Characterization of a Unique γδ 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.

Automated summary

V gamma 9(neg)V delta 2(pos) T cells are identified as key effectors in the immune response against CMV, exhibiting significant cytotoxic potential and activation capabilities. In transplant recipients with CMV infection, the expansion of these cells is closely associated with disease severity.