Small Molecules for the Activation of Human γ δ T Cell Responses Against Infection

γδ T lymphocytes contribute to immune defense against infection through the production of cytokines, chemokines, anti-bacterial compounds, and killing of infected cells. The major subpopulation of human peripheral blood γδ T cells expresses a Vγ9Vδ2 T cell receptor. Vγ9Vδ2 T cells recognize at picomolar concentrations pyrophosphate molecules generated by bacteria and parasites through the 2-C-methyl-D-erythritol 4-phosphate (also termed 1-deoxy-Dxylulose 5-phosphate) pathway. Pyrophosphates including isopentenyl pyrophosphate (IPP) generated in mammalian cells through the alternative mevalonate pathway also activate Vγ9Vδ2 T cells, but require 1,000- to 10,000-fold higher concentrations. Synthetic compounds have been patented which efficiently activate Vγ9Vδ2 T cells in vitro and in vivo. In addition, the mevalonate pathway of IPP synthesis in mammalian cells can be manipulated by aminobisphosphonates and alkylamines, giving rise to the development of additional strategies for the therapeutic activation of anti-infective γδ T cells. The recent developments in the discovery of new and selective γδ T cell-activating compounds open new avenues for cell-based therapies of infectious diseases.