Activation of Human γδ T Cells: Modulation by Toll-Like Receptor 8 Ligands and Role of Monocytes

Background: Human V gamma 9V delta 2 gamma delta 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 gamma delta T-cell activation by TLR7/8 ligands. Methods: Peripheral blood mononuclear cells (PBMC) or purified gamma delta 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-gamma induction and cellular expansion of gamma delta T cells, as well as viability, cell surface antigen modulation, and IL-1 beta and TNF-alpha production of monocytes. Results: TLR8 ligand TL8-506 and TLR7/8 ligand Resiquimod (but not TLR7 ligands) rapidly induced IFN-gamma expression in gamma delta T cells within PBMC, and co-stimulated phosphoantigen-induced IFN-gamma expression in gamma delta T cells. On the other hand, TLR8 ligands potently suppressed gamma delta T-cell expansion in response to zoledronic acid and phosphoantigen. Purified monocytes secreted large amounts of IL-1 beta and TNF-alpha when stimulated with TLR8 ligands but simultaneously underwent substantial cell death after 24 h. Conclusions: TLR8 ligand-activated monocytes potently co-stimulate early gamma delta T-cell activation but failed to provide accessory cell function for in vitro expansion of gamma delta T cells.