Escherichia coli Produces Phosphoantigens Activating Human γδ T Cells

Human Vγ9δ2 T lymphocytes are suggested to play an important role in the immune response to various microbial pathogens. In contrast to αβ T cells, γδ T lymphocytes recognize small, non-protein, phosphate-bearing antigens (phosphoantigens) in a major histocompatibility complex-independent manner. Four different phosphoantigens termed TUBag1 to TUBag4 with a common 3-formyl-1-butyl-pyrophosphate moiety and isopentenyl-pyrophosphate have been isolated and identified from mycobacteria. However, natural occurring γδ T cell ligands from other bacterial species were not characterized so far. Here, we describe the structural identification of the two compounds responsible for the γδ T cell-stimulating capacity of Escherichia coli as similar to the mycobacterial phosphoantigens 3-formyl-1-butyl-pyrophosphate and its M r 275 homologue TUBag2. In addition, E. coli phosphoantigens exert bioactivities on γδ T cells with similar potencies to the mycobacterial phosphoantigens at 5–15 n m concentration. Furthermore, our results clearly prove that the deoxyxylulose 5-phophate pathway (also referred to as Rohmer metabolic route of isoprenoid biosynthesis) is essential for the biosynthesis of the phosphoantigens in E. coli . Because this pathway is absent from human cells, it proves an ideal target for focusing efficiently the antimicrobial selectivity of human γδ T lymphocytes.