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(E)-4-Hydroxy-3-methyl-but-2 enyl pyrophosphate-stimulated Vγ9Vδ2 T cells possess T helper type 1-promoting adjuvant activity for human monocyte-derived dendritic cells

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Abstract

Vγ9Vδ2 T cells respond to pyrophosphate antigens and display potent antitumour activity in vitro. We have investigated the potential of the most potent phosphoantigen known to activate Vγ9Vδ2 T cells, (E)-4-hydroxy-3-methyl-but-2 enyl pyrophosphate (HMB-PP), as an adjuvant for dendritic cell (DC)-based vaccines. A single stimulation of peripheral blood mononuclear cells with HMB-PP and IL-2 was sufficient to generate lines of effector memory Vγ9Vδ2 T cells that retained their cytolytic and cytokine secretion activities. These cells induced differentiation of DC into semi-mature antigen-presenting cells expressing CD86, CD11c, CD54, HLA-DR, CD83 and CD40, which secreted low levels of bioactive IL-12 but no IL-10. Vγ9Vδ2 T cells also strongly costimulated IL-12 release but inhibited IL-10 production by lipopolysaccharide (LPS)-stimulated DC. When substituted for Vγ9Vδ2 T cells, IFN-γ did not induce full DC maturation but it augmented IL-12 and inhibited IL-10 release by LPS-stimulated DC, in a manner similar to HMB-PP-activated Vγ9Vδ2 T cells. Our findings indicate that Vγ9Vδ2 T cells, stimulated with nanomolar concentrations of HMB-PP, strongly promote T helper type 1 (Th1) responses through their ability to induce DC maturation and IL-12 secretion. This adjuvant activity may prove useful in DC-based cancer therapies.

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Abbreviations

APC:

Antigen-presenting cell

BrHPP:

Bromohydrin pyrophosphate

α-GalCer:

α-Galactosylceramide

DC:

Dendritic cell

ELISA:

Enzyme-linked immunosorbent assay

HMB-PP:

(E)-4-Hydroxy-3-methyl-but-2 enyl pyrophosphate

iDC:

Immature dendritic cell

IFN-γ:

Interferon-γ

iNKT cell:

Invariant natural killer T cell

IPP:

Isopentenyl pyrophosphate

LPS:

Lipopolysaccharide

mAb:

Monoclonal antibody

MHC:

Major histocompatibility complex

Ns:

Not significant

PAM:

Pamidronate

PBMC:

Peripheral blood mononuclear cells

poly I:C:

Polyinosinic–polycytidylic acid double-stranded RNA

TCM :

Central memory T cell

TCR:

T cell receptor

TEM :

Effector memory T cell

TEMRA :

Terminally differentiated memory T cell

Th:

Helper T cell

TNF-α:

Tumour necrosis factor-α

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Acknowledgments

We thank Hassan Jomaa, Armin Reichenberg and Matthias Eberl for providing HMB-PP. Thanks to Conleth Feighery, John Jackson, Jacinta Kelly, Andrew Hogan, Melissa Conroy and Shijuan Grace Zeng for helpful discussions. This work was supported by grants from the Irish Research Council for Science Engineering and Technology (to MRD) and Science Foundation Ireland (LME).

Conflict of interest statement

The authors declare no financial or commercial conflicts of interest.

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Authors and Affiliations

  1. Department of Immunology and Institute of Molecular Medicine, Trinity College Dublin, St. James’s Hospital, Dublin 8, Ireland

    Margaret R. Dunne & Derek G. Doherty

  2. Institute of Immunology, National University of Ireland, Maynooth, Ireland

    Margaret R. Dunne, Laura Madrigal-Estebas, Laura M. Tobin & Derek G. Doherty

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  1. Margaret R. Dunne
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  2. Laura Madrigal-Estebas
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Correspondence to Derek G. Doherty.

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Dunne, M.R., Madrigal-Estebas, L., Tobin, L.M. et al. (E)-4-Hydroxy-3-methyl-but-2 enyl pyrophosphate-stimulated Vγ9Vδ2 T cells possess T helper type 1-promoting adjuvant activity for human monocyte-derived dendritic cells. Cancer Immunol Immunother 59, 1109–1120 (2010). https://doi.org/10.1007/s00262-010-0839-8

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