Gamma/delta T cells: From bench to bedside

Abstract Protection from exogenous invaders and elimination of endogenous aberrations are the main contributions of T cells to homeostasis. T cells with Vγ9Vδ2-encoded T-cell receptors (TCRs) have a unique ability to interact with a plethora of phosphoantigens in a major histocompatibility complex (MHC)-unrestricted manner. The biological function of this recognition is largely unclear. However, since Vγ9Vδ2 T cells are potent cytotoxic effectors capable of killing tumor cells and target cells infected with numerous viruses including human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), herpes viruses and many others, it is likely that they are involved in antitumor and antiviral immunosurveillance. The observations of tumor-infiltrating γδ T cells with cytotoxic properties and profound quantitative and functional changes in γδ T cells associated with various infectious diseases (including those caused by viruses) are compatible with this hypothesis. For example, the most frequent human peripheral blood γδ T-cell subset expressing Vγ9Vδ2 TCRs is functionally disabled and numerically decreased in some HIV-infected persons. The nonresponsiveness of Vγ9Vδ2 T cells is accompanied by their decreased IFNγ and TNFα production. The overall level of γδ T-cell activation at different stages of HIV infection may be clinically relevant. At an initial stage of HIV infection, the extremely potent antiviral cytotoxic activities of Vγ9Vδ2 T cells may limit the viral spread. At later stages of disease, Vγ9Vδ2 T-cell dysfunction may contribute to the loss of resistance to opportunistic pathogens (such as atypical mycobacteria) and neoplasms (e.g., lymphomas) frequently associated with HIV infections. The activity of Vγ9Vδ2 T cells both in vivo and can be regulated by nonpeptidic antigens. These molecules are being assessed as potential therapeutic vaccines in acquired immunodeficiency syndrome (AIDS) and certain cancers susceptible to the Vγ9Vδ2 T-cell attack.