Nonpeptide ligands for human γδ T cells

γδ T cells respond to a variety of microbial pathogens and transformed cells. Their limited receptor repertoire and activation by mycobacterial antigens resistant to proteases suggest that they may recognize nonpeptide antigens. We have tested a variety of nonpeptide molecules for stimulation of human γδ T cells. Synthetic alkyl phosphates, particularly monoethyl phosphate (MEP), selectively activated γδ T cells and stimulated their proliferation in vitro. All γδ T cells stimulated by MEP expressed Vγ2/Vδ2 receptors. The purified natural ligand of mycobacteria is chemically similar to, though distinct from, MEP and contains a phosphate residue that is critical for biological activity. Recognition and expansion of a specific T-cell receptor-bearing population to nonpeptide ligands is unprecedented among T cells. We suggest that MEP mimics small natural ligands capable of expanding one subset of γδ T cells and that this recognition of nonpeptide antigens may play an important role in human immunity to pathogens.