Vγ39Vδ2 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 Vγ39Vδ2 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 Vγ39Vδ2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation.
The ATP-binding cassette transporter A1 regulates phosphoantigen release and Vγ39Vδ2 T cell activation by dendritic cells / B. Castella, J. Kopecka, P. Sciancalepore, G. Mandili, M. Foglietta, N. Mitro, D. Caruso, F. Novelli, C. Riganti, M. Massaia. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 8:(2017 Jun 05). [10.1038/ncomms15663]
The ATP-binding cassette transporter A1 regulates phosphoantigen release and Vγ39Vδ2 T cell activation by dendritic cells
N. MitroMembro del Collaboration Group
;D. Caruso;
2017
Abstract
Vγ39Vδ2 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 Vγ39Vδ2 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 Vγ39Vδ2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation.File | Dimensione | Formato | |
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