T LYMPHOCYTES express either αβ or γδ T-cell receptor heterodimers1,2. Most αβ T cells recognize antigenic peptides bound to major histocompatibility complex molecules but the antigen recognition and biological function of γδ T cells is unknown. A major human γδ T-cell subset expressing Vγ2 and Vδ2 germline genes, but having diverse junctional sequences, is found in human mycobacterial lesions3 and responds in vitro to antigens of bacteria and parasites4–8. In addition, certain haematopoietic tumour cells are specifically recognized and lysed by these T cells9. Vγ2Vδ2-bearing T cells were shown to recognize mycobacterial antigens that are protease resistant and phosphatase sensitive10–13. Because of the difficulty in isolating natural antigens from mycobacterial culture filtrates or extracts, we synthesized a series of monoalkyl 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 natural antigens produced by mycobacteria recognized by human Vγ2Vδ2-bearing T cells as isopentenyl pyrophosphate and related prenyl pyrophosphate derivatives, compounds involved in the synthesis of complex polyisoprenoid compounds in microbial and mammalian 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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Tanaka, Y., Morita, C., Tanaka, Y. et al. Natural and synthetic non-peptide antigens recognized by human γδ T cells. Nature 375, 155–158 (1995) doi:10.1038/375155a0
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