HDMAPP is a metabolite of the microbial dioxyxylulose-phosphate pathway, which is analogous to the isopentenyl pyrophosphate pathway in mammals. It is a protease-resistant and phosphatase-sensitive pyrophosphate produced by bacteria and plants.[1] [2] HDMAPP is a non-peptide ligand, also called a phosphoantigen, that binds the T cell receptor on Vγ9Vδ2 peripheral blood lymphocytes with high affinity (EC50 = 0.39 nM).[3] It induces the expansion of human memory Vγ9Vδ2 T cells, but does not increase their ability to inhibit intracellular mycobacterial growth.[4][5] Neonatal Vγ9Vδ2 T cells require micromolar concentrations of HDMAPP to drive expansion.[6]

Reference：
[1]. Poupot, M., and Fournié, J.J. Non-peptide antigens activating human Vg9/Vd2 T lymphocytes. Immunology Letters 95, 129-138 (2004).
[2]. Tanaka, Y., Morita, C.T., Tanaka, Y., et al. Natural and synthetic non-peptide antigens recognized by humanγδT cells. Nature 375, 155-158 (1995).
[3]. Boedec, A., Sicard, H., Dessolin, J., et al. Synthesis and biological activity of phosphonate analogues and geometric isomers of the highly potent phosphoantigen (E)-1-hydroxy-2-methylbut-2-enyl 4-diphosphate. Journal of Medicinal Chemistry 51, 1747-1754 (2008).
[4]. DeBarros, A., Chevas-Ferreira, M., d'Orey, F., et al. CD70-CD27 interactions provide survival and proliferative signals that regulate T cell receptor-driven activation of human γδ peripheral blood lymphocytes. European Journal of Immunology 41(1), 195-201 (2011).
[5]. Spencer, C.T., Abate, G., Blazevic, A., et al. Only a subset of phosphoantigen-responsive γ9δ2 T cells mediate protective TB immunity. Journal of Immunology 181(7), 4471-4484 (2008).
[6]. Moens, E., Brouwer, M., Dimova, T., et al. IL-23R and TCR signaling drives the generation of neonatal Vγ9Vδ2 T cells expressing high levels of cytotoxic mediators and producing IFN-γ and IL-17. Journal of Leukocyte Biology 89(5), 743-752 (2011).