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Human plasmacytoid dendritic cells express the functional purinergic halo (CD39/CD73)

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Abstract

Plasmacytoid dendritic cells (pDCs) are a specialized DC subset mainly associated with sensing viral pathogens and high-type I interferon (IFN-I) release in response to toll-like receptor (TLR)-7 and TLR-9 signaling. Currently, pDC contribution to inflammatory responses is extensively described; nevertheless, their regulatory mechanisms require further investigation. CD39 and CD73 are ectoenzymes driving a shift from an ATP-proinflammatory milieu to an anti-inflammatory environment by converting ATP to adenosine. Although the regulatory function of the purinergic halo CD39/CD73 has been reported in some immune cells like regulatory T cells and conventional DCs, its presence in pDCs has not been examined. In this study, we uncover for the first time the expression and functionality of the purinergic halo in human blood pDCs. In healthy donors, CD39 was expressed in the cell surface of 14.0 ± 12.5% pDCs under steady-state conditions, while CD73 showed an intracellular location and was only expressed in 8.0 ± 2.2% of pDCs. Nevertheless, pDCs stimulation with a TLR-7 agonist (R848) induced increased surface expression of both molecules (43.3 ± 23.7% and 18.6 ± 9.3%, respectively), as well as high IFN-α secretion. Furthermore, exogenous ATP addition to R848-activated pDCs significantly increased adenosine generation. This effect was attributable to the superior CD73 expression and activity because blocking CD73 reduced adenosine production and improved pDC allostimulatory capabilities on CD4 + T cells. The functional expression of the purinergic halo in human pDCs described in this work opens new areas to investigate its participation in the regulatory pDC mechanisms in health and disease.

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References

  1. Ye Y, Gaugler B, Mohty M, Malard F (2020) Plasmacytoid dendritic cell biology and its role in immune-mediated diseases. Clin Transl Immunol 9(5):e1139. https://doi.org/10.1002/cti2.1139

    Article  Google Scholar 

  2. Villani AC, Satija R, Reynolds G, Sarkizova S, Shekhar K, Fletcher J, Griesbeck M, Butler A, Zheng S, Lazo S, Jardine L, Dixon D, Stephenson E, Nilsson E, Grundberg I, McDonald D, Filby A, Li W, De Jager PL, Rozenblatt-Rosen O, Lane AA, Haniffa M, Regev A, Hacohen N (2017) Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science 356(6335):eaah4573. https://doi.org/10.1126/science.aah4573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T, Takaoka A, Taya C, Taniguchi T (2005) Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434(7036):1035–1040. https://doi.org/10.1038/nature03547

    Article  CAS  PubMed  Google Scholar 

  4. Bao M, Liu YJ (2013) Regulation of TLR7/9 signaling in plasmacytoid dendritic cells. Protein Cell 4(1):40–52. https://doi.org/10.1007/s13238-012-2104-8

    Article  CAS  PubMed  Google Scholar 

  5. Alculumbre SG, Saint-André V, Di Domizio J, Vargas P, Sirven P, Bost P, Maurin M, Maiuri P, Wery M, Roman MS, Savey L, Touzot M, Terrier B, Saadoun D, Conrad C, Gilliet M, Morillon A, Soumelis V (2018) Diversification of human plasmacytoid predendritic cells in response to a single stimulus. Nat Immunol 19(1):63–75. https://doi.org/10.1038/s41590-017-0012-z

    Article  CAS  PubMed  Google Scholar 

  6. Alculumbre S, Raieli S, Hoffmann C, Chelbi R, Danlos FX, Soumelis V (2019) Plasmacytoid pre-dendritic cells (pDC): from molecular pathways to function and disease association. Semin Cell Dev Biol 86:24–35. https://doi.org/10.1016/j.semcdb.2018.02.014

    Article  CAS  PubMed  Google Scholar 

  7. Sakata K, Nakayamada S, Miyazaki Y, Kubo S, Ishii A, Nakano K, Tanaka Y (2018) Up-regulation of TLR7-mediated IFN-α production by plasmacytoid dendritic cells in patients with systemic lupus erythematosus. Front Immunol 9:1957. https://doi.org/10.3389/fimmu.2018.01957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gilliet M, Conrad C, Geiges M, Cozzio A, Thürlimann W, Burg G, Nestle FO, Dummer R (2004) Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors. Arch Dermatol 140(12):1490–1495. https://doi.org/10.1001/archderm.140.12.1490

    Article  CAS  PubMed  Google Scholar 

  9. Swiecki M, Colonna M (2015) The multifaceted biology of plasmacytoid dendritic cells. Nat Rev Immunol 15(8):471–485. https://doi.org/10.1038/nri3865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Faget J, Bendriss-Vermare N, Gobert M, Durand I, Olive D, Biota C, Bachelot T, Treilleux I, Goddard-Leon S, Lavergne E, Chabaud S, Blay JY, Caux C, Ménétrier-Caux C (2012) ICOS-ligand expression on plasmacytoid dendritic cells supports breast cancer progression by promoting the accumulation of immunosuppressive CD4+ T cells. Cancer Res 72(23):6130–6141. https://doi.org/10.1158/0008-5472.CAN-12-2409

    Article  CAS  PubMed  Google Scholar 

  11. Mitchell D, Chintala S, Dey M (2018) Plasmacytoid dendritic cell in immunity and cancer. J Neuroimmunol 322:63–73. https://doi.org/10.1016/j.jneuroim.2018.06.012

    Article  CAS  PubMed  Google Scholar 

  12. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, Robson SC (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204(6):1257–1265. https://doi.org/10.1084/jem.20062512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Antonioli L, Pacher P, Vizi ES, Haskó G (2013) CD39 and CD73 in immunity and inflammation. Trends Mol Med 19(6):355–367. https://doi.org/10.1016/j.molmed.2013.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Allard B, Longhi MS, Robson SC, Stagg J (2017) The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev 276(1):121–144. https://doi.org/10.1111/imr.12528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cauwels A, Rogge E, Vandendriessche B, Shiva S, Brouckaert P (2014) Extracellular ATP drives systemic inflammation, tissue damage and mortality. Cell Death Dis 5(3):e1102. https://doi.org/10.1038/cddis.2014.70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Effendi WI, Nagano T, Kobayashi K, Nishimura Y (2020) Focusing on adenosine receptors as a potential targeted therapy in human diseases. Cells 9(3):785. https://doi.org/10.3390/cells9030785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bono MR, Fernández D, Flores-Santibáñez F, Rosemblatt M, Sauma D (2015) CD73 and CD39 ectonucleotidases in T cell differentiation: beyond immunosuppression. FEBS Lett 589(22):3454–3460. https://doi.org/10.1016/j.febslet.2015.07.027

    Article  CAS  PubMed  Google Scholar 

  18. Dong K, Gao ZW, Zhang HZ (2016) The role of adenosinergic pathway in human autoimmune diseases. Immunol Res 64(5–6):1133–1141. https://doi.org/10.1007/s12026-016-8870-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Schuler PJ, Saze Z, Hong CS, Muller L, Gillespie DG, Cheng D, Harasymczuk M, Mandapathil M, Lang S, Jackson EK, Whiteside TL (2014) Human CD4+ CD39+ regulatory T cells produce adenosine upon coexpression of surface CD73 or contact with CD73+ exosomes or CD73+ cells. Clin Exp Immunol 177(2):531–543. https://doi.org/10.1111/cei.12354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Alam MS, Costales MG, Cavanaugh C, Williams K (2015) Extracellular adenosine generation in the regulation of proinflammatory responses and pathogen colonization. Biomolecules 5(2):775–792. https://doi.org/10.3390/biom5020775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Regateiro FS, Howie D, Nolan KF, Agorogiannis EI, Greaves DR, Cobbold SP, Waldmann H (2011) Generation of antiinflammatory adenosine by leukocytes is regulated by TGF-β. Eur J Immunol 41(10):2955–2965. https://doi.org/10.1002/eji.201141512

    Article  CAS  PubMed  Google Scholar 

  22. Ray A, Song Y, Du T, Buon L, Tai YT, Chauhan D, Anderson KC (2022) Identification and validation of ecto-5’ nucleotidase as an immunotherapeutic target in multiple myeloma. Blood Cancer J 12(4):50. https://doi.org/10.1038/s41408-022-00635-3

    Article  PubMed  PubMed Central  Google Scholar 

  23. Panda SK, Kolbeck R, Sanjuan MA (2017) Plasmacytoid dendritic cells in autoimmunity. Curr Opin Immunol 44:20–25. https://doi.org/10.1016/j.coi.2016.10.006

    Article  CAS  PubMed  Google Scholar 

  24. Ohta A, Sitkovsky M (2014) Extracellular adenosine-mediated modulation of regulatory T cells. Front Immunol 5:304. https://doi.org/10.3389/fimmu.2014.00304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Torres-Aguilar H, Aguilar-Ruiz SR, González-Pérez G, Munguía R, Bajaña S, Meraz-Ríos MA, Sánchez-Torres C (2010) Tolerogenic dendritic cells generated with different immunosuppressive cytokines induce antigen-specific anergy and regulatory properties in memory CD4+ T cells. J Immunol 184(4):1765–1775. https://doi.org/10.4049/jimmunol.0902133

    Article  CAS  PubMed  Google Scholar 

  26. See P, Dutertre CA, Chen J, Günther P, McGovern N, Irac SE, Gunawan M, Beyer M, Händler K, Duan K, Sumatoh HRB, Ruffin N, Jouve M, Gea-Mallorquí E, Hennekam RCM, Lim T, Yip CC, Wen M, Malleret B, Low I, Shadan NB, Fen CFS, Tay A, Lum J, Zolezzi F, Larbi A, Poidinger M, Chan JKY, Chen Q, Rénia L, Haniffa M, Benaroch P, Schlitzer A, Schultze JL, Newell EW, Ginhoux F (2017) Mapping the human DC lineage through the integration of high-dimensional techniques. Science 356(6342):eaag3009. https://doi.org/10.1126/science.aag3009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mandapathil M, Hilldorfer B, Szczepanski MJ, Czystowska M, Szajnik M, Ren J, Lang S, Jackson EK, Gorelik E, Whiteside TL (2009) Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells. J Biol Chem 285(10):7176–7186. https://doi.org/10.1074/jbc.M109.047423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lehto MT, Sharom FJ (1998) Release of the glycosylphosphatidylinositol-anchored enzyme ecto-5’-nucleotidase by phospholipase C: catalytic activation and modulation by the lipid bilayer. Biochem J. 332(Pt 1):101–109. https://doi.org/10.1042/bj3320101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schneider E, Rissiek A, Winzer R, Puig B, Rissiek B, Haag F, Mittrücker HW, Magnus T, Tolosa E (2019) Generation and function of non-cell-bound CD73 in inflammation. Front Immunol 10:1729. https://doi.org/10.3389/fimmu.2019.01729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nedeljkovic N (2019) Complex regulation of ecto-5’-nucleotidase/CD73 and A2AR-mediated adenosine signaling at neurovascular unit: a link between acute and chronic neuroinflammation. Pharmacol Res 144:99–115. https://doi.org/10.1016/j.phrs.2019.04.007

    Article  CAS  PubMed  Google Scholar 

  31. Pettengill M, Robson S, Tresenriter M, Millán JL, Usheva A, Bingham T, Belderbos M, Bergelson I, Burl S, Kampmann B, Gelinas L, Kollmann T, Bont L, Levy O (2013) Soluble ecto-5’-nucleotidase (5’-NT), alkaline phosphatase, and adenosine deaminase (ADA1) activities in neonatal blood favor elevated extracellular adenosine. J Biol Chem 288(38):27315–27326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fredholm B (2007) Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 14(7):1315–1323. https://doi.org/10.1038/sj.cdd.4402132

    Article  CAS  PubMed  Google Scholar 

  33. Bajnok A, Ivanova M, Rigó J Jr, Toldi G (2017) The distribution of activation markers and selectins on peripheral T lymphocytes in preeclampsia. Mediators Inflamm 2017:8045161. https://doi.org/10.1155/2017/8045161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Young LJ, Wilson NS, Schnorrer P, Proietto A, ten Broeke T, Matsuki Y, Mount AM, Belz GT, O’Keeffe M, Ohmura-Hoshino M, Ishido S, Stoorvogel W, Heath WR, Shortman K, Villadangos JA (2008) Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells. Nat Immunol 11:1244–1252. https://doi.org/10.1038/ni.1665

    Article  CAS  Google Scholar 

  35. Linnemann C, Schildberg FA, Schurich A, Diehl L, Hegenbarth SI, Endl E, Lacher S, Müller CE, Frey J, Simeoni L, Schraven B, Stabenow D, Knolle PA (2009) Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling. Immunology 128(1 Suppl):e728–e737. https://doi.org/10.1111/j.1365-2567.2009.03075.x

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the National Laboratory of Cytometry (LABNACIT-UNAM-UABJO-UACH), and the doctoral fellowships of Consejo Nacional de Ciencia y Tecnologia [660793 SLSA], [827788 RRWJ], and [AAA]. Dr. Jose Luis Maravillas Montero for his support in the methodological development of this work.

Funding

This work was supported by the Consejo Nacional de Ciencia y Tecnologia (CONACyT): grants #285480 and SEP-CONACYT #A1-S-9430, and the Department of Clinical Immunology Research of the Biochemical Sciences Faculty, Universidad Autónoma “Benito Juárez” de Oaxaca.

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Authors and Affiliations

  1. Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Av. Instituto Politécnico Nacional 2508. Col. San Pedro Zacatenco, C.P. 07360, Mexico City, México

    S. A. Sosa-Luis & C. Sánchez-Torres

  2. Clinical Immunology Research Department, Faculty of Biochemical Sciences, Universidad Autónoma “Benito Juárez” de Oaxaca, Av. Universidad S/N Ex-Hacienda Cinco Señores, C.P. 68120, Oaxaca de Juárez, Oaxaca, México

    W. J. Ríos-Ríos, A. Almaraz-Arreortua & H. Torres-Aguilar

  3. CONACYT-UABJO, Faculty of Medicine and Surgery, Ex Hacienda de Aguilera S/N, Sur, 68020 San Felipe del Agua, Oaxaca de Juárez, Oaxaca, México

    M. A. Romero-Tlalolini

  4. Molecular Immunology Research Department, Faculty of Medicine and Surgery, Universidad Autónoma “Benito Juárez” de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, 68020 San Felipe del Agua, Oaxaca, México

    S. R. Aguilar-Ruiz

  5. Research Division, Faculty of Medicine, Universidad Nacional Autónoma de México (UNAM), C.P. 04360, Mexico City, Mexico

    R. Valle-Ríos

  6. Hospital Infantil de México Federico Gómez, Unidad de Investigación en Inmunología Y Proteómica, C.P. 06720, Mexico City, Mexico

    R. Valle-Ríos

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  1. S. A. Sosa-Luis
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Contributions

Conceptualization: T.A.H. and S.T.C.; experimental and methodologic investigation: S.L.S.A, R.R.W.J., and A.A.A.; methodologic support: R.T.M.A., V.R.R., and A.R.S.R.; writing original draft preparation, S.L.S.A. and R.R.W.J.; writing—review and editing: T.A.H. and S.T.C.; supervision: T.A.H. and S.T.C.; funding acquisition: T.A.H. All authors have read and agreed to the published version of the manuscript.

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Correspondence to H. Torres-Aguilar.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Bioethics Committee of the Hospital Regional de Alta Especialidad de Oaxaca (HRAEO-CIC-CEI 013/16).

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Sosa-Luis, S.A., Ríos-Ríos, W.J., Almaraz-Arreortua, A. et al. Human plasmacytoid dendritic cells express the functional purinergic halo (CD39/CD73). Purinergic Signalling 20, 73–82 (2024). https://doi.org/10.1007/s11302-023-09940-3

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