Figure 8: Mechanisms involved in IPP release from untreated and ZA-treated DC.

(a): Mevalonate (Mev) pathway of untreated DC generates isoprenoids (IPP: red circles; FPP/GGPP: yellow circles) and cholesterol (blue circles). Ras is prenylated in untreated DC (Ras-GTP) and causes the activation of the PI3K/Akt/mTOR signalling pathway and suppression of LXRα transcriptional activity. ABCA1 and apoA-I expression is finalized to tune the intracellular concentrations of cholesterol and other mevalonate pathway metabolites that were generated in physiological conditions. The supernatant obtained from untreated DC is unable to induce the proliferation of Vγ9Vδ2 T cells as extracellular IPP concentrations are below a critical threshold. (b) Farnesyl pyrophosphate synthase (FPPS) is inhibited in ZA-treated DC, which causes intracellular IPP accumulation (red circles), and isoprenoid (yellow circles) and cholesterol (blue circles) deprivation. Intracellular IPP induces LXRα nuclear translocation (a), which enhances Abca1 and apoA-1 gene transcription and upregulation of ABCA1 and apoA-I expression. Isoprenoid deprivation concurrently causes Ras deprenylation (Ras), which relieves the inhibition operated by the PI3K/Akt/mTOR pathway on LXRα nuclear translocation (b). Thus, two mechanisms are operative in ZA-treated DC, which causes upregulation of ABCA1 and apoA-1 expression and extracellular IPP and apoA-I release. The supernatant from ZA-treated DC contains sufficient amounts of IPP and apoA-I to induce the activation of Vγ9Vδ2 T cells. The question mark in the right panel indicates that the mechanisms by which soluble IPP released in the supernatant from ZA-treated DC induces Vγ9Vδ2 T cell activation remain to be elucidated.