T lymphocytes express either αβ or γδ T-cell receptoi heterodimers1, 2. Most αβ T cells recognize antigenic peptide; bound to major histocompatibility complex molecules but the anti gen recognition and biological function of γδ T cells is unknown A major human γδ T-cell subset expressing Vγ2 and Vδ2 germlim genes, but having diverse junctional sequences, is found in humai mycobacterial lesions3 and responds in vitro to antigens of bacteris and parasites4-8. In addition, certain haematopoietic tumour cell9 are specifically recognized and lysed by these T cells9. Vγ2 and Vδ2-bearing T cells were shown to recognize mycobacterial antigens that are protease resistant and phosphatase sensitive10-13. Becaus* of the difficulty in isolating natural antigens from mycobacteria culture filtrates or extracts, we synthesized a series of monoalky phosphates, and found that some, particularly monoethyl phosphate, could mimic the activity of mycobacterial antigens in stimulating these γδ T cells10. Here we report the identification of natura antigens produced by mycobacteria recognized by human Vγ2 and Vδ-bearing T cells as isopentenyl pyrophosphate and related preny pyrophosphate derivatives, compounds involved in the synthesis ol complex polyisoprenoid compounds in microbial and mammaliar cells. Substitution of phosphate for the pyrophosphate moiety, or elimination of the double bond, greatly reduced antigenic activity of these compounds. These results provide formal evidence that in contrast to recognition of major histocompatibility complex-bound peptide antigens by αβ T cells, human γδ T cells can recognize naturally occurring small non-peptidic antigens.
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