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001     278998
005     20250606100750.0
024 7 _ |a 10.1111/imm.13931
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024 7 _ |a pmid:40264329
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024 7 _ |a 0019-2805
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024 7 _ |a 1365-2567
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037 _ _ |a DZNE-2025-00662
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Suen, Tsz Kin
|b 0
245 _ _ |a Human γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition.
260 _ _ |a Oxford [u.a.]
|c 2025
|b Wiley-Blackwell
336 7 _ |a article
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520 _ _ |a Vδ2 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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650 _ 7 |a T cell
|2 Other
650 _ 7 |a cytokines
|2 Other
650 _ 7 |a flow cytometry
|2 Other
650 _ 7 |a human
|2 Other
650 _ 7 |a protein kinases/phophatases
|2 Other
650 _ 7 |a Mevalonic Acid
|0 S5UOB36OCZ
|2 NLM Chemicals
650 _ 7 |a Zoledronic Acid
|0 6XC1PAD3KF
|2 NLM Chemicals
650 _ 7 |a Receptors, Antigen, T-Cell, gamma-delta
|2 NLM Chemicals
650 _ 7 |a mevalonate kinase
|0 EC 2.7.1.36
|2 NLM Chemicals
650 _ 7 |a Phosphotransferases (Alcohol Group Acceptor)
|0 EC 2.7.1.-
|2 NLM Chemicals
650 _ 7 |a Hydroxymethylglutaryl-CoA Reductase Inhibitors
|2 NLM Chemicals
650 _ 7 |a HAVCR2 protein, human
|2 NLM Chemicals
650 _ 7 |a Diphosphonates
|2 NLM Chemicals
650 _ 7 |a Cytokines
|2 NLM Chemicals
650 _ 7 |a Hepatitis A Virus Cellular Receptor 2
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Mevalonic Acid: metabolism
|2 MeSH
650 _ 2 |a Zoledronic Acid: pharmacology
|2 MeSH
650 _ 2 |a Receptors, Antigen, T-Cell, gamma-delta: metabolism
|2 MeSH
650 _ 2 |a Receptors, Antigen, T-Cell, gamma-delta: immunology
|2 MeSH
650 _ 2 |a Signal Transduction: drug effects
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Mevalonate Kinase Deficiency: immunology
|2 MeSH
650 _ 2 |a Cells, Cultured
|2 MeSH
650 _ 2 |a Lymphocyte Activation: drug effects
|2 MeSH
650 _ 2 |a Phosphotransferases (Alcohol Group Acceptor): genetics
|2 MeSH
650 _ 2 |a Phosphotransferases (Alcohol Group Acceptor): metabolism
|2 MeSH
650 _ 2 |a Hydroxymethylglutaryl-CoA Reductase Inhibitors: pharmacology
|2 MeSH
650 _ 2 |a Diphosphonates: pharmacology
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Cytokines: metabolism
|2 MeSH
650 _ 2 |a Cell Proliferation: drug effects
|2 MeSH
650 _ 2 |a T-Lymphocytes: immunology
|2 MeSH
650 _ 2 |a T-Lymphocytes: drug effects
|2 MeSH
650 _ 2 |a Protein Prenylation: drug effects
|2 MeSH
650 _ 2 |a Intraepithelial Lymphocytes: immunology
|2 MeSH
650 _ 2 |a Intraepithelial Lymphocytes: drug effects
|2 MeSH
650 _ 2 |a Intraepithelial Lymphocytes: metabolism
|2 MeSH
650 _ 2 |a Hepatitis A Virus Cellular Receptor 2
|2 MeSH
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700 1 _ |a Al, Burcu
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700 1 _ |a Ulas, Thomas
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700 1 _ |a Reusch, Nico
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700 1 _ |a van de Veerdonk, Frank L
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700 1 _ |a van Lennep, Jeanine Roeters
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700 1 _ |a Riksen, Niels P
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700 1 _ |a Joosten, Leo A B
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700 1 _ |a Netea, Mihai G
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700 1 _ |a Placek, Katarzyna
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773 _ _ |a 10.1111/imm.13931
|g Vol. 175, no. 3, p. 300 - 322
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|y 2025
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