A power law function describes the time- and dose-dependency of Vγ9Vδ2 T cell activation by phosphoantigens

Phosphoantigens stimulate Vγ9Vδ2 T cells after binding to BTN3A1 in target cells and cell-cell contact. We evaluated phosphoantigens including diphosphates, bisphosphonates, and prodrugs for ability to induce leukemia cells to stimulate Vγ9Vδ2 T cell interferon-γ secretion. Most compounds displayed time-dependent activity at exposure times between 15 and 240 min. Potency (EC₅₀ values) ranged between 8.4 nM and >100 µM. The diphosphate C-HMBPP displayed a shallow dose-response slope (Hill slope = 0.71), while the bisphosphonate slopes were steep (Hill slopes > 2), and the prodrugs intermediate. The bis-acyloxyalkyl POM₂-C-HMBP showed low nanomolar potency even at an exposure time of 1 min. Mixed aryl-POM prodrugs also retained excellent potency at 15 min, while aryl-amidates were time dependent below 240 min. The sum of the dose and time logarithms is often constant, while a power law function fits most compounds. Collectively, these findings illustrate the exquisite activity of prodrugs relative to diphosphates and bisphosphonates.