Cytokine-mediated activation of human ex vivo-expanded Vγ9Vδ2 T cells

Eisuke Domae,Yoji Shimizu,Takashi Ikeo,Seiji Goda,Yuya Hirai

doi:10.18632/oncotarget.17498

Abstract

Vγ9Vδ2 T cells, the major subset of the human peripheral blood γδ T-cell, respond to microbial infection and stressed cells through the recognition of phosphoantigens. In contrast to the growing knowledge of antigen-mediated activation mechanisms, the antigen-independent and cytokine-mediated activation mechanisms of Vγ9Vδ2 T cells are poorly understood. Here, we show that interleukin (IL) -12 and IL-18 synergize to activate human ex vivo-expanded Vγ9Vδ2 T cells. Vγ9Vδ2 T cells treated with IL-12 and IL-18 enhanced effector functions, including the expression of IFN-γ and granzyme B, and cytotoxicity. These enhanced effector responses following IL-12 and IL-18 treatment were associated with homotypic aggregation, enhanced expression of ICAM-1 and decreased expression of the B- and T-lymphocyte attenuator (BTLA), a co-inhibitory receptor. IL-12 and IL-18 also induced the antigen-independent proliferation of Vγ9Vδ2 T cells. Increased expression of IκBζ, IL-12Rβ2 and IL-18Rα following IL-12 and IL-18 stimulation resulted in sustained activation of STAT4 and NF-κB. The enhanced production of IFN-γ and cytotoxic activity are critical for cancer immunotherapy using Vγ9Vδ2 T cells. Thus, the combined treatment of ex vivo-expanded Vγ9Vδ2 T cells with IL-12 and IL-18 may serve as a new strategy for the therapeutic activation of these cells.

Highlights

Human Vγ9Vδ2 T cells predominate in the population of peripheral blood γδ T cells and play a key role in immunity against microbial infection and tumors [1]
To determine whether the ability of cytokines to induce robust expression of IFN-γ in Vγ9Vδ2 T cells is unique for the combination of IL-12 and IL-18, we treated ex vivoexpanded Vγ9Vδ2 T cells with combinations of cytokines including IL-2, IL-12, IL-15, and IL-18
In addition to NK or T cell receptor activation, NK cells and αβ T cells can respond to certain combinations of cytokines, IL-12 and IL-18 [26, 27]

Summary

Introduction

Human Vγ9Vδ2 T cells predominate in the population of peripheral blood γδ T cells and play a key role in immunity against microbial infection and tumors [1]. The Vγ9Vδ2 T cell receptor (TCR) recognizes a conformational change in butyrophilin 3A1 induced by the association with phosphoantigens such as isopentenyl pyrophosphate (IPP) [2,3,4,5]. Vγ9Vδ2 T cells express natural-killer group 2, member D (NKG2D) and recognize stress-induced self ligands such as MHC class I-related chains A and B (MICA/B) and UL16 binding proteins (ULBPs) [7]. Co-stimulation by these ligands through NKG2D enhances Vγ9Vδ2 T cell-mediated cytotoxicity against tumor cells [7]. In concert with TCR and NK-receptor stimulation, inflammatory cytokines such as IL-12 and IL-18 provide a critical signal to promote effector functions such as cytotoxicity and IFN-γ expression and enhance the clonal expansion of Vγ9Vδ2 T cells [8,9,10,11]

Methods

Results

Conclusion