The ATP-binding cassette transporter A1 regulates phosphoantigen release and Vγ9Vδ2 T cell activation by dendritic cells

Abstract

Vγ9Vδ2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells. IPP is released in the extracellular microenvironment via unknown mechanisms. Here we show that the ATP-binding cassette transporter A1 (ABCA1) mediates extracellular IPP release from dendritic cells (DC) in cooperation with apolipoprotein A-I (apoA-I) and butyrophilin-3A1. IPP concentrations in the supernatants are sufficient to induce Vγ9Vδ2 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA). ZA treatment increases ABCA1 and apoA-I expression via IPP-dependent LXRα nuclear translocation and PI3K/Akt/mTOR pathway inhibition. These results close the mechanistic gap in our understanding of extracellular IPP release from DC and provide a framework to fine-tune Vγ9Vδ2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation.

Integrated analysis of isopentenyl pyrophosphate (IPP) toxicity in isoprenoid-producing Escherichia coli

“…While cell lysis could still play a role in the "export" of IPP, follow-up analysis indicated that IPP is transported, or at least taken-up, by the engineered E. coli DH1 used in this study ( Figure 5). Recent work in mammalian dendritic cells showed that ATP-binding cassette transporter A1 (ABCA1) plays a role in extracellular IPP release (Castella et al, 2017). Several ABC transporters with homology to ABCA1 such as MetN were upregulated in strain 3Amk, though we are unable to link any of these transporters with IPP efflux with the current data set (Supplemental File S2, Jupyter R notebook "IPP_transcriptomics").…”

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

“…All data in the text and figures are provided as means ± SD. The results were analyzed by a one-way analysis of variance (ANOVA), using the Statistical Package for Social Science (SPSS) software (IBM SPSS Statistics v. 19). p < 0.05 was considered significant.…”

“…In the present work, we focused on a recently-discovered function of ABCA1, i.e., the efflux of the isoprenoid metabolite IPP that activates Vγ9Vδ2 T-cells [19], a subset of T-lymphocytes with potential killing activity against transformed cells that act also when αβ T-cell-mediated immunity is impaired [11,12,14]. Our gain-and loss-of-function experiments provided the demonstration that ABCA1 transports IPP and modulates the activity of Vγ9Vδ2 T-lymphocytes in osteosarcoma, as it does in antigen-presenting cells [19]. Moreover, we report for the first time a new chemo-immune-resistant phenotype, based on the simultaneous up-regulation of ABCB1 and down-regulation of ABCA1.…”

“…We next investigated if ABCA1 mediates the efflux of IPP and the anti-tumor activity of Vγ9δ2 T-lymphocytes in osteosarcoma, as it does in dendritic cells [19]. 2D U-2OS cells knocked-down for ABCA1 ( Figure 2A) had a reduced efflux of IPP to the same level of 3D U-2OS cells ( Figure 2B).…”

“…A strong endogenous activator of Vγ9Vδ2 T-cells is isopentenyl pyrophosphate (IPP), an isoprenoid metabolite produced during cholesterol synthesis [17]. We recently identified ATP Binding Cassette transporter A1 (ABCA1), a protein physiologically involved in cholesterol efflux and assembly of nascent HDL [18], as the efflux transporter of IPP in antigen-presenting cells, bone marrow stromal cells, and hematopoietic cells [19]. Moreover, we demonstrated that aminobisphosphonates such as zoledronic acid, a strong inhibitor of farnesyl pyrophosphate synthase (FPPS) [20], increase the intracellular accumulation and extracellular release of IPP in dendritic cells [17,19], activating Vγ9Vδ2 T-lymphocytes with anti-tumor activity.…”