NKG2D costimulates human V gamma 9V delta 2 T cell antitumor cytotoxicity through protein kinase C theta-dependent modulation of early TCR-induced calcium and transduction signals.

Human Vgamma9Vdelta2 T cells, a major innate-like peripheral T cell subset, are thought to play in vivo an important role in innate and adaptive immune responses to infection agents and tumors. However, the mechanisms regulating their broad effector functions, such as cytotoxicity and cytokine responses, remain poorly understood. In this study, we used single-cell calcium video imaging to analyze the early intracellular events associated with TCR-induced Vgamma9Vdelta2 T cell functional responses. When compared with other human T cell subsets, including NKT and Vdelta2(neg) gammadelta T cells, TCR/CD3-activated Vgamma9Vdelta2 T cells displayed an unusually delayed and sustained intracellular calcium mobilization, which was dramatically quickened and shortened on costimulation by NKG2D, a main activating NKR regulating gammadelta T cell tumor cytolysis. Importantly, the protein kinase C transduction pathway was identified as a main regulator of the NKG2D-mediated costimulation of antitumor Vgamma9Vdelta2 cytolytic responses. Therefore, this study identifies a new mechanism regulating Vgamma9Vdelta2 T cell functional plasticity through fine-tuning of early signal transduction events.