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000278998 0247_ $$2ISSN$$a1365-2567
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000278998 1001_ $$aSuen, Tsz Kin$$b0
000278998 245__ $$aHuman γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition.
000278998 260__ $$aOxford [u.a.]$$bWiley-Blackwell$$c2025
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000278998 520__ $$aVδ2 T cells, a predominant human peripheral γδ T cell population, are a promising candidate for the development of immunotherapies against cancer and infected cells. Aminobisphosphonate drugs, such as zoledronate, are commonly used to expand Vδ2 T cells. Yet, such in vitro generated cells have limited efficacy in the clinic. We found that despite inducing excessive proliferation of Vδ2 T cells, zoledronate impaired their effector function and caused the upregulation of the inhibitory receptor TIM3. This effect was due to the inhibition of mevalonate metabolism and dysregulation of downstream biological processes such as protein prenylation and intracellular signalling. In vitro and in vivo inhibition of mevalonate metabolism with zoledronate, statins, and 6-fluoromevalonate, as well as genetic deficiency of the mevalonate kinase, all resulted in compromised cytokine and cytotoxic molecule production by Vδ2 T cells. Impaired Vδ2 T cell function was accompanied by transcriptome and kinome changes. Our findings reveal the importance of mevalonate metabolism for the proper functioning of Vδ2 T cells. This observation provides important considerations for improving their therapeutic use and has repercussions for patients with statin or aminobisphosphonate treatments.
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000278998 650_7 $$2Other$$aT cell
000278998 650_7 $$2Other$$acytokines
000278998 650_7 $$2Other$$aflow cytometry
000278998 650_7 $$2Other$$ahuman
000278998 650_7 $$2Other$$aprotein kinases/phophatases
000278998 650_7 $$0S5UOB36OCZ$$2NLM Chemicals$$aMevalonic Acid
000278998 650_7 $$06XC1PAD3KF$$2NLM Chemicals$$aZoledronic Acid
000278998 650_7 $$2NLM Chemicals$$aReceptors, Antigen, T-Cell, gamma-delta
000278998 650_7 $$0EC 2.7.1.36$$2NLM Chemicals$$amevalonate kinase
000278998 650_7 $$0EC 2.7.1.-$$2NLM Chemicals$$aPhosphotransferases (Alcohol Group Acceptor)
000278998 650_7 $$2NLM Chemicals$$aHydroxymethylglutaryl-CoA Reductase Inhibitors
000278998 650_7 $$2NLM Chemicals$$aHAVCR2 protein, human
000278998 650_7 $$2NLM Chemicals$$aDiphosphonates
000278998 650_7 $$2NLM Chemicals$$aCytokines
000278998 650_7 $$2NLM Chemicals$$aHepatitis A Virus Cellular Receptor 2
000278998 650_2 $$2MeSH$$aHumans
000278998 650_2 $$2MeSH$$aMevalonic Acid: metabolism
000278998 650_2 $$2MeSH$$aZoledronic Acid: pharmacology
000278998 650_2 $$2MeSH$$aReceptors, Antigen, T-Cell, gamma-delta: metabolism
000278998 650_2 $$2MeSH$$aReceptors, Antigen, T-Cell, gamma-delta: immunology
000278998 650_2 $$2MeSH$$aSignal Transduction: drug effects
000278998 650_2 $$2MeSH$$aAnimals
000278998 650_2 $$2MeSH$$aMevalonate Kinase Deficiency: immunology
000278998 650_2 $$2MeSH$$aCells, Cultured
000278998 650_2 $$2MeSH$$aLymphocyte Activation: drug effects
000278998 650_2 $$2MeSH$$aPhosphotransferases (Alcohol Group Acceptor): genetics
000278998 650_2 $$2MeSH$$aPhosphotransferases (Alcohol Group Acceptor): metabolism
000278998 650_2 $$2MeSH$$aHydroxymethylglutaryl-CoA Reductase Inhibitors: pharmacology
000278998 650_2 $$2MeSH$$aDiphosphonates: pharmacology
000278998 650_2 $$2MeSH$$aMice
000278998 650_2 $$2MeSH$$aCytokines: metabolism
000278998 650_2 $$2MeSH$$aCell Proliferation: drug effects
000278998 650_2 $$2MeSH$$aT-Lymphocytes: immunology
000278998 650_2 $$2MeSH$$aT-Lymphocytes: drug effects
000278998 650_2 $$2MeSH$$aProtein Prenylation: drug effects
000278998 650_2 $$2MeSH$$aIntraepithelial Lymphocytes: immunology
000278998 650_2 $$2MeSH$$aIntraepithelial Lymphocytes: drug effects
000278998 650_2 $$2MeSH$$aIntraepithelial Lymphocytes: metabolism
000278998 650_2 $$2MeSH$$aHepatitis A Virus Cellular Receptor 2
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000278998 7001_ $$aAl, Burcu$$b1
000278998 7001_ $$0P:(DE-2719)9000845$$aUlas, Thomas$$b2$$udzne
000278998 7001_ $$0P:(DE-2719)9000843$$aReusch, Nico$$b3$$udzne
000278998 7001_ $$aBahrar, Harsh$$b4
000278998 7001_ $$aBekkering, Siroon$$b5
000278998 7001_ $$aBhat, Jaydeep$$b6
000278998 7001_ $$aKabelitz, Dieter$$b7
000278998 7001_ $$0P:(DE-2719)2811660$$aSchultze, Joachim L$$b8$$udzne
000278998 7001_ $$avan de Veerdonk, Frank L$$b9
000278998 7001_ $$avan Lennep, Jeanine Roeters$$b10
000278998 7001_ $$aRiksen, Niels P$$b11
000278998 7001_ $$aJoosten, Leo A B$$b12
000278998 7001_ $$aNetea, Mihai G$$b13
000278998 7001_ $$00000-0002-4944-6375$$aPlacek, Katarzyna$$b14
000278998 773__ $$0PERI:(DE-600)2006481-0$$a10.1111/imm.13931$$gVol. 175, no. 3, p. 300 - 322$$n3$$p300 - 322$$tImmunology$$v175$$x0019-2805$$y2025
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