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 Vg9Vd2 T cells with antitumor potential. We show here that Vg9Vd2 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. Vg9Vd2 T cells induced this way effectively proliferated even under severe lymphopenic conditions and the antioxidant N-acetylcysteine significantly improved reconstitution of gd 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 g (IFNg) upon antigen re-encounter. IL-15 induced effector gd 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 Vg9Vd2 T cell subsets for effective cancer immunotherapy.

Butyrophilin 3A/CD277–Dependent Activation of Human γδ T Cells: Accessory Cell Capacity of Distinct Leukocyte Populations

“…We used two different approaches; that is, stimuli were either added in soluble form to cocultures of freshly isolated gd T cells and accessory cells, or, alternatively, accessory cells were preincubated with the respective stimuli for 2 h and washed extensively before being cocultured with gd T cells. With the limited number of purified gd responder T cells used in our study (8,000-10,000 per microculture well) we did not observe any Vg9 T cell expansion in the absence of accessory cells, even in the presence of exogenous IL-18, which has been shown to strongly support gd T cell proliferation (45)(46)(47)(48).…”

“…mAb or HMBPP) were functional in neutrophils, at least in the presence of IL-18. IL-18 is an important regulator of gd T cell activation and proliferation (45)(46)(47)(48). Specifically, gd T cells respond to the proliferation-promoting effect of IL-18 when the TCR is triggered in a CD277-dependent manner.…”

T lymphocyte regulation by mevalonate metabolism

“…Vg9Vd2 T cells are potently activated not only by IPP but also by the downstream isoprenoid pyrophosphates DMAPP, GPP, FPP, and GGPP (83). Moreover, pretreatment with the stress-related, inflammasome-dependent cytokine IL-18 enhances the responses of Vg9Vd2 T cells to all mevalonate-derived isoprenoid pyrophosphates.…”

Trial Watch—Immunostimulation with cytokines in cancer therapy

“…5,6 Indeed, novel functions for members of the cytokine family as well as new cytokine-like proteins are discovered every year. [9][10][11][12] Owing to their capacity to regulate various cellular responses including proliferation, differentiation, activation and regulated cell death, cytokines orchestrate complex organismal functions as different as hematopoiesis, angiogenesis, wound healing and inflammation. [13][14][15][16][17][18][19] Moreover, some cytokines play a critical role in the initiation, propagation and extinction of innate and adaptive immune responses, irrespective of whether such responses are initiated by microbial challenges or endogenous states of danger.…”