Advertisement

Plasmacytoid Dendritic Cells in Tolerance

  • Eric Gehrie
  • William Van der Touw
  • Jonathan S. Bromberg
  • Jordi C. OchandoEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 677)

Abstract

Dendritic cells (DC) are professional antigen-presenting cells (APCs) that modulate the outcome of the immune response toward immunity or tolerance. There are a large variety of DC subsets according to surface phenotype, function, and tissue distribution. Murine plasmacytoid DC (pDC) represent a distinctive DC population and are characterized by the expression of CD11c, B220, Gr-1, CD45RA, Ly49Q, BST2, and siglec-H on the cell surface. PDC act as immunogenic cell sentinels by secreting large amounts of type I interferon (IFN) in the lymph nodes in response to viral stimulation. PDC also act as tolerogenic cells when expressing the inducible tolerogenic enzyme indoleamine 2,3-dioxygenase (IDO), the inducible costimulator ligand (ICOS-L), and/or the programmed death 1 ligand (PD-L1), which mediate regulatory T-cell (Treg) development and suppression of self- and alloreactive cells. The PDC ability to induce Treg development is associated with capture and presentation of antigenic peptides associated with major histocompatibility complex (MHC) class I and II. Here, we provide the tools to study PDC development from bone marrow cultures, their antigen presentation properties, and their interactions with Treg under a tolerogenic setting of sterile inflammation.

Key words

Plasmacytoid dendritic cells Antigen presentation Regulatory T cells 

Notes

Acknowledgments

We acknowledge Dr. Tamar Hermesh for technical assistance. We also wish to acknowledge the efforts of the Mount Sinai Sorting Core Facility. This work was supported by the Programa Ramón y Cajal RYC-2006-1588, Ministerio de Educación y Ciencia SAF2007-63579, Programa José Castillejo JC2008-00065, and Programa de Investigación de Grupos Emergentes del ISCIII (to JCO), NIH R01 AI-41428, AI-72039 (to JSB), and Howard Hughes Medical Institute (to EG).

References

  1. 1.
    Onai N, Obata-Onai A, Schmid MA, Ohteki T, Jarrossay D, Manz MG: Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nat Immunol 2007, 8:1207–1216.PubMedCrossRefGoogle Scholar
  2. 2.
    Nakano H, Yanagita M, Gunn MD: CD11c(+)B220(+)Gr-1(+) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells. J Exp Med 2001, 194:1171–1178.PubMedCrossRefGoogle Scholar
  3. 3.
    Naik SH, Sathe P, Park HY, Metcalf D, Proietto AI, Dakic A, Carotta S, O’Keeffe M, Bahlo M, Papenfuss A, et al.: Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat Immunol 2007, 8:1217–1226.PubMedCrossRefGoogle Scholar
  4. 4.
    Omatsu Y, Iyoda T, Kimura Y, Maki A, Ishimori M, Toyama-Sorimachi N, Inaba K: Development of murine plasmacytoid dendritic cells defined by increased expression of an inhibitory NK receptor, Ly49Q. J Immunol 2005, 174:6657–6662.PubMedGoogle Scholar
  5. 5.
    Zhang J, Raper A, Sugita N, Hingorani R, Salio M, Palmowski MJ, Cerundolo V, Crocker PR: Characterization of Siglec-H as a novel endocytic receptor expressed on murine plasmacytoid dendritic cell precursors. Blood 2006, 107:3600–3608.PubMedCrossRefGoogle Scholar
  6. 6.
    Blasius A, Vermi W, Krug A, Facchetti F, Cella M, Colonna M: A cell-surface molecule selectively expressed on murine natural interferon-producing cells that blocks secretion of interferon-alpha. Blood 2004, 103:4201–4206.PubMedCrossRefGoogle Scholar
  7. 7.
    Blasius AL, Giurisato E, Cella M, Schreiber RD, Shaw AS, Colonna M: Bone marrow stromal cell antigen 2 is a specific marker of type I IFN-producing cells in the naive mouse, but a promiscuous cell surface antigen following IFN stimulation. J Immunol 2006, 177:3260–3265.PubMedGoogle Scholar
  8. 8.
    Martin P, Del Hoyo GM, Anjuere F, Arias CF, Vargas HH, Fernandez LA, Parrillas V, Ardavin C: Characterization of a new subpopulation of mouse CD8alpha+ B220+ dendritic cells endowed with type 1 interferon production capacity and tolerogenic potential. Blood 2002, 100:383–390.PubMedCrossRefGoogle Scholar
  9. 9.
    Hadeiba H, Sato T, Habtezion A, Oderup C, Pan J, Butcher EC: CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nat Immunol 2008, 9:1253–1260.PubMedCrossRefGoogle Scholar
  10. 10.
    Jongbloed SL, Benson RA, Nickdel MB, Garside P, McInnes IB, Brewer JM: Plasma cytoid dendritic cells regulate breach of self-tolerance in autoimmune arthritis. J Immunol 2009, 182:963–968.PubMedGoogle Scholar
  11. 11.
    Dubois B, Joubert G, Gomez de Aguero M, Gouanvic M, Goubier A, Kaiserlian D: Sequential role of plasmacytoid dendritic cells and regulatory T cells in oral tolerance. Gastroenterology 2009, 137:1019–1028.PubMedCrossRefGoogle Scholar
  12. 12.
    Chen X, Makala LH, Jin Y, Hopkins D, Muir A, Garge N, Podolsky RH, She JX: Type 1 diabetes patients have significantly lower frequency of plasmacytoid dendritic cells in the peripheral blood. Clin Immunol 2008, 129:413–418.PubMedCrossRefGoogle Scholar
  13. 13.
    Hinkmann C, Knerr I, Hahn EG, Lohmann T, Seifarth CC: Reduced frequency of peripheral plasmacytoid dendritic cells in type 1 diabetes. Horm Metab Res 2008, 40:767–771.PubMedCrossRefGoogle Scholar
  14. 14.
    Saxena V, Ondr JK, Magnusen AF, Munn DH, Katz JD: The countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes in the nonobese diabetic mouse. J Immunol 2007, 179:5041–5053.PubMedGoogle Scholar
  15. 15.
    Tokita D, Sumpter TL, Raimondi G, Zahorchak AF, Wang Z, Nakao A, Mazariegos GV, Abe M, Thomson AW: Poor allostimulatory function of liver plasmacytoid DC is associated with pro-apoptotic activity, dependent on regulatory T cells. J Hepatol 2008, 49:1008–1018.PubMedCrossRefGoogle Scholar
  16. 16.
    Goubier A, Dubois B, Gheit H, Joubert G, Villard-Truc F, Asselin-Paturel C, Trinchieri G, Kaiserlian D: Plasmacytoid dendritic cells mediate oral tolerance. Immunity 2008, 29:464–475.PubMedCrossRefGoogle Scholar
  17. 17.
    Manches O, Munn D, Fallahi A, Lifson J, Chaperot L, Plumas J, Bhardwaj N: HIV-acti vated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J Clin Invest 2008, 118:3431–3439.PubMedCrossRefGoogle Scholar
  18. 18.
    Puccetti P, Fallarino F: Generation of T cell regulatory activity by plasmacytoid dendritic cells and tryptophan catabolism. Blood Cells Mol Dis 2008, 40:101–105.PubMedCrossRefGoogle Scholar
  19. 19.
    Wang L, Pino-Lagos K, de Vries VC, Guleria I, Sayegh MH, Noelle RJ: Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci U S A 2008, 105:9331–9336.PubMedCrossRefGoogle Scholar
  20. 20.
    Tokita D, Mazariegos GV, Zahorchak AF, Chien N, Abe M, Raimondi G, Thomson AW: High PD-L1/CD86 ratio on plasmacytoid dendritic cells correlates with elevated T-regulatory cells in liver transplant tolerance. Transplantation 2008, 85:369–377.PubMedCrossRefGoogle Scholar
  21. 21.
    Ito T, Yang M, Wang YH, Lande R, Gregorio J, Perng OA, Qin XF, Liu YJ, Gilliet M: Plasma cytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costi mulator ligand. J Exp Med 2007, 204:105–115.PubMedCrossRefGoogle Scholar
  22. 22.
    Munn DH, Sharma MD, Hou D, Baban B, Lee JR, Antonia SJ, Messina JL, Chandler P, Koni PA, Mellor AL: Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J Clin Invest 2004, 114:280–290.PubMedGoogle Scholar
  23. 23.
    Sharma MD, Baban B, Chandler P, Hou DY, Singh N, Yagita H, Azuma M, Blazar BR, Mellor AL, Munn DH: Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 2007, 117:2570–2582.PubMedCrossRefGoogle Scholar
  24. 24.
    Sapoznikov A, Fischer JA, Zaft T, Krauthgamer R, Dzionek A, Jung S: Organ-dependent in vivo priming of naive CD4+, but not CD8+, T cells by plasmacytoid dendritic cells. J Exp Med 2007, 204:1923–1933.PubMedCrossRefGoogle Scholar
  25. 25.
    Pepper M, Dzierszinski F, Wilson E, Tait E, Fang Q, Yarovinsky F, Laufer TM, Roos D, Hunter CA: Plasmacytoid dendritic cells are activated by Toxoplasma gondii to present antigen and produce cytokines. J Immunol 2008, 180:6229–6236.PubMedGoogle Scholar
  26. 26.
    Koyama M, Hashimoto D, Aoyama K, Matsuoka K, Karube K, Niiro H, Harada M, Tanimoto M, Akashi K, Teshima T: Plasma cytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells. Blood 2009, 113:2088–2095.PubMedCrossRefGoogle Scholar
  27. 27.
    Sadaka C, Marloie-Provost MA, Soumelis V, Benaroch P: Developmental regulation of MHC II expression and transport in human plasmacytoid-derived dendritic cells. Blood 2009, 113:2127–2135.PubMedCrossRefGoogle Scholar
  28. 28.
    Young LJ, Wilson NS, Schnorrer P, Proietto A, ten Broeke T, Matsuki Y, Mount AM, Belz GT, O’Keeffe M, Ohmura-Hoshino M, et al.: Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells. Nat Immunol 2008, 9:1244–1252.PubMedCrossRefGoogle Scholar
  29. 29.
    Darrasse-Jeze G, Deroubaix S, Mouquet H, Victora GD, Eisenreich T, Yao KH, Masilamani RF, Dustin ML, Rudensky A, Liu K, et al.: Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J Exp Med 2009, 206:1853–1862.PubMedCrossRefGoogle Scholar
  30. 30.
    Ochando JC, Homma C, Yang Y, Hidalgo A, Garin A, Tacke F, Angeli V, Li Y, Boros P, Ding Y, et al.: Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat Immunol 2006, 7:652–662.PubMedCrossRefGoogle Scholar
  31. 31.
    Maraskovsky E, Brasel K, Teepe M, Roux ER, Lyman SD, Shortman K, McKenna HJ: Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J Exp Med 1996, 184:1953–1962.PubMedCrossRefGoogle Scholar
  32. 32.
    Maraskovsky E, Daro E, Roux E, Teepe M, Maliszewski CR, Hoek J, Caron D, Lebsack ME, McKenna HJ: In vivo generation of human dendritic cell subsets by Flt3 ligand. Blood 2000, 96:878–884.PubMedGoogle Scholar
  33. 33.
    Brasel K, De Smedt T, Smith JL, Maliszewski CR: Generation of murine dendritic cells from flt3-ligand-supplemented bone marrow cultures. Blood 2000, 96:3029–3039.PubMedGoogle Scholar
  34. 34.
    Gilliet M, Boonstra A, Paturel C, Antonenko S, Xu XL, Trinchieri G, O’Garra A, Liu YJ: The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3-ligand and granulocyte/macrophage colony-stimulating factor. J Exp Med 2002, 195:953–958.PubMedCrossRefGoogle Scholar
  35. 35.
    Brawand P, Fitzpatrick DR, Greenfield BW, Brasel K, Maliszewski CR, De Smedt T: Murine plasmacytoid pre-dendritic cells generated from Flt3 ligand-supplemented bone marrow cultures are immature APCs. J Immunol 2002, 169:6711–6719.PubMedGoogle Scholar
  36. 36.
    Swee LK, Bosco N, Malissen B, Ceredig R, Rolink A: Expansion of peripheral naturally occurring T regulatory cells by Fms-like tyrosine kinase 3 ligand treatment. Blood 2009, 113:6277–6287.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press 2010

Authors and Affiliations

  • Eric Gehrie
    • 1
  • William Van der Touw
    • 1
  • Jonathan S. Bromberg
    • 1
  • Jordi C. Ochando
    • 1
    • 2
    Email author
  1. 1.Department of Gene and Cell MedicineMount Sinai School of MedicineNew YorkUSA
  2. 2.Laboratorio de Immunología de TrasplantesCentro Nacional de Microbiología, Instituto de Salud Carlos IIIMadridSpain

Personalised recommendations