Characterization of a unique γδ T cell subset as a specific marker of CMV infection severity.

Cytomegalovirus is a major infectious cause of mortality and morbidity following transplantation. We have previously demonstrated that the tissue-associated adaptive Vδ2neg γδ T-cells are key effectors responding to CMV and associated to recovery, contrasting with their innate-like circulating counterparts, the Vγ9posVδ2pos T-cells that respond to phosphoantigens but not to CMV. A third additional Vγ9negVδ2pos subgroup with adaptive functions has been recently described in adults. Here, we demonstrate that these Vγ9negVδ2pos T-cells are also components of the CMV immune response while presenting with distinct characteristics from Vδ2neg γδT-cells. In a cohort of kidney transplant recipients, CMV seropositivity was the unique clinical parameter associated with Vγ9negVδ2posT-cell expansion and differentiation. Extensive phenotyping demonstrated their substantial cytotoxic potential and activation during acute CMV primary infection or reinfection. In vitro, Vγ9negVδ2pos T-cells responded specifically to CMV-infected cells in a T-Cell Receptor-dependent manner and through strong IFNγ production. Finally, Vγ9negVδ2pos T-cells were the only γδT-cell subset which expansion tightly correlated with the severity of CMV disease. To conclude, our results identify a new player in the immune response against CMV and open interesting clinical perspectives for using Vγ9negVδ2pos T-cells as an immune marker for CMV disease severity in immunocompromised patients.