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; Massimo Massaia

doi:10.1038/ncomms15663

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

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

Authors

Barbara Castella^{1

2}, Joanna Kopecka³, Patrizia Sciancalepore^{1

2}, Giorgia Mandili^{1

4}, Myriam Foglietta^{1

2}, Nico Mitro⁵, Donatella Caruso⁵, Francesco Novelli^{1

4}, Chiara Riganti^{2

3}, Massimo Massaia^{1

2

4

6}

Affiliations

¹ Dipartimento di Biotecnologie Molecolari e Scienze della Salute, Università degli Studi di Torino, Via Nizza 52, Torino 10126, Italy.
² Centro di Ricerca in Medicina Sperimentale (CeRMS), AOU Città della Salute e della Scienza di Torino, Via Santena 5, Torino 10126, Italy.
³ Dipartimento di Oncologia, Università degli Studi di Torino, Via Santena 5/bis, Torino 10126, Italy.
⁴ Centro Interdipartimentale di Ricerca per le Biotecnologie Molecolari (CIRBM), Via Nizza 52, Torino 10126, Italy.
⁵ Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, Milano 20133, Italy.
⁶ SC. Ematologia, AO S. Croce e Carle, Via Michele Coppino 26, Cuneo 12100, Italy.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter 1 / metabolism*
Active Transport, Cell Nucleus
Adenosine Triphosphate / chemistry*
Antigens, CD / metabolism
Apolipoprotein A-I / metabolism
Butyrophilins / metabolism
Cell Proliferation
Dendritic Cells / cytology
Dendritic Cells / immunology
Dendritic Cells / metabolism*
Hemiterpenes
Humans
Immunophenotyping
Lipid Metabolism
Lymphocyte Activation / immunology*
Organophosphorus Compounds
Phosphatidylinositol 3-Kinases / metabolism
Protein Binding
Receptors, Antigen, T-Cell, gamma-delta / immunology
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
T-Lymphocytes / immunology
U937 Cells
Zoledronic Acid

Substances

ABCA1 protein, human
ATP Binding Cassette Transporter 1
Antigens, CD
Apolipoprotein A-I
BTN3A1 protein, human
Butyrophilins
Hemiterpenes
Organophosphorus Compounds
Receptors, Antigen, T-Cell, gamma-delta
isopentenyl pyrophosphate
Zoledronic Acid
Adenosine Triphosphate
Phosphatidylinositol 3-Kinases