HUMAN V-GAMMA-9-V-DELTA-2 CELLS ARE STIMULATED IN A CROSS-REACTIVE FASHION BY A VARIETY OF PHOSPHORYLATED METABOLITES

Many different pathogens stimulate cells bearing the V gamma 9-V delta 2 T cell receptor (TCR), which represent the most abundant population of human gamma delta cells. The antigens responsible for the stimulat ion of these gamma delta cells are not well characterized. Here, we de scribe six non-peptidic molecules which share this property: isopenten ylpyrophosphate, dimethylallylpyrophosphate, 2,3-diphosphoglyceric aci d, glycerol-3-phosphoric acid, xylose-1-phosphate, and ribose-1-phosph ate. All these molecules are naturally occurring metabolites in prokar yotic and eukaryotic cells, and stimulate freshly isolated gamma delta cells from peripheral blood of different donors as well as establishe d gamma delta clones. Comparison of their structure with that of simil ar but inactive molecules showed that both the number and position of the phosphate groups, as well as the residues connected with the carbo n backbone are required for stimulation. The CD3-TCR complex is involv ed in cell triggering as shown by inhibition with anti-CDS Fab fragmen ts. However, all gamma delta clones were broadly cross-reactive and we could not isolate cells specific for only one ligand. The capacity of this frequent subset of gamma delta cells to recognize common bacteri al metabolites confers the advantage to react rapidly to different inv ading pathogens.