The ATP-binding cassette transporter A1 regulates phosphoantigen release and V\u03b39V\u03b42 T cell activation by dendritic cells

Barbara Castella,Joanna Kopecka,Nico Mitro,Francesco Novelli,Patrizia Sciancalepore,Massimo Massaia,Giorgia Mandili,Donatella Caruso,Myriam Foglietta,Chiara Riganti

doi:10.1038/ncomms15663

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.

Highlights

Vg9Vd2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells
Vg9Vd2 T cells are activated by antigen-presenting cells, such as dendritic cells (DC), when intracellular IPP generation is boosted with zoledronic acid (ZA), which is an inhibitor of the farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway[3,4,5]
We confirm that soluble IPP can induce Vg9Vd2 T cell activation[3,34] and demonstrate that the plasma-membraneassociated transporter ATP-binding cassette transporter A1 (ABCA1) plays a major role in the extracellular IPP release from ZA-treated DC and other cells. apoA-1 and BTN3A1 are important contributors to this process, which causes the activation of Vg9Vd2 T cells

Summary

Introduction

Vg9Vd2 T cells are activated by phosphoantigens, such as isopentenyl pyrophosphate (IPP), which is generated in the mevalonate pathway of antigen-presenting cells. Exogenously added apoA-I and apoE promoted extracellular IPP release only in cells with detectable ABCA1 expression, that is, untreated and ZA-treated DCU937 and DC. Vg9Vd2 T cell proliferation induced by supernatants from Abca1- and/or Btn3A1-silenced ZA-treated DC matched the extracellular IPP concentrations (Fig. 5g).

Results

Conclusion