Small molecules for the activation of human gammadelta T cell responses against infection.

gamma delta 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 gammadelta T cells expresses a Vgamma9Vdelta2 T cell receptor. Vgamma9Vdelta2 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-D-xylulose 5-phosphate) pathway. Pyrophosphates including isopentenyl pyrophosphate (IPP) generated in mammalian cells through the alternative mevalonate pathway also activate Vgamma9Vdelta2 T cells, but require 1,000- to 10,000-fold higher concentrations. Synthetic compounds have been patented which efficiently activate Vgamma9Vdelta2 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 gammadelta T cells. The recent developments in the discovery of new and selective gammadelta T cell-activating compounds open new avenues for cell-based therapies of infectious diseases.