Differential Poly(I:C) Responses of Human Vγ9Vδ2 T Cells Stimulated with Pyrophosphates Versus Aminobisphosphonates

Abstract

Bacterial pyrophosphates or aminobisphosphonates induce cytokine secretion and expansion of freshly isolated (resting) human V 9V 2 T cells. The initial expansion of T cells strictly depends on co-stimulatory signals of accessory cells and IL-2. However, resting T cells produce cytokines after stimulation with pyrophosphates combined with TLR3 ligand poly(I:C) in the absence of accessory cells. We observed that aminobisphosphonate together with poly(I:C) stimulation did not induce cytokine secretion in resting T cells. Moreover, proliferation of T cells within PBMC was enhanced after stimulation with pyrophosphates and poly(I:C), but not after stimulation with aminobisphosphonates plus poly(I:C), even though accessory cells were present. Aminobisphosphonate together with poly(I:C) induced a delayed up-regulation of co-stimulatory molecules and cell survival of monocytes within PBMC. In contrast to resting T cells, activated V 9V 2 T cells produced IFNafter stimulation with pyrophosphate antigens as well as with aminobisphosphonate in the absence of accessory cells and poly(I:C). However, aminobisphosphonate stimulation resulted in much lower IFNproduction than pyrophosphate stimulation, which fits well with the weaker aminobisphosphonate induced activation of extracellular regulated kinase (ERK) involved in IFNsecretion. Poly(I:C) failed to enhance cytokine production and proliferation of activated T cell lines after aminobisphosphonate stimulation unless accessory cells were added. Taken together, the results suggest a differential regulation of V 9V 2 T cell activation by pyrophosphates and aminobisphosphonates, especially after co-stimulation with poly(I:C). This might be relevant when using such pyrophosphates or aminobisphosphonates together with TLR3 agonists as adjuvants in T cell-based