Human VÎ´2+ Î³Î´ T Cells Differentially Induce Maturation, Cytokine Production, and Alloreactive T Cell Stimulation by Dendritic Cells and B Cells

Andreea Petrasca,Derek G Doherty

doi:10.3389/fimmu.2014.00650

Abstract

Human γδ T cells expressing the Vγ9Vδ2 T cell receptor can induce maturation of dendritic cells (DC) into antigen-presenting cells (APC) and B cells into antibody-secreting plasma cells. Since B cells are capable of presenting antigens to T cells, we investigated if Vγ9Vδ2 T cells can influence antigen-presentation by these cells. We report that Vγ9Vδ2 T cells induced expression of CD86, HLA-DR, and CD40 by B cells and stimulated the release of IL-4, IL-6, TNF-α, and IgG, IgA, and IgM. Vγ9Vδ2 T cells also augmented the ability of B cells to stimulate proliferation but not IFN-γ or IL-4 release by alloreactive T cells. In contrast, Vγ9Vδ2 T cells induced expression of CD86 and HLA-DR and the release of IFN-γ, IL-6, and TNF-α by DC and these DC stimulated proliferation and IFN-γ production by conventional T cells. Furthermore, CD86, TNF-α, IFN-γ, and cell contact were found to be important in DC activation by Vγ9Vδ2 T cells but not in the activation of B cells. These data suggest that Vγ9Vδ2 T cells can induce maturation of B cells and DC into APC, but while they prime DC to stimulate T helper 1 (TH1) responses, they drive maturation of B cells into APC that can stimulate different T cell responses. Thus, Vγ9Vδ2 T cells can control different arms of the immune system through selective activation of B cells and DC in vitro, which may have important applications in immunotherapy and for vaccine adjuvants.

Highlights

T cells expressing the Vγ9Vδ2 T cell receptor (TCR) comprise the most abundant γδ T cell subset in human blood, where they typically account for 1–5% of T cells in healthy adults [1,2,3,4]
Our results show that Vγ9Vδ2 T cells induce maturation of both dendritic cells (DC) and B cells into antigen-presenting cells (APC) that express co-stimulatory molecules and produce cytokines, and that these mature DC and B cells are capable of inducing alloreactive T cell proliferation
The results show that cell contact is important for CD86 expression by DC (Figure 1A), while CD86, TNF-α, and IFN-γ are important for HLA-DR expression by DC (Figure 1C)

Summary

Introduction

T cells expressing the Vγ9Vδ2 T cell receptor (TCR) comprise the most abundant γδ T cell subset in human blood, where they typically account for 1–5% of T cells in healthy adults [1,2,3,4]. The Vγ9Vδ2 TCR recognizes a variety of low molecular weight pyrophosphate intermediates of isoprenoid biosynthesis (phosphoantigens), but the most potent phosphoantigen known is (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), an intermediate of the non-mevalonate pathway that is found in the majority of Gram-negative bacteria, some Gram-positive species and some parasites, such as Plasmodium falciparum and Toxoplasma gondii [1, 6]. Butyrophilin 3A (BTN3A/CD277) was shown to bind to phosphoantigens within cells, resulting in activation of Vγ9Vδ2 T cells [7, 8]. HMB-PP can be used to induce in vitro expansion and activation of Vγ9Vδ2 T cells [9, 10]. Activated Vγ9Vδ2 T cells exhibit a range of effector functions including direct cytotoxicity of infected and tumor cells, the induction of inflammatory and immunoregulatory processes and promotion of the survival, differentiation and activation of monocytes, neutrophils, dendritic cells (DC), αβ T cells, and B cells [1,2,3,4]

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