Shared reactivity of V δ2neg γδ T cells against cytomegalovirus-infected cells and tumor intestinal epithelial cells

Long-lasting expansion of V delta 2(neg) gamma delta T cells is a hallmark of cytomegalovirus (CMV) infection in kidney transplant recipients. The ligands of these cells and their role remain elusive. To better understand their immune function, we generated gamma delta T cell clones from several transplanted patients. Numerous patient V delta 1(+), V delta 3(+), and V delta 5(+) gamma delta T cell clones expressing diverse V gamma chains, but not control V gamma 9V delta 2(+) T clones, displayed strong reactivity against CMV-infected cells, as shown by their production of tumor necrosis factor-alpha. V delta 2(neg) gamma delta T lymphocytes could also kill CMV-infected targets and limit CMV propagation in vitro. Their anti-CMV reactivity was specific for this virus among herpesviridae and required T cell receptor engagement, but did not involve major histocompatibility complex class I molecules or NKG2D. V delta 2(neg) gamma delta T lymphocytes expressed receptors essential for intestinal homing and were strongly activated by intestinal tumor, but not normal, epithelial cell lines. High frequencies of CMV- and tumor-specific V delta 2(neg) gamma delta T lymphocytes were found among patients' gamma delta T cells. In conclusion, V delta 2(neg) gamma delta T cells may play a role in protecting against CMV and tumors, probably through mucosal surveillance of cellular stress, and represent a population that is largely functionally distinct from V gamma 9V delta 2(+) T cells.