Synthesis of Prenyl Pyrophosphonates as New Potent Phosphoantigens Inducing Selective Activation of Human Vγ9Vδ2 T Lymphocytes

Abstract

Gamma9delta2T cells represent the most abundant population of human blood gammadeltaT lymphocytes. They produce and promote strong cytotoxic activity against many pathogens that are implicated in several human infectious diseases. Their activation requires their exposure to small phosphorus-containing antigens in the family of prenyl pyrophosphates and their related biosynthetic precursors such as isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are naturally occurring metabolites in mycobacteria and several other microbial pathogens. The broad specificity in the recognition of these molecules by the T-lymphocyte population expressing a Vgamma9Vdelta2 cell receptor might facilitate their manipulation by designing small potent synthetic agonist ligands. In this paper, we describe the synthesis and the biological evaluation of new pyrophosphonate compounds as new isosteric analogues of natural prenyl pyrophosphates. Several prenyl and alkenyl pyrophosphonate with different chain lengths and degrees of insaturation (24-28, 48-50, and 64-66) were tested as well as the alkoxymethylpyrophosphonic analogue of IPP (compound 76) as its closest isostere. Several of them appeared to be better activators of Vgamma9Vdelta2 T cell proliferation than IPP. These results open the perspective of a potential use of isoprenoides pyrophosphonates as specific immunoregulatory molecules.

Indirect Stimulation of Human Vγ2Vδ2 T Cells through Alterations in Isoprenoid Metabolism

“…Other classes of phosphonate compounds that stimulate Vγ2Vδ2 T cells include alkenyl pyrophosphonates containing -CPOP moieties (52, 53), alkenyl-methylene diphosphonates (-OPCP), and alkenyl-phosphorylmethylphosphonates (-CPCP). These compounds can either stimulate Vγ2Vδ2 T cells (for example HMB-OPCP, 34, 54) or antagonize prenyl pyrophosphate responses (for example BrH-OPCP, 44, 55).…”

γδ T cells in cancer immunotherapy

“…by activating related enzymes [72]. Finally, γδ T cells interacting with professional APCs, that process and display antigens and provide stimulated signals necessary for inducing the target cell killing [73] (Figure 2). …”

γδ T Cells and Their Potential for Immunotherapy

“…In contrast to many bacteria and protozoas, human cells utilize the mevalonate pathway for isoprenoid and IPP biosynthesis 62, 63, which also activates Vγ9Vδ2 T cells in vitro following presentation by professional antigen-presenting cells or tumor cells 64, 65, but only at concentrations not achieved physiologically in non-transformed cells. However, certain tumors yield higher concentrations of IPP, which can be sensed by Vγ9Vδ2 T cells 66, 67.…”

“…γδ T cells can be utilized for antitumor therapies in an unconventional manner 64, because they exhibit a potent MHC-unrestricted lytic activity against a wide variety of tumor cells in vitro . In clinical studies, γδ T cells have been shown to infiltrate into different kinds of tumors, including lung carcinomas 124, renal cell carcinomas 125, and breast carcinomas 126.…”