ABCA1, apoA-I, and BTN3A1: A Legitimate Ménage à Trois in Dendritic Cells.

Chiara Riganti,Barbara Castella,Massimo Massaia

doi:10.3389/fimmu.2018.01246

Chiara Riganti, Barbara Castella + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2018.01246

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Abstract

Human Vγ9Vδ2 T cells have the capacity to detect supra-physiological concentrations of phosphoantigens (pAgs) generated by the mevalonate (Mev) pathway of mammalian cells under specific circumstances. Isopentenyl pyrophosphate (IPP) is the prototypic pAg recognized by Vγ9Vδ2 T cells. B-cell derived tumor cells (i.e., lymphoma and myeloma cells) and dendritic cells (DCs) are privileged targets of Vγ9Vδ2 T cells because they generate significant amounts of IPP which can be boosted with zoledronic acid (ZA). ZA is the most potent aminobisphosphonate (NBP) clinically available to inhibit osteoclast activation and a very potent inhibitor of farnesyl pyrophosphate synthase in the Mev pathway. ZA-treated DCs generate and release in the supernatants picomolar IPP concentrations which are sufficient to induce the activation of Vγ9Vδ2 T cells. We have recently shown that the ATP-binding cassette transporter A1 (ABCA1) plays a major role in the extracellular release of IPP from ZA-treated DCs. This novel ABCA1 function is fine-tuned by physical interactions with IPP, apolipoprotein A-I (apoA-I), and butyrophilin-3A1 (BTN3A1). The mechanisms by which soluble IPP induces Vγ9Vδ2 T-cell activation remain to be elucidated. It is possible that soluble IPP binds to BTN3A1, apoA-I, or other unknown molecules on the cell surface of bystander cells like monocytes, NK cells, Vγ9Vδ2 T cells, or any other cell locally present. Investigating this scenario may represent a unique opportunity to further characterize the role of BTN3A1 and other molecules in the recognition of soluble IPP by Vγ9Vδ2 T cells.

Highlights

A very peculiar feature of Vγ9Vδ2 T cells is their TCR-dependent, MHC-independent recognition of phosphoantigens [1]. pAgs are pyrophosphorylated isoprenoids generated in the mevalonate (Mev) pathway of mammalian cells
We have found that ATP-binding cassette transporter A1 (ABCA1) plays a major role in the extracellular Isopentenyl pyrophosphate (IPP) release from zoledronic acid (ZA)-treated dendritic cells (DCs) and other cells, and that IPP cannot be released in the SNs of ZA-treated DCs if ABCA1 is not present or functionally active
We have shown that IPP extracellular release by ABCA1 overcomes that of cholesterol only when supra-physiological concentration of IPP are reached as a consequence of ZA-induced farnesylpyrophosphate synthase (FPPS) inhibitions [31]

Summary

INTRODUCTION

A very peculiar feature of Vγ9Vδ2 T cells is their TCR-dependent, MHC-independent recognition of phosphoantigens (pAgs) [1]. pAgs are pyrophosphorylated isoprenoids generated in the mevalonate (Mev) pathway of mammalian cells. Several technologies have been used to generate pAg prodrugs with the aim to overcome the poor cell membrane permeability and limited in vivo stability of pyrophosphate containing pAgs [14, 15] Another strategy which has been used in vivo and in vitro to activate Vγ9Vδ2 T cells is to intentionally increase intracellular IPP concentrations in tumor cells and/or antigen-presenting cells (APCs) like monocytes or dendritic cells (DCs) with aminobisphosphonates (NBP) [16], and alkylamines [17, 18]. HMBPP, HDMAPP, and all HDMAPP-adenylated, thymidylated, and uridylated pyrophosphoric derivatives are potent Vγ9Vδ2 T-cell activators without any capacity to bind F1-ecto-ATPase [9, 38] These nucleotides are released in the extracellular microenvironment by non-apoptotic cells or bacteria and cleaved by extracellular pyrophosphatase [39]. All these findings have enforced the idea that apoA-I is a necessary player in the efflux, delivery and pAg presentation to Vγ9Vδ2 T cells [32]

LOOKING FOR SOLUBLE pAg

CONCLUSION