Stress-related and homeostatic cytokines regulate Vγ9Vδ2 T-cell surveillance of mevalonate metabolism

摘要: The potentially oncogenic mevalonate pathway provides building blocks for protein prenylation and induces cell proliferation as such is an important therapeutic target. Among metabolites, only isopentenyl pyrophosphate (IPP) has been considered to be immunologically relevant antigen primate-specific, innate-like Vγ9Vδ2 T cells with antitumor potential. We show here that pretreated the stress-related, inflammasome-dependent cytokine interleukin 18 (IL-18) were potently activated not by IPP but also all downstream isoprenoid pyrophosphates exhibit combined features of antigens cell-extrinsic metabolic cues. induced this way effectively proliferated even under severe lymphopenic conditions antioxidant N-acetylcysteine significantly improved reconstitution γδ predominantly a central memory phenotype. homeostatic IL-15 differentiation effector in antigen-independent fashion, which rapidly produced abundant interferon γ (IFNγ) upon re-encounter. displayed increased levels cytotoxic lymphocyte-associated proteins CD56, CD96, CD161 perforin. In response stimulation pyrophosphates, these upregulated surface expression CD107a exhibited strong cytotoxicity against tumor vitro. Our data clarify understanding innate immunosurveillance mechanisms will facilitate controlled generation robust subsets effective cancer immunotherapy.