Aminobisphosphonates reveal a selective anti-viral potential of V gamma 9V delta 2 T cells
Résumé
Vγ9Vδ2 cells are activated by stressed cells producing endogenous phosphoantigens (PAgs) following tumoral transformation or treatment with aminobisphosphonates (ABP) such as zoledronate (Zol). Alternatively they respond to exogenous PAgs produced by bacteria. Their potential interest in viral infections is not well established. We analyzed in vitro their activation and activity against HCMV-infected cells. Although they were not activated by HCMV-infected fibroblasts, following treatment of targets with ABPs they were preferentially and more potently activated by infected cells, resulting in a stronger IFNγ production and induction of TNF. In conditions where uninfected cells were not affected, they limited viral replication through an IFNγ and TNF-dependent mechanism, whereas cytotoxicity did not play a significant role. This could be explained by an increased uptake of a fluorescent Zol derivative by infected cells. In addition, HCMV infection stimulated the transcription of mevalonate pathway enzymes HMG-CoA reductase and synthase evaluated by RT PCR. As a result, the production of endogenous PAgs IPP and ApppI following low-dose treatment with Zol was also boosted. Cytokines such as IL18, putatively produced by infected cells did not play a significant role in the synergistic effect of HCMV and Zol. In order to examine whether this was true for other viruses, we infected hepatocytoma cells with the hepatitis E virus and treated them with Zol. In this case, viral infection only moderately increased Zol-induced IFNγ production, but not TNF, by Vγ9Vδ2 cells. Our results suggest that ABPs could be used to target the anti-viral potential of Vγ9Vδ2 T cells against selected viruses responsible for chronic infections.