Human Vgamma9Vdelta2 T cells, a major innate-like peripheral T cell subset, are thought to play in vivo a key role in innate and adaptive immune responses to infection agents and tumors. Vgamma9Vdelta2 T cell activation is tightly regulated by a variety of activating or inhibitory receptors which are specific for constitutively expressed or stress-modulated ligands. However, the mechanisms and signal transduction pathways regulating their broad effector functions, such as cytotoxicity and cytokine responses, remain poorly understood. Here we provide an updated overview of the activation modalities of Vgamma9Vdelta2 T cells by highlighting the respective role played by T cell receptor (TCR) versus non-TCR stimuli, and focus on recent studies showing how Vgamma9Vdelta2 T cells integrate the numerous activating and inhibitory signals and translate them into a particular effector and biological function. A better understanding of these critical issues should help optimize immunotherapeutic approaches targeting Vgamma9Vdelta2 T cells.

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