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Nat Commun. 2017 Jun 5;8:15663. doi: 10.1038/ncomms15663.

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

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Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Via Nizza 52, Torino 10126, Italy.
Centro di Ricerca in Medicina Sperimentale (CeRMS), AOU Città della Salute e della Scienza di Torino, Via Santena 5, Torino 10126, Italy.
Dipartimento di Oncologia, Università degli Studi di Torino, Via Santena 5/bis, Torino 10126, Italy.
Centro Interdipartimentale di Ricerca per le Biotecnologie Molecolari (CIRBM), Via Nizza 52, Torino 10126, Italy.
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, Milano 20133, Italy.
SC. Ematologia, AO S. Croce e Carle, Via Michele Coppino 26, Cuneo 12100, Italy.


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.

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