IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

The Role of Plasmacytoid Dendritic Cells in Gut Health

  • Hye-Yeon Won (Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University College of Pharmacy) ;
  • Ju-Young Lee (Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University College of Pharmacy) ;
  • Dahye Ryu (Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University College of Pharmacy) ;
  • Hyung-Taek Kim (Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University College of Pharmacy) ;
  • Sun-Young Chang (Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University College of Pharmacy)
  • Received : 2018.10.16
  • Accepted : 2018.12.19
  • Published : 2019.02.28
Download PDF
⟨ Previous Next ⟩

Abstract

Plasmacytoid dendritic cells (pDCs) are a unique subset of cells with different functional characteristics compared to classical dendritic cells. The pDCs are critical for the production of type I IFN in response to microbial and self-nucleic acids. They have an important role for host defense against viral pathogen infections. In addition, pDCs have been well studied as a critical player for breaking tolerance to self-nucleic acids that induce autoimmune disorders such as systemic lupus erythematosus. However, pDCs have an immunoregulatory role in inducing the immune tolerance by generating Tregs and various regulatory mechanisms in mucosal tissues. Here, we summarize the recent studies of pDCs that focused on the functional characteristics of gut pDCs, including interactions with other immune cells in the gut. Furthermore, the dynamic role of gut pDCs will be investigated with respect to disease status including gut infection, inflammatory bowel disease, and cancers.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT and future Planning (NRF-2017R1A2B4002419).

References

  1. Mann ER, Li X. Intestinal antigen-presenting cells in mucosal immune homeostasis: crosstalk between dendritic cells, macrophages and B-cells. World J Gastroenterol 2014;20:9653-9664.
  2. Persson EK, Scott CL, Mowat AM, Agace WW. Dendritic cell subsets in the intestinal lamina propria: ontogeny and function. Eur J Immunol 2013;43:3098-3107.
  3. 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.
  4. See P, Dutertre CA, Chen J, Gunther P, McGovern N, Irac SE, Gunawan M, Beyer M, Handler K, Duan K, et al. Mapping the human DC lineage through the integration of high-dimensional techniques. Science 2017;356:eaag3009.
  5. Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY. Retinoic acid imprints gut-homing specificity on T cells. Immunity 2004;21:527-538.
  6. Kim CH. Control of innate and adaptive lymphocytes by the RAR-retinoic acid axis. Immune Netw 2018;18:e1.
  7. Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL, Yokota A, Takeuchi H, Ricciardi-Castagnoli P, et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 2006;314:1157-1160.
  8. Bogunovic M, Ginhoux F, Helft J, Shang L, Hashimoto D, Greter M, Liu K, Jakubzick C, Ingersoll MA, Leboeuf M, et al. Origin of the lamina propria dendritic cell network. Immunity 2009;31:513-525.
  9. Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, Calderon B, Schraml BU, Unanue ER, Diamond MS, et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 2008;322:1097-1100.
  10. Edelson BT, Kc W, Juang R, Kohyama M, Benoit LA, Klekotka PA, Moon C, Albring JC, Ise W, Michael DG, et al. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells. J Exp Med 2010;207:823-836.
  11. Jackson JT, Hu Y, Liu R, Masson F, D'Amico A, Carotta S, Xin A, Camilleri MJ, Mount AM, Kallies A, et al. Id2 expression delineates differential checkpoints in the genetic program of CD8α+ and CD103+ dendritic cell lineages. EMBO J 2011;30:2690-2704.
  12. Satpathy AT, Briseno CG, Lee JS, Ng D, Manieri NA, Kc W, Wu X, Thomas SR, Lee WL, Turkoz M, et al. Notch2-dependent classical dendritic cells orchestrate intestinal immunity to attaching-and-effacing bacterial pathogens. Nat Immunol 2013;14:937-948.
  13. Persson EK, Uronen-Hansson H, Semmrich M, Rivollier A, Hagerbrand K, Marsal J, Gudjonsson S, Hakansson U, Reizis B, Kotarsky K, et al. IRF4 transcription-factor-dependent CD103(+)CD11b(+) dendritic cells drive mucosal T helper 17 cell differentiation. Immunity 2013;38:958-969.
  14. Gilliet M, Cao W, Liu YJ. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol 2008;8:594-606.
  15. Dzionek A, Sohma Y, Nagafune J, Cella M, Colonna M, Facchetti F, Gunther G, Johnston I, Lanzavecchia A, Nagasaka T, et al. BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. J Exp Med 2001;194:1823-1834.
  16. Colonna M, Trinchieri G, Liu YJ. Plasmacytoid dendritic cells in immunity. Nat Immunol 2004;5:1219-1226.
  17. Contractor N, Louten J, Kim L, Biron CA, Kelsall BL. Cutting edge: Peyer's patch plasmacytoid dendritic cells (pDCs) produce low levels of type I interferons: possible role for IL-10, TGFbeta, and prostaglandin E2 in conditioning a unique mucosal pDC phenotype. J Immunol 2007;179:2690-2694.
  18. 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.
  19. Cisse B, Caton ML, Lehner M, Maeda T, Scheu S, Locksley R, Holmberg D, Zweier C, den Hollander NS, Kant SG, et al. Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 2008;135:37-48.
  20. Ghosh HS, Cisse B, Bunin A, Lewis KL, Reizis B. Continuous expression of the transcription factor e2-2 maintains the cell fate of mature plasmacytoid dendritic cells. Immunity 2010;33:905-916.
  21. Rodrigues PF, Alberti-Servera L, Eremin A, Grajales-Reyes GE, Ivanek R, Tussiwand R. Distinct progenitor lineages contribute to the heterogeneity of plasmacytoid dendritic cells. Nat Immunol 2018;19:711-722.
  22. Wu X, Briseno CG, Grajales-Reyes GE, Haldar M, Iwata A, Kretzer NM, Kc W, Tussiwand R, Higashi Y, Murphy TL, et al. Transcription factor Zeb2 regulates commitment to plasmacytoid dendritic cell and monocyte fate. Proc Natl Acad Sci U S A 2016;113:14775-14780.
  23. Scott CL, Soen B, Martens L, Skrypek N, Saelens W, Taminau J, Blancke G, Van Isterdael G, Huylebroeck D, Haigh J, et al. The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs by repressing Id2. J Exp Med 2016;213:897-911.
  24. Kohara H, Omatsu Y, Sugiyama T, Noda M, Fujii N, Nagasawa T. Development of plasmacytoid dendritic cells in bone marrow stromal cell niches requires CXCL12-CXCR4 chemokine signaling. Blood 2007;110:4153-4160.
  25. Wendland M, Czeloth N, Mach N, Malissen B, Kremmer E, Pabst O, Forster R. CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proc Natl Acad Sci U S A 2007;104:6347-6352.
  26. Clahsen T, Pabst O, Tenbrock K, Schippers A, Wagner N. Localization of dendritic cells in the gut epithelium requires MAdCAM-1. Clin Immunol 2015;156:74-84.
  27. Lombardi VC, Khaiboullina SF. Plasmacytoid dendritic cells of the gut: relevance to immunity and pathology. Clin Immunol 2014;153:165-177.
  28. Dasgupta S, Erturk-Hasdemir D, Ochoa-Reparaz J, Reinecker HC, Kasper DL. Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms. Cell Host Microbe 2014;15:413-423.
  29. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004;303:1526-1529.
  30. Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 2003;198:513-520.
  31. Koblansky AA, Jankovic D, Oh H, Hieny S, Sungnak W, Mathur R, Hayden MS, Akira S, Sher A, Ghosh S. Recognition of profilin by Toll-like receptor 12 is critical for host resistance to Toxoplasma gondii. Immunity 2013;38:119-130.
  32. Swiecki M, Colonna M. The multifaceted biology of plasmacytoid dendritic cells. Nat Rev Immunol 2015;15:471-485.
  33. Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 2009;461:788-792.
  34. Karthaus N, van Spriel AB, Looman MW, Chen S, Spilgies LM, Lieben L, Carmeliet G, Ansems M, Adema GJ. Vitamin D controls murine and human plasmacytoid dendritic cell function. J Invest Dermatol 2014;134:1255-1264.
  35. Yrlid U, Cerovic V, Milling S, Jenkins CD, Zhang J, Crocker PR, Klavinskis LS, MacPherson GG. Plasmacytoid dendritic cells do not migrate in intestinal or hepatic lymph. J Immunol 2006;177:6115-6121.
  36. Yrlid U, Milling SW, Miller JL, Cartland S, Jenkins CD, MacPherson GG. Regulation of intestinal dendritic cell migration and activation by plasmacytoid dendritic cells, TNF-alpha and type 1 IFNs after feeding a TLR7/8 ligand. J Immunol 2006;176:5205-5212.
  37. Uto T, Takagi H, Fukaya T, Nasu J, Fukui T, Miyanaga N, Arimura K, Nakamura T, Choijookhuu N, Hishikawa Y, et al. Critical role of plasmacytoid dendritic cells in induction of oral tolerance. J Allergy Clin Immunol 2018;141:2156-2167.e9.
  38. Bonnefoy F, Couturier M, Clauzon A, Remy-Martin JP, Gaugler B, Tiberghien P, Chen W, Saas P, Perruche S. TGF-beta-exposed plasmacytoid dendritic cells participate in Th17 commitment. J Immunol 2011;186:6157-6164.
  39. Tezuka H, Abe Y, Asano J, Sato T, Liu J, Iwata M, Ohteki T. Prominent role for plasmacytoid dendritic cells in mucosal T cell-independent IgA induction. Immunity 2011;34:247-257.
  40. Juelke K, Romagnani C. Differentiation of human innate lymphoid cells (ILCs). Curr Opin Immunol 2016;38:75-85.
  41. Simoni Y, Fehlings M, Kloverpris HN, McGovern N, Koo SL, Loh CY, Lim S, Kurioka A, Fergusson JR, Tang CL, et al. Human innate lymphoid cell subsets possess tissue-type based heterogeneity in phenotype and frequency. Immunity 2017;46:148-161.
  42. Ferlazzo G, Munz C. Dendritic cell interactions with NK cells from different tissues. J Clin Immunol 2009;29:265-273.
  43. Swann JB, Hayakawa Y, Zerafa N, Sheehan KC, Scott B, Schreiber RD, Hertzog P, Smyth MJ. Type I IFN contributes to NK cell homeostasis, activation, and antitumor function. J Immunol 2007;178:7540-7549.
  44. Fuchs A, Cella M, Kondo T, Colonna M. Paradoxic inhibition of human natural interferon-producing cells by the activating receptor NKp44. Blood 2005;106:2076-2082.
  45. Ju X, Zenke M, Hart DN, Clark GJ. CD300a/c regulate type I interferon and TNF-alpha secretion by human plasmacytoid dendritic cells stimulated with TLR7 and TLR9 ligands. Blood 2008;112:1184-1194.
  46. Maazi H, Banie H, Aleman Muench GR, Patel N, Wang B, Sankaranarayanan I, Bhargava V, Sato T, Lewis G, Cesaroni M, et al. Activated plasmacytoid dendritic cells regulate type 2 innate lymphoid cell-mediated airway hyperreactivity. J Allergy Clin Immunol 2018;141:893-905.e6.
  47. Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, Sawa S, Lochner M, Rattis F, Mention JJ, Thiam K, Cerf-Bensussan N, Mandelboim O, et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 2008;29:958-970.
  48. Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, Lennerz JK, Doherty JM, Mills JC, Colonna M. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 2009;457:722-725.
  49. Zhang Z, Cheng L, Zhao J, Li G, Zhang L, Chen W, Nie W, Reszka-Blanco NJ, Wang FS, Su L. Plasmacytoid dendritic cells promote HIV-1-induced group 3 innate lymphoid cell depletion. J Clin Invest 2015;125:3692-3703.
  50. Guo X, Fu YX. The tragic fate of group 3 innate lymphoid cells during HIV-1 infection. J Clin Invest 2015;125:3430-3432.
  51. 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.
  52. Mouries J, Moron G, Schlecht G, Escriou N, Dadaglio G, Leclerc C. Plasmacytoid dendritic cells efficiently cross-prime naive T cells in vivo after TLR activation. Blood 2008;112:3713-3722.
  53. Zhang H, Gregorio JD, Iwahori T, Zhang X, Choi O, Tolentino LL, Prestwood T, Carmi Y, Engleman EG. A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes. Proc Natl Acad Sci U S A 2017;114:1988-1993.
  54. Guery L, Dubrot J, Lippens C, Brighouse D, Malinge P, Irla M, Pot C, Reith W, Waldburger JM, Hugues S. Ag-presenting CpG-activated pDCs prime Th17 cells that induce tumor regression. Cancer Res 2014;74:6430-6440.
  55. Yu CF, Peng WM, Oldenburg J, Hoch J, Bieber T, Limmer A, Hartmann G, Barchet W, Eis-Hubinger AM, Novak N. Human plasmacytoid dendritic cells support Th17 cell effector function in response to TLR7 ligation. J Immunol 2010;184:1159-1167.
  56. Hubo M, Jonuleit H. Plasmacytoid dendritic cells are inefficient in activation of human regulatory T cells. PLoS One 2012;7:e44056.
  57. Konieczna P, Groeger D, Ziegler M, Frei R, Ferstl R, Shanahan F, Quigley EM, Kiely B, Akdis CA, O'Mahony L. Bifidobacterium infantis 35624 administration induces Foxp3 T regulatory cells in human peripheral blood: potential role for myeloid and plasmacytoid dendritic cells. Gut 2012;61:354-366.
  58. Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol 2008;181:5396-5404.
  59. Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS, Keskin DB, Marshall B, Chandler P, Antonia SJ, Burgess R, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 2002;297:1867-1870.
  60. Mann ER, Bernardo D, Ng SC, Rigby RJ, Al-Hassi HO, Landy J, Peake ST, Spranger H, English NR, Thomas LV, et al. Human gut dendritic cells drive aberrant gut-specific t-cell responses in ulcerative colitis, characterized by increased IL-4 production and loss of IL-22 and IFNγ. Inflamm Bowel Dis 2014;20:2299-2307.
  61. Wittmann A, Autenrieth IB, Frick JS. Plasmacytoid dendritic cells are crucial in Bifidobacterium adolescentis-mediated inhibition of Yersinia enterocolitica infection. PLoS One 2013;8:e71338.
  62. Aoki-Yoshida A, Yamada K, Hachimura S, Sashihara T, Ikegami S, Shimizu M, Totsuka M. Enhancement of oral tolerance induction in do11.10 mice by Lactobacillus gasseri oll2809 via increase of effector regulatory t cells. PLoS One 2016;11:e0158643.
  63. Fagarasan S, Honjo T. Intestinal IgA synthesis: regulation of front-line body defences. Nat Rev Immunol 2003;3:63-72.
  64. Fagarasan S, Kinoshita K, Muramatsu M, Ikuta K, Honjo T. In situ class switching and differentiation to IgA-producing cells in the gut lamina propria. Nature 2001;413:639-643.
  65. Tsuji M, Suzuki K, Kitamura H, Maruya M, Kinoshita K, Ivanov II, Itoh K, Littman DR, Fagarasan S. Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 2008;29:261-271.
  66. Moro-Sibilot L, This S, Blanc P, Sanlaville A, Sisirak V, Bardel E, Boschetti G, Bendriss-Vermare N, Defrance T, Dubois B, et al. Plasmacytoid dendritic cells are dispensable for noninfectious intestinal IgA responses in vivo. Eur J Immunol 2016;46:354-359.
  67. Cho H, Kelsall BL. The role of type I interferons in intestinal infection, homeostasis, and inflammation. Immunol Rev 2014;260:145-167.
  68. Deal EM, Lahl K, Narvaez CF, Butcher EC, Greenberg HB. Plasmacytoid dendritic cells promote rotavirus-induced human and murine B cell responses. J Clin Invest 2013;123:2464-2474.
  69. Davidson S, Crotta S, McCabe TM, Wack A. Pathogenic potential of interferon αβ in acute influenza infection. Nat Commun 2014;5:3864.
  70. Alculumbre S, Raieli S, Hoffmann C, Chelbi R, Danlos FX, Soumelis V. Plasmacytoid pre-dendritic cells (pDC): from molecular pathways to function and disease association. Semin Cell Dev Biol 2018:S1084-9521(17)30385-3.
  71. Lehmann C, Jung N, Forster K, Koch N, Leifeld L, Fischer J, Mauss S, Drebber U, Steffen HM, Romerio F, et al. Longitudinal analysis of distribution and function of plasmacytoid dendritic cells in peripheral blood and gut mucosa of HIV infected patients. J Infect Dis 2014;209:940-949.
  72. Manches O, Munn D, Fallahi A, Lifson J, Chaperot L, Plumas J, Bhardwaj N. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J Clin Invest 2008;118:3431-3439.
  73. Tam MA, Wick MJ. Differential expansion, activation and effector functions of conventional and plasmacytoid dendritic cells in mouse tissues transiently infected with Listeria monocytogenes. Cell Microbiol 2006;8:1172-1187.
  74. Toivonen R, Kong L, Rasool O, Lund RJ, Lahesmaa R, Hanninen A. Activation of plasmacytoid dendritic cells in colon-draining lymph nodes during Citrobacter rodentium infection involves pathogen-sensing and inflammatory pathways distinct from conventional dendritic cells. J Immunol 2016;196:4750-4759.
  75. Podolsky DK. Inflammatory bowel disease (1). N Engl J Med 1991;325:928-937.
  76. Baumgart DC, Metzke D, Guckelberger O, Pascher A, Grotzinger C, Przesdzing I, Dorffel Y, Schmitz J, Thomas S. Aberrant plasmacytoid dendritic cell distribution and function in patients with Crohn's disease and ulcerative colitis. Clin Exp Immunol 2011;166:46-54.
  77. Arimura K, Takagi H, Uto T, Fukaya T, Nakamura T, Choijookhuu N, Hishikawa Y, Yamashita Y, Sato K. Crucial role of plasmacytoid dendritic cells in the development of acute colitis through the regulation of intestinal inflammation. Mucosal Immunol 2017;10:957-970.
  78. Sawai CM, Serpas L, Neto AG, Jang G, Rashidfarrokhi A, Kolbeck R, Sanjuan MA, Reizis B, Sisirak V. Plasmacytoid dendritic cells are largely dispensable for the pathogenesis of experimental inflammatory bowel disease. Front Immunol 2018;9:2475.
  79. Sainathan SK, Hanna EM, Gong Q, Bishnupuri KS, Luo Q, Colonna M, White FV, Croze E, Houchen C, Anant S, et al. Granulocyte macrophage colony-stimulating factor ameliorates DSS-induced experimental colitis. Inflamm Bowel Dis 2008;14:88-99.
  80. Katakura K, Lee J, Rachmilewitz D, Li G, Eckmann L, Raz E. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J Clin Invest 2005;115:695-702.
  81. Vijay-Kumar M, Wu H, Aitken J, Kolachala VL, Neish AS, Sitaraman SV, Gewirtz AT. Activation of toll-like receptor 3 protects against DSS-induced acute colitis. Inflamm Bowel Dis 2007;13:856-864.
  82. Yang JY, Kim MS, Kim E, Cheon JH, Lee YS, Kim Y, Lee SH, Seo SU, Shin SH, Choi SS, et al. Enteric viruses ameliorate gut inflammation via toll-like receptor 3 and toll-like receptor 7-mediated interferon-β production. Immunity 2016;44:889-900.
  83. Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY, Keller BC, Kambal A, Monaco CL, Zhao G, Fleshner P, et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 2015;160:447-460.
  84. Demoulin S, Herfs M, Delvenne P, Hubert P. Tumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular mechanisms. J Leukoc Biol 2013;93:343-352.
  85. Sisirak V, Vey N, Goutagny N, Renaudineau S, Malfroy M, Thys S, Treilleux I, Labidi-Galy SI, Bachelot T, Dezutter-Dambuyant C, et al. Breast cancer-derived transforming growth factor-β and tumor necrosis factor-α compromise interferon-β production by tumor-associated plasmacytoid dendritic cells. Int J Cancer 2013;133:771-778.
  86. Terra M, Oberkampf M, Fayolle C, Rosenbaum P, Guillerey C, Dadaglio G, Leclerc C. Tumor-derived TGFβ alters the ability of plasmacytoid dendritic cells to respond to innate immune signaling. Cancer Res 2018;78:3014-3026.
  87. Ito T, Yang M, Wang YH, Lande R, Gregorio J, Perng OA, Qin XF, Liu YJ, Gilliet M. Plasmacytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costimulator ligand. J Exp Med 2007;204:105-115.
  88. 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.
  89. Gai XD, Song Y, Li C, Lei YM, Yang B. Potential role of plasmacytoid dendritic cells for FOXP3+ regulatory T cell development in human colorectal cancer and tumor draining lymph node. Pathol Res Pract 2013;209:774-778.
  90. Legitimo A, Consolini R, Failli A, Orsini G, Spisni R. Dendritic cell defects in the colorectal cancer. Hum Vaccin Immunother 2014;10:3224-3235.
  91. Jahrsdorfer B, Vollmer A, Blackwell SE, Maier J, Sontheimer K, Beyer T, Mandel B, Lunov O, Tron K, Nienhaus GU, et al. Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell expansion. Blood 2010;115:1156-1165.
  92. 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.
  93. Castelli C, Triebel F, Rivoltini L, Camisaschi C. Lymphocyte activation gene-3 (LAG-3, CD223) in plasmacytoid dendritic cells (pDCs): a molecular target for the restoration of active antitumor immunity. OncoImmunology 2014;3:e967146.
  94. Huang XM, Liu XS, Lin XK, Yu H, Sun JY, Liu XK, Chen C, Jin HL, Zhang GE, Shi XX, et al. Role of plasmacytoid dendritic cells and inducible costimulator-positive regulatory T cells in the immunosuppression microenvironment of gastric cancer. Cancer Sci 2014;105:150-158.
  95. Labidi-Galy SI, Sisirak V, Meeus P, Gobert M, Treilleux I, Bajard A, Combes JD, Faget J, Mithieux F, Cassignol A, et al. Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer. Cancer Res 2011;71:5423-5434.
  96. Le Mercier I, Poujol D, Sanlaville A, Sisirak V, Gobert M, Durand I, Dubois B, Treilleux I, Marvel J, Vlach J, et al. Tumor promotion by intratumoral plasmacytoid dendritic cells is reversed by TLR7 ligand treatment. Cancer Res 2013;73:4629-4640.
  97. Bonaccorsi I, Morandi B, Antsiferova O, Costa G, Oliveri D, Conte R, Pezzino G, Vermiglio G, Anastasi GP, Navarra G, et al. Membrane transfer from tumor cells overcomes deficient phagocytic ability of plasmacytoid dendritic cells for the acquisition and presentation of tumor antigens. J Immunol 2014;192:824-832.
  98. Ioannou M, Alissafi T, Boon L, Boumpas D, Verginis P. In vivo ablation of plasmacytoid dendritic cells inhibits autoimmunity through expansion of myeloid-derived suppressor cells. J Immunol 2013;190:2631-2640.
  99. Zoglmeier C, Bauer H, Noerenberg D, Wedekind G, Bittner P, Sandholzer N, Rapp M, Anz D, Endres S, Bourquin C. CpG blocks immunosuppression by myeloid-derived suppressor cells in tumor-bearing mice. Clin Cancer Res 2011;17:1765-1775.
  100. Drobits B, Holcmann M, Amberg N, Swiecki M, Grundtner R, Hammer M, Colonna M, Sibilia M. Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells. J Clin Invest 2012;122:575-585.
  101. Liu C, Lou Y, Lizee G, Qin H, Liu S, Rabinovich B, Kim GJ, Wang YH, Ye Y, Sikora AG, et al. Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest 2008;118:1165-1175.