TY  - JOUR
AU  - Suen, Tsz Kin
AU  - Al, Burcu
AU  - Ulas, Thomas
AU  - Reusch, Nico
AU  - Bahrar, Harsh
AU  - Bekkering, Siroon
AU  - Bhat, Jaydeep
AU  - Kabelitz, Dieter
AU  - Schultze, Joachim L
AU  - van de Veerdonk, Frank L
AU  - van Lennep, Jeanine Roeters
AU  - Riksen, Niels P
AU  - Joosten, Leo A B
AU  - Netea, Mihai G
AU  - Placek, Katarzyna
TI  - Human γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition.
JO  - Immunology
VL  - 175
IS  - 3
SN  - 0019-2805
CY  - Oxford [u.a.]
PB  - Wiley-Blackwell
M1  - DZNE-2025-00662
SP  - 300 - 322
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Mevalonic Acid: metabolism
KW  - Zoledronic Acid: pharmacology
KW  - Receptors, Antigen, T-Cell, gamma-delta: metabolism
KW  - Receptors, Antigen, T-Cell, gamma-delta: immunology
KW  - Signal Transduction: drug effects
KW  - Animals
KW  - Mevalonate Kinase Deficiency: immunology
KW  - Cells, Cultured
KW  - Lymphocyte Activation: drug effects
KW  - Phosphotransferases (Alcohol Group Acceptor): genetics
KW  - Phosphotransferases (Alcohol Group Acceptor): metabolism
KW  - Hydroxymethylglutaryl-CoA Reductase Inhibitors: pharmacology
KW  - Diphosphonates: pharmacology
KW  - Mice
KW  - Cytokines: metabolism
KW  - Cell Proliferation: drug effects
KW  - T-Lymphocytes: immunology
KW  - T-Lymphocytes: drug effects
KW  - Protein Prenylation: drug effects
KW  - Intraepithelial Lymphocytes: immunology
KW  - Intraepithelial Lymphocytes: drug effects
KW  - Intraepithelial Lymphocytes: metabolism
KW  - Hepatitis A Virus Cellular Receptor 2
KW  - T cell (Other)
KW  - cytokines (Other)
KW  - flow cytometry (Other)
KW  - human (Other)
KW  - protein kinases/phophatases (Other)
KW  - Mevalonic Acid (NLM Chemicals)
KW  - Zoledronic Acid (NLM Chemicals)
KW  - Receptors, Antigen, T-Cell, gamma-delta (NLM Chemicals)
KW  - mevalonate kinase (NLM Chemicals)
KW  - Phosphotransferases (Alcohol Group Acceptor) (NLM Chemicals)
KW  - Hydroxymethylglutaryl-CoA Reductase Inhibitors (NLM Chemicals)
KW  - HAVCR2 protein, human (NLM Chemicals)
KW  - Diphosphonates (NLM Chemicals)
KW  - Cytokines (NLM Chemicals)
KW  - Hepatitis A Virus Cellular Receptor 2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40264329
DO  - DOI:10.1111/imm.13931
UR  - https://pub.dzne.de/record/278998
ER  -