The ATP-binding Cassette Transporter A1 Regulates Phosphoantigen Release and Vγ9Vδ2 T Cell Activation by Dendritic Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Jun 6

PMID 28580927

Citations 44

Authors

Barbara Castella

Joanna Kopecka

Patrizia Sciancalepore

Giorgia Mandili

Myriam Foglietta

Nico Mitro

Donatella Caruso

Francesco Novelli

Chiara Riganti

Massimo Massaia

Affiliations

Soon will be listed here.

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.

Citing Articles

Cholesterol efflux protein, ABCA1, supports anti-cancer functions of myeloid immune cells.

Bendre S, Wang Y, Hajyousif B, K C R, Rajendra K, Bhogale S bioRxiv. 2025; .

PMID: 40027727 PMC: 11870514. DOI: 10.1101/2025.02.19.638515.

TFEB controls sensitivity to chemotherapy and immuno-killing in non-small cell lung cancer.

Akman M, Monteleone C, Doronzo G, Godel M, Napoli F, Merlini A J Exp Clin Cancer Res. 2024; 43(1):219.

PMID: 39107857 PMC: 11304671. DOI: 10.1186/s13046-024-03142-4.

Intersecting Blood Cytokines With Cholesterol Parameters to Profile Patients With Advanced Solid Tumors Receiving Immune Checkpoint Inhibitors.

Mazzaschi G, Perrone F, Maglietta G, Favari E, Verze M, Pluchino M J Immunother. 2024; 47(9):388-394.

PMID: 38989743 PMC: 11441731. DOI: 10.1097/CJI.0000000000000534.

Cystatin from the helminth upregulates mevalonate and cholesterol biosynthesis pathways and immunomodulatory genes in human monocyte-derived dendritic cells.

Acevedo N, Lozano A, Zakzuk J, Llinas-Caballero K, Brodin D, Nejsum P Front Immunol. 2024; 15:1328401.

PMID: 38481989 PMC: 10936004. DOI: 10.3389/fimmu.2024.1328401.

Lymph-targeted high-density lipoprotein-mimetic nanovaccine for multi-antigenic personalized cancer immunotherapy.

Liu M, Feng Y, Lu Y, Huang R, Zhang Y, Zhao Y Sci Adv. 2024; 10(11):eadk2444.

PMID: 38478602 PMC: 10936870. DOI: 10.1126/sciadv.adk2444.

References

Mandili G, Khadjavi A, Gallo V, Minero V, Bessone L, Carta F . Characterization of the protein ubiquitination response induced by Doxorubicin. FEBS J. 2012; 279(12):2182-91. DOI: 10.1111/j.1742-4658.2012.08602.x. View

Hafiane A, Genest J . HDL, Atherosclerosis, and Emerging Therapies. Cholesterol. 2013; 2013:891403. PMC: 3678415. DOI: 10.1155/2013/891403. View

Riganti C, Castella B, Kopecka J, Campia I, Coscia M, Pescarmona G . Zoledronic acid restores doxorubicin chemosensitivity and immunogenic cell death in multidrug-resistant human cancer cells. PLoS One. 2013; 8(4):e60975. PMC: 3625183. DOI: 10.1371/journal.pone.0060975. View

Miraglia E, Viarisio D, Riganti C, Costamagna C, Ghigo D, Bosia A . Na+/H+ exchanger activity is increased in doxorubicin-resistant human colon cancer cells and its modulation modifies the sensitivity of the cells to doxorubicin. Int J Cancer. 2005; 115(6):924-9. DOI: 10.1002/ijc.20959. View

Dong F, Mo Z, Eid W, Courtney K, Zha X . Akt inhibition promotes ABCA1-mediated cholesterol efflux to ApoA-I through suppressing mTORC1. PLoS One. 2014; 9(11):e113789. PMC: 4240609. DOI: 10.1371/journal.pone.0113789. View

Riano F, Karunakaran M, Starick L, Li J, Scholz C, Kunzmann V . Vγ9Vδ2 TCR-activation by phosphorylated antigens requires butyrophilin 3 A1 (BTN3A1) and additional genes on human chromosome 6. Eur J Immunol. 2014; 44(9):2571-6. DOI: 10.1002/eji.201444712. View

Harly C, Guillaume Y, Nedellec S, Peigne C, Monkkonen H, Monkkonen J . Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset. Blood. 2012; 120(11):2269-79. PMC: 3679641. DOI: 10.1182/blood-2012-05-430470. View

Campia I, Sala V, Kopecka J, Leo C, Mitro N, Costamagna C . Digoxin and ouabain induce the efflux of cholesterol via liver X receptor signalling and the synthesis of ATP in cardiomyocytes. Biochem J. 2012; 447(2):301-11. DOI: 10.1042/BJ20120200. View

Beck L, Leroy C, Beck-Cormier S, Forand A, Salaun C, Paris N . The phosphate transporter PiT1 (Slc20a1) revealed as a new essential gene for mouse liver development. PLoS One. 2010; 5(2):e9148. PMC: 2818845. DOI: 10.1371/journal.pone.0009148. View

10.

Kilcollins A, Li J, Hsiao C, Wiemer A . HMBPP Analog Prodrugs Bypass Energy-Dependent Uptake To Promote Efficient BTN3A1-Mediated Malignant Cell Lysis by Vγ9Vδ2 T Lymphocyte Effectors. J Immunol. 2016; 197(2):419-28. PMC: 4935553. DOI: 10.4049/jimmunol.1501833. View

11.

dos Santos G, Reinders J, Ouwehand K, Rustemeyer T, Scheper R, Gibbs S . Progress on the development of human in vitro dendritic cell based assays for assessment of the sensitizing potential of a compound. Toxicol Appl Pharmacol. 2009; 236(3):372-82. DOI: 10.1016/j.taap.2009.02.004. View

12.

Lan Y, Chang C, Sung M, Yin P, Hsu C, Wang K . Zoledronic acid-induced cytotoxicity through endoplasmic reticulum stress triggered REDD1-mTOR pathway in breast cancer cells. Anticancer Res. 2013; 33(9):3807-14. View

13.

Okkenhaug K . Signaling by the phosphoinositide 3-kinase family in immune cells. Annu Rev Immunol. 2013; 31:675-704. PMC: 4516760. DOI: 10.1146/annurev-immunol-032712-095946. View

14.

Takahashi K, Kimura Y, Kioka N, Matsuo M, Ueda K . Purification and ATPase activity of human ABCA1. J Biol Chem. 2006; 281(16):10760-8. DOI: 10.1074/jbc.M513783200. View

15.

Nagarajan S, Raj R, Saravanakumar V, Balaguru U, Behera J, Rajendran V . Mechanical perturbations trigger endothelial nitric oxide synthase activity in human red blood cells. Sci Rep. 2016; 6:26935. PMC: 4921846. DOI: 10.1038/srep26935. View

16.

Castella B, Riganti C, Fiore F, Pantaleoni F, Canepari M, Peola S . Immune modulation by zoledronic acid in human myeloma: an advantageous cross-talk between Vγ9Vδ2 T cells, αβ CD8+ T cells, regulatory T cells, and dendritic cells. J Immunol. 2011; 187(4):1578-90. DOI: 10.4049/jimmunol.1002514. View

17.

Roelofs A, Thompson K, Gordon S, Rogers M . Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res. 2006; 12(20 Pt 2):6222s-6230s. DOI: 10.1158/1078-0432.CCR-06-0843. View

18.

Gan X, Kaplan R, Menke J, MacNaul K, Chen Y, Sparrow C . Dual mechanisms of ABCA1 regulation by geranylgeranyl pyrophosphate. J Biol Chem. 2001; 276(52):48702-8. DOI: 10.1074/jbc.M109402200. View

19.

Scotet E, Martinez L, Grant E, Barbaras R, Jeno P, Guiraud M . Tumor recognition following Vgamma9Vdelta2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A-I. Immunity. 2005; 22(1):71-80. DOI: 10.1016/j.immuni.2004.11.012. View

20.

Kopecka J, Salzano G, Campia I, Lusa S, Ghigo D, De Rosa G . Insights in the chemical components of liposomes responsible for P-glycoprotein inhibition. Nanomedicine. 2013; 10(1):77-87. DOI: 10.1016/j.nano.2013.06.013. View