation and intracellular signalling. In\u00a0vitro and in\u00a0vivo inhibition of mevalonate metabolism with zoledronate, statins, and 6\u2010fluoromevalonate, as well as genetic deficiency of the mevalonate kinase, all resulted in compromised cytokine and cytotoxic molecule production by V\u03b42 T cells. Impaired V\u03b42 T cell function was accompanied by transcriptome and kinome changes. Our findings reveal the importance of mevalonate metabolism for the proper functioning of V\u03b42 T cells. This observation provides important considerations for improving their therapeutic use and has repercussions for patients with statin or aminobisphosphonate treatments.<\/jats:p>","DOI":"10.1111\/imm.13931","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T02:54:12Z","timestamp":1745376852000},"page":"300-322","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Human \u03b3\u03b4 T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition"],"prefix":"10.1111","volume":"175","author":[{"given":"Tsz Kin","family":"Suen","sequence":"first","affiliation":[{"name":"Immunology and Metabolism, Life and Medical Sciences Institute University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burcu","family":"Al","sequence":"additional","affiliation":[{"name":"Immunology and Metabolism, Life and Medical Sciences Institute University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Ulas","sequence":"additional","affiliation":[{"name":"Systems Medicine, German Center for Neurodegenerative Diseases (DZNE)  Bonn Germany"},{"name":"PRECISE Platform for Single Cell Genomics and Epigenomics at the DZNE and the University of Bonn  Bonn Germany"},{"name":"Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nico","family":"Reusch","sequence":"additional","affiliation":[{"name":"Systems Medicine, German Center for Neurodegenerative Diseases (DZNE)  Bonn Germany"},{"name":"PRECISE Platform for Single Cell Genomics and Epigenomics at the DZNE and the University of Bonn  Bonn Germany"},{"name":"Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harsh","family":"Bahrar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siroon","family":"Bekkering","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaydeep","family":"Bhat","sequence":"additional","affiliation":[{"name":"Institute of Immunology University of Kiel, University Hospital Schleswig\u2010Holstein Campus Kiel  Kiel Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"Kabelitz","sequence":"additional","affiliation":[{"name":"Institute of Immunology University of Kiel, University Hospital Schleswig\u2010Holstein Campus Kiel  Kiel Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim L.","family":"Schultze","sequence":"additional","affiliation":[{"name":"Systems Medicine, German Center for Neurodegenerative Diseases (DZNE)  Bonn Germany"},{"name":"PRECISE Platform for Single Cell Genomics and Epigenomics at the DZNE and the University of Bonn  Bonn Germany"},{"name":"Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank L.","family":"van de Veerdonk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanine Roeters","family":"van Lennep","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Erasmus MC University Center  Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels P.","family":"Riksen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo A. 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