Characterization Of A Unique Gamma Delta T-Cell Subset As A Specific Marker Of Cytomegalovirus Infection Severity

Cytomegalovirus (CMV) is a major infectious cause of death and disease after transplantation. We have previously demonstrated that the tissue-associated adaptive V delta 2(neg)gamma delta T cells are key effectors responding to CMV and associated with recovery, contrasting with their innatelike circulating counterparts, the V gamma 9(pos)V delta 2(pos) T cells that respond to phosphoantigens but not to CMV. A third V gamma 9(neg)V delta 2(pos) subgroup with adaptive functions has been described in adults. In the current study, we demonstrate that these V gamma 9(neg)V delta 2(pos) T cells are also components of the CMV immune response while presenting with distinct characteristics from V delta 2(neg)gamma delta T cells. In a cohort of kidney transplant recipients, CMV seropositivity was the unique clinical parameter associated with V gamma 9(neg)V delta 2(pos) T-cell expansion and differentiation. Extensive phenotyping demonstrated their substantial cytotoxic potential and activation during acute CMV primary infection or reinfection. In vitro, V gamma 9(neg)V delta 2(pos) T cells responded specifically to CMV-infected cells in a T-cell receptor-dependent manner and through strong interferon. production. Finally, V gamma 9(neg)V delta 2(pos) T cells were the only gamma delta T-cell subset in which expansion was 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 V gamma 9(neg)V delta 2(pos) T cells as an immune marker for CMV disease severity in immunocompromised patients.