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

Barbara Castella, Joanna Kopecka, Patrizia Sciancalepore, Giorgia Mandili, Myriam Foglietta, Nico Mitro, Donatella Caruso, Francesco Novelli, Chiara Riganti () and Massimo Massaia ()
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Barbara Castella: Università degli Studi di Torino
Joanna Kopecka: Università degli Studi di Torino
Patrizia Sciancalepore: Università degli Studi di Torino
Giorgia Mandili: Università degli Studi di Torino
Myriam Foglietta: Università degli Studi di Torino
Nico Mitro: Università degli Studi di Milano
Donatella Caruso: Università degli Studi di Milano
Francesco Novelli: Università degli Studi di Torino
Chiara Riganti: Centro di Ricerca in Medicina Sperimentale (CeRMS), AOU Città della Salute e della Scienza di Torino
Massimo Massaia: Università degli Studi di Torino

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15663

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