Premium
Human γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition
Author(s) -
Suen Tsz Kin,
Al Burcu,
Ulas Thomas,
Reusch Nico,
Bahrar Harsh,
Bekkering Siroon,
Bhat Jaydeep,
Kabelitz Dieter,
Schultze Joachim L.,
Veerdonk Frank L.,
Lennep Jeanine Roeters,
Riksen Niels P.,
Joosten Leo A. B.,
Netea Mihai G.,
Placek Katarzyna
Publication year - 2025
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.13931
Subject(s) - mevalonate pathway , cytotoxic t cell , biology , microbiology and biotechnology , cancer research , downregulation and upregulation , population , cell growth , pharmacology , in vitro , biochemistry , medicine , enzyme , environmental health , gene , reductase
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.