title: Stress-related and homeostatic cytokines regulate Vγ9Vδ2 T-cell surveillance of mevalonate metabolism.
abstract: The potentially oncogenic mevalonate pathway provides building blocks for protein prenylation and induces cell proliferation and as such is an important therapeutic target. Among mevalonate metabolites, only isopentenyl pyrophosphate (IPP) has been considered to be an immunologically relevant antigen for primate-specific, innate-like Vγ9Vδ2 T cells with antitumor potential. We show here that Vγ9Vδ2 T cells pretreated with the stress-related, inflammasome-dependent cytokine interleukin 18 (IL-18) were potently activated not only by IPP but also by all downstream isoprenoid pyrophosphates that exhibit combined features of antigens and cell-extrinsic metabolic cues. Vγ9Vδ2 T cells induced this way effectively proliferated even under severe lymphopenic conditions and the antioxidant N-acetylcysteine significantly improved reconstitution of γδ T cells predominantly with a central memory phenotype. The homeostatic cytokine IL-15 induced the differentiation of effector cells in an antigen-independent fashion, which rapidly produced abundant interferon γ (IFNγ) upon antigen re-encounter. IL-15 induced effector γδ T cells displayed increased levels of the cytotoxic lymphocyte-associated proteins CD56, CD96, CD161 and perforin. In response to stimulation with isoprenoid pyrophosphates, these effector cells upregulated surface expression of CD107a and exhibited strong cytotoxicity against tumor cells in vitro. Our data clarify understanding of innate immunosurveillance mechanisms and will facilitate the controlled generation of robust Vγ9Vδ2 T cell subsets for effective cancer immunotherapy.
authors.affiliation: Cell Therapy Unit; Department of Urology; K1 Center for Personalized Cancer Medicine; Innsbruck Medical University and oncotyrol ; Innsbruck, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Gruenbacher
authors.affiliation: Peter Gorer Department of Immunobiology; King's College London ; London, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Nussbaumer
authors.affiliation: Cell Therapy Unit; Department of Urology; K1 Center for Personalized Cancer Medicine; Innsbruck Medical University and oncotyrol ; Innsbruck, Austria.
authors.forename: Hubert
authors.initials: H
authors.lastname: Gander
authors.affiliation: Cell Therapy Unit; Department of Urology; K1 Center for Personalized Cancer Medicine; Innsbruck Medical University and oncotyrol ; Innsbruck, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Steiner
authors.affiliation: Cell Therapy Unit; Department of Urology; K1 Center for Personalized Cancer Medicine; Innsbruck Medical University and oncotyrol ; Innsbruck, Austria.
authors.forename: Nicolai
authors.initials: N
authors.lastname: Leonhartsberger
authors.affiliation: Cell Therapy Unit; Department of Urology; K1 Center for Personalized Cancer Medicine; Innsbruck Medical University and oncotyrol ; Innsbruck, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Thurnher
keywords: BTN, butyrophilin; CD107a; CD56; CFSE, carboxyfluorescein succinimidyl ester; DMAPP, dimethylallyl pyrophosphate; FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate; GPP, geranyl pyrophosphate; IL-15; IL-18; IPP, isopentenyl pyrophosphate; N-BP, nitrogen-containing bisphosphonate; NAC, N-acetylcysteine; NK, natural killer; TCR, T cell receptor; immune surveillance; metabolic cues; mevalonate pathway; γδ T cells