Recognition and destruction of virus-infected cells by human gamma delta CTL

We examined the response of human gamma delta T cells to herpes simplex virus (HSV). PBMC from HSV seropositive individuals were stimulated with autologous HSV-infected PHA blasts. There was a 4- to 28-fold expansion of gamma delta T cells that were > 95% positive for TCR variable region genes V gamma 2 paired with V delta 2 (V gamma 2V delta 2 T cells). PBMC from these cultures lysed Daudi cells and HSV-infected, but not mock-infected targets. The cytotoxicity was contained predominantly within the gamma delta T cell subset, because depletion of alpha beta T cells enriched the cytotoxic activity, whereas depletion of gamma delta T cells abrogated it. Surprisingly, cloned V gamma 2V delta 2 T cells derived from PHA or mycobacterial stimulation also lysed HSV-infected, but not mock-infected targets. Moreover, both the polyclonal HSV-stimulated gamma delta T cells and the cloned V gamma 2V delta 2 T cells derived from unrelated stimulators (PHA or mycobacteria) also lysed targets infected with vaccinia virus, which is unrelated to HSV. Cytotoxic activity was not restricted by classical HLA class I or class II molecules, and could be blocked with mAbs to CD3 and the gamma delta TCR. These data demonstrate that gamma delta T cells proliferate in response to virus-infected cells and mediate their destruction. Such virus-stimulated gamma delta T cells seem to mediate a TCR-dependent antiviral effector function which is most likely not directed against Ags specific to a particular virus, but presumably directed against a cellular ligand induced or modified by acute viral infection.