Abstract
Background: Human Vγ9Vδ2 γδ T cells can kill a variety of cancer cells and have attracted substantial interest for cancer immunotherapy. Toll-like receptor (TLR) ligands are promising adjuvants for cancer immunotherapy, but TLR7/8 ligand Resiquimod has been shown to inhibit CD4 T-cell activation in a monocyte-dependent manner. Therefore, we studied the modulation of human γδ T-cell activation by TLR7/8 ligands. Methods: Peripheral blood mononuclear cells (PBMC) or purified γδ T cells together with purified monocytes were stimulated with zoledronic acid or phosphoantigens in the absence or presence of various imidazoquinoline TLR7 or TLR8 agonists. Read-out systems included interferon-γ induction and cellular expansion of γδ T cells, as well as viability, cell surface antigen modulation, and IL-1β and TNF-α production of monocytes. Results: TLR8 ligand TL8-506 and TLR7/8 ligand Resiquimod (but not TLR7 ligands) rapidly induced IFN-γ expression in γδ T cells within PBMC, and co-stimulated phosphoantigen-induced IFN-γ expression in γδ T cells. On the other hand, TLR8 ligands potently suppressed γδ T-cell expansion in response to zoledronic acid and phosphoantigen. Purified monocytes secreted large amounts of IL-1β and TNF-α when stimulated with TLR8 ligands but simultaneously underwent substantial cell death after 24 h. Conclusions: TLR8 ligand-activated monocytes potently co-stimulate early γδ T-cell activation but failed to provide accessory cell function for in vitro expansion of γδ T cells.
Highlights
The major subset of γδ T cells in human peripheral blood expresses the T-cell receptor (TCR) variable elements Vγ9 paired with Vδ2 (Vγ9Vδ2; hereafter referred to as Vγ9 or Vδ2)
We studied the effects of TLR7 and TLR8 ligands on the in vitro activation of human Vγ9Vδ2 γδ
The delayed addition of Resiquimod after one and after two days abrogated the inhibitory effect. These results clearly demonstrate that the proliferative expansion of freshly isolated γδ T cells is potently suppressed by TLR8 ligands which need to be added at the set-up of cell cultures for maximal inhibition
Summary
The major subset of γδ T cells in human peripheral blood expresses the T-cell receptor (TCR) variable elements Vγ9 paired with Vδ2 (Vγ9Vδ2; hereafter referred to as Vγ9 or Vδ2). Vδ2 T cells recognize in a TCR-dependent manner pyrophosphate intermediates of the eukaryotic and prokaryotic pathways of cholesterol synthesis, collectively termed phosphoantigens (pAg). Intermediates of the mevalonate pathway, notably isopentenyl pyrophosphate (IPP), have been shown to selectively activate. The non-mevalonate intermediate (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) activates human Vδ2 T cells at picoto nanomolar concentrations [5]. Synthetic homologs of naturally occurring pAg like bromohydrin pyrophosphate (BrHPP) are potent and selective activators of Vδ2 T cells [6]. We studied the modulation of human γδ T-cell activation by TLR7/8 ligands. TLR8 ligands potently suppressed γδ T-cell expansion in response to zoledronic acid and phosphoantigen. Purified monocytes secreted large amounts of IL-1β and TNF-α when stimulated with TLR8 ligands but simultaneously underwent substantial cell death after 24 h
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