Human γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition

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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Publication Details

Journal
Immunology
Published
2025-04-22
DOI
https://doi.org/10.1111/imm.13931
Citations
3
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
2.39

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article

Human γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition

Thomas Ulas, Jaydeep Bhat, Siroon Bekkering, Leo A. B. Joosten et al.
3 citations
Immunology
Immune Cell Function and Interaction
2.39
article

Human γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition

Thomas Ulas, Jaydeep Bhat, Siroon Bekkering, Leo A. B. Joosten, Niels Peter Riksen, Tsz Kin Suen, Harsh Bahrar, Burcu Al, Joachim L. Schultze, Frank L. van de Veerdonk, Nico Reusch, Katarzyna Placek, Mihai G. Netea, Jeanine Roeters van Lennep, Dieter Kabelitz
article en
3 citations

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.

ImmunologyVol. 175(3)
University of Bonn (DE), Radboud University Nijmegen (NL), Iuliu Hațieganu University of Medicine and Pharmacy (RO), German Center for Neurodegenerative Diseases (DE), Erasmus MC (NL), Radboud University Medical Center (NL), Christian-Albrechts-Universität zu Kiel (DE), University Hospital Schleswig-Holstein (DE), Epigenomics (Germany) (DE), University of Lübeck (DE)
Dutch Cardiovascular Alliance, European Commission, Deutsche Forschungsgemeinschaft
Good health and well-being
Openalex Percentile: Top 12%
Immune Cell Function and Interaction
2.39
DOIOpen Access PDFOpenAlex
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