Human γδ T Cell Function Is Impaired Upon Mevalonate Pathway Inhibition

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Vδ2 T cells are key players in immunotherapy for cancer and infections.
• Aminobisphosphonates like zoledronate are used to expand Vδ2 T cells in vitro.
• Current in vitro generated Vδ2 T cells show limited clinical efficacy.

Purpose of the Study:

• To investigate the impact of zoledronate on Vδ2 T cell effector function.
• To elucidate the molecular mechanisms underlying zoledronate-induced Vδ2 T cell dysfunction.
• To explore the role of mevalonate metabolism in Vδ2 T cell function.

Main Methods:

• In vitro and in vivo experiments using zoledronate, statins, and 6-fluoromevalonate.
• Assessment of Vδ2 T cell proliferation, effector function, and TIM3 expression.
• Analysis of mevalonate metabolism, protein prenylation, and intracellular signaling.
• Transcriptome and kinome profiling.

Main Results:

• Zoledronate induced excessive Vδ2 T cell proliferation but impaired effector function and upregulated TIM3.
• Inhibition of mevalonate metabolism by zoledronate, statins, or genetic deficiency compromised Vδ2 T cell cytokine and cytotoxic molecule production.
• Disruption of mevalonate metabolism led to altered transcriptome and kinome profiles.
• Impaired protein prenylation and intracellular signaling were observed.

Conclusions:

• Mevalonate metabolism is essential for optimal Vδ2 T cell function.
• Zoledronate's inhibition of mevalonate metabolism underlies Vδ2 T cell dysfunction.
• Findings necessitate re-evaluation of Vδ2 T cell expansion protocols and have implications for patients on statin or aminobisphosphonate therapy.