Journal Article

DZNE-2025-00662

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Human γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition.

Suen, T. K. ; Al, B. ; Ulas, T.DZNE* ; Reusch, N.DZNE* ; Bahrar, H. ; Bekkering, S. ; Bhat, J. ; Kabelitz, D. ; Schultze, J. L.DZNE* ; van de Veerdonk, F. L. ; van Lennep, J. R. ; Riksen, N. P. ; Joosten, L. A. B. ; Netea, M. G. ; Placek, K.

2025
Wiley-Blackwell Oxford [u.a.]

This record in other databases:  

Please use a persistent id in citations: doi:10.1111/imm.13931

Abstract: 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.

Keyword(s): Humans (MeSH) ; Mevalonic Acid: metabolism (MeSH) ; Zoledronic Acid: pharmacology (MeSH) ; Receptors, Antigen, T-Cell, gamma-delta: metabolism (MeSH) ; Receptors, Antigen, T-Cell, gamma-delta: immunology (MeSH) ; Signal Transduction: drug effects (MeSH) ; Animals (MeSH) ; Mevalonate Kinase Deficiency: immunology (MeSH) ; Cells, Cultured (MeSH) ; Lymphocyte Activation: drug effects (MeSH) ; Phosphotransferases (Alcohol Group Acceptor): genetics (MeSH) ; Phosphotransferases (Alcohol Group Acceptor): metabolism (MeSH) ; Hydroxymethylglutaryl-CoA Reductase Inhibitors: pharmacology (MeSH) ; Diphosphonates: pharmacology (MeSH) ; Mice (MeSH) ; Cytokines: metabolism (MeSH) ; Cell Proliferation: drug effects (MeSH) ; T-Lymphocytes: immunology (MeSH) ; T-Lymphocytes: drug effects (MeSH) ; Protein Prenylation: drug effects (MeSH) ; Intraepithelial Lymphocytes: immunology (MeSH) ; Intraepithelial Lymphocytes: drug effects (MeSH) ; Intraepithelial Lymphocytes: metabolism (MeSH) ; Hepatitis A Virus Cellular Receptor 2 (MeSH) ; T cell ; cytokines ; flow cytometry ; human ; protein kinases/phophatases ; Mevalonic Acid ; Zoledronic Acid ; Receptors, Antigen, T-Cell, gamma-delta ; mevalonate kinase ; Phosphotransferases (Alcohol Group Acceptor) ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; HAVCR2 protein, human ; Diphosphonates ; Cytokines ; Hepatitis A Virus Cellular Receptor 2

---

Contributing Institute(s):

1. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
2. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2025

---

Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---