Stress-related and homeostatic cytokines regulate V?9V?2 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 V?9V?2 T cells with antitumor potential. We show here that V?9V?2 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. V?9V?2 T cells induced this way effectively proliferated even under severe lymphopenic conditions and the antioxidant N-acetylcysteine significantly improved reconstitution of ?? 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 ? (IFN?) upon antigen re-encounter. IL-15 induced effector ?? 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 V?9V?2 T cell subsets for effective cancer immunotherapy.

SUBMITTER: Gruenbacher G 

PROVIDER: S-EPMC4368140 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature