期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms15663
关键词
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资金
- Italian Association for Cancer Research (AIRC) [MFAG11475, IG15232, 12182, IG 15257, IG 13119, IG 16985]
- PRIN [2010NECHBX_002]
- Compagnia San Paolo-University of Turin
- Progetti Ateneo [2014-PC_METHAIMMUNOTHER, 2011-RETHE]
- Fondazione Ricerca Molinette
- AIRC
- Fondazione Umberto Veronesi
V gamma 9V delta 2 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 V gamma 9V delta 2 T cell proliferation after DC mevalonate pathway inhibition with zoledronic acid (ZA). ZA treatment increases ABCA1 and apoA-I expression via IPP-dependent LXR alpha 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 V gamma 9V delta 2 T cell activation via mevalonate and PI3K/Akt/mTOR pathway modulation.
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