The innate immune cells sense microbial infection and self-ligands by pathogen recognition receptors (PRRs), such as toll-like receptors (TLRs) and regulatory receptors (RRs), associated with immunoreceptor tyrosine-based activation motif (ITAM). Rapid activation and concerted action of PRRs signaling and feedback inhibitory mechanisms must be engaged to ensure the host defense functions and to prevent cytotoxicity associated with excessive activation. ITAM-associated RRs can generate stimulatory or, paradoxically, inhibitory signals. The network of ITAM-associated RR, together with TLR-signaling pathways, are responsible for immunogenic or tolerogenic responses of macrophages and dendritic cells to their microenvironment. In macrophages, TLR4 signaling is inhibited by low-avidity ligation of ITAM-associated receptors, while high-avidity ligation of ITAM-associated receptors results in potentiation of TLR4 signaling together with resistance to extracellular cytokine microenvironment signals. In contrast to macrophages, TLR7/9 signaling in plasmacytoid DCs (pDCs) is inhibited by high-avidity ligation of ITAM-associated RR, while low-avidity ligation does not show any effect. Surprisingly, interference of ITAM-associated receptor signaling with TLR pathways has not been reported in conventional dendritic cells. Here, we present an overview of molecular mechanisms acting at the crossroads of TLR and ITAM-signaling pathways and address the question of how the high-avidity engagement of the ITAM-associated receptors in pDCs inhibits TLR7/9 signaling. Cellular context and spatiotemporal engagement of ITAM- and TLR-signaling pathways are responsible for different outcomes of macrophage versus pDC activation. While the cross-regulation of cytokine and TLR signaling, together with antigen presentation, are the principal functions of ITAM-associated RR in macrophages, the major role of these receptors in pDCs seems to be related to inhibition of cytokine production and reestablishment of a tolerogenic state following pDC activation. Pharmacologic targeting of TLR and ITAM signaling could be an attractive new therapeutic approach for treatment of chronic infections, cancer, and autoimmune and inflammatory diseases related to pDCs.

Cancer Research Center Marseille INSERM U 1068 CNRS UMR7258 Marseille France

Faculty of Science Charles University Prague Czech Republic

INSERM 1052 CNRS 5286 Centre Léon Bérard Centre de Recherche en Cancérologie de Lyon Univ Lyon Université Claude Bernard Lyon 1 Lyon France

Institut Paoli Calmettes Aix Marseille University Marseille France

Institute of Molecular Genetics ASCR Prague Czech Republic

Institute of Organic Chemistry and Biochemistry ASCR Prague Czech Republic

Zobrazit více v PubMed

Hirsch I, Caux C, Hasan U, Bendriss-Vermare N, Olive D. Impaired toll-like receptor 7 and 9 signaling: from chronic viral infections to cancer. Trends Immunol (2010) 31(10):391–7.10.1016/j.it.2010.07.004 PubMed DOI

Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol (2010) 11(5):373–84.10.1038/ni.1863 PubMed DOI

Bao M, Liu YJ. Regulation of TLR7/9 signaling in plasmacytoid dendritic cells. Protein Cell (2013) 4(1):40–52.10.1007/s13238-012-2104-8 PubMed DOI PMC

Brubaker SW, Bonham KS, Zanoni I, Kagan JC. Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol (2015) 33:257–90.10.1146/annurev-immunol-032414-112240 PubMed DOI PMC

Swiecki M, Colonna M. The multifaceted biology of plasmacytoid dendritic cells. Nat Rev Immunol (2015) 15(8):471–85.10.1038/nri3865 PubMed DOI PMC

Sancho D, Reis e Sousa C. Signaling by myeloid C-type lectin receptors in immunity and homeostasis. Annu Rev Immunol (2012) 30:491–529.10.1146/annurev-immunol-031210-101352 PubMed DOI PMC

Hu X, Chakravarty SD, Ivashkiv LB. Regulation of interferon and toll-like receptor signaling during macrophage activation by opposing feedforward and feedback inhibition mechanisms. Immunol Rev (2008) 226:41–56.10.1111/j.1600-065X.2008.00707.x PubMed DOI PMC

Ivashkiv LB. A signal-switch hypothesis for cross-regulation of cytokine and TLR signalling pathways. Nat Rev Immunol (2008) 8(10):816–22.10.1038/nri2396 PubMed DOI PMC

Ivashkiv LB. How ITAMs inhibit signaling. Sci Signal (2011) 4(169):e20.10.1126/scisignal.2001917 PubMed DOI PMC

Sasai M, Linehan MM, Iwasaki A. Bifurcation of toll-like receptor 9 signaling by adaptor protein 3. Science (2010) 329(5998):1530–4.10.1126/science.1187029 PubMed DOI PMC

Leifer CA, Medvedev AE. Molecular mechanisms of regulation of toll-like receptor signaling. J Leukoc Biol (2016) 100(5):927–41.10.1189/jlb.2MR0316-117RR PubMed DOI PMC

Gough DJ, Messina NL, Clarke CJ, Johnstone RW, Levy DE. Constitutive type I interferon modulates homeostatic balance through tonic signaling. Immunity (2012) 36(2):166–74.10.1016/j.immuni.2012.01.011 PubMed DOI PMC

Pauls E, Shpiro N, Peggie M, Young ER, Sorcek RJ, Tan L, et al. Essential role for IKKbeta in production of type 1 interferons by plasmacytoid dendritic cells. J Biol Chem (2012) 287(23):19216–28.10.1074/jbc.M112.345405 PubMed DOI PMC

Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, et al. Integral role of IRF-5 in the gene induction programme activated by toll-like receptors. Nature (2005) 434(7030):243–9.10.1038/nature03308 PubMed DOI

Purtha WE, Swiecki M, Colonna M, Diamond MS, Bhattacharya D. Spontaneous mutation of the Dock2 gene in Irf5-/- mice complicates interpretation of type I interferon production and antibody responses. Proc Natl Acad Sci U S A (2012) 109(15):E898–904.10.1073/pnas.1118155109 PubMed DOI PMC

Rock J, Schneider E, Grun JR, Grutzkau A, Kuppers R, Schmitz J, et al. CD303 (BDCA-2) signals in plasmacytoid dendritic cells via a BCR-like signalosome involving Syk, Slp65 and PLCgamma2. Eur J Immunol (2007) 37(12):3564–75.10.1002/eji.200737711 PubMed DOI

Dzionek A, Sohma Y, Nagafune J, Cella M, Colonna M, Facchetti F, 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(12):1823–34.10.1084/jem.194.12.1823 PubMed DOI PMC

Cao W, Zhang L, Rosen DB, Bover L, Watanabe G, Bao M, et al. BDCA2/Fc epsilon RI gamma complex signals through a novel BCR-like pathway in human plasmacytoid dendritic cells. PLoS Biol (2007) 5(10):e248.10.1371/journal.pbio.0050248 PubMed DOI PMC

Cao W, Rosen DB, Ito T, Bover L, Bao M, Watanabe G, et al. Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilonRI gamma inhibits toll-like receptor-induced interferon production. J Exp Med (2006) 203(6):1399–405.10.1084/jem.20052454 PubMed DOI PMC

Cao W, Bover L, Cho M, Wen X, Hanabuchi S, Bao M, et al. Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction. J Exp Med (2009) 206(7):1603–14.10.1084/jem.20090547 PubMed DOI PMC

Schroeder JT, Bieneman AP, Xiao H, Chichester KL, Vasagar K, Saini S, et al. TLR9- and Fc epsilonRI-mediated responses oppose one another in plasmacytoid dendritic cells by down-regulating receptor expression. J Immunol (2005) 175(9):5724–31.10.4049/jimmunol.175.9.5724 PubMed DOI

Fuchs A, Cella M, Kondo T, Colonna M. Paradoxic inhibition of human natural interferon-producing cells by the activating receptor NKp44. Blood (2005) 106(6):2076–82.10.1182/blood-2004-12-4802 PubMed DOI

Blasius AL, Cella M, Maldonado J, Takai T, Colonna M. Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12. Blood (2006) 107(6):2474–6.10.1182/blood-2005-09-3746 PubMed DOI PMC

Meyer-Wentrup F, Benitez-Ribas D, Tacken PJ, Punt CJ, Figdor CG, de Vries IJ, et al. Targeting DCIR on human plasmacytoid dendritic cells results in antigen presentation and inhibits IFN-alpha production. Blood (2008) 111(8):4245–53.10.1182/blood-2007-03-081398 PubMed DOI

Piccioli D, Tavarini S, Borgogni E, Steri V, Nuti S, Sammicheli C, et al. Functional specialization of human circulating CD16 and CD1c myeloid dendritic-cell subsets. Blood (2007) 109(12):5371–9.10.1182/blood-2006-08-038422 PubMed DOI

Poulin LF, Salio M, Griessinger E, Anjos-Afonso F, Craciun L, Chen JL, et al. Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells. J Exp Med (2010) 207(6):1261–71.10.1084/jem.20092618 PubMed DOI PMC

Zhang S, Kodys K, Li K, Szabo G. Human type 2 myeloid dendritic cells produce interferon-lambda and amplify interferon-alpha in response to hepatitis C virus infection. Gastroenterology (2013) 144(2):414–425.e7.10.1053/j.gastro.2012.10.034 PubMed DOI PMC

Geijtenbeek TB, Gringhuis SI. Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol (2009) 9(7):465–79.10.1038/nri2569 PubMed DOI PMC

Hammer GE, Ma A. Molecular control of steady-state dendritic cell maturation and immune homeostasis. Annu Rev Immunol (2013) 31:743–91.10.1146/annurev-immunol-020711-074929 PubMed DOI PMC

Kingeter LM, Lin X. C-type lectin receptor-induced NF-kappaB activation in innate immune and inflammatory responses. Cell Mol Immunol (2012) 9(2):105–12.10.1038/cmi.2011.58 PubMed DOI PMC

Del Fresno C, Soulat D, Roth S, Blazek K, Udalova I, Sancho D, et al. Interferon-beta production via dectin-1-Syk-IRF5 signaling in dendritic cells is crucial for immunity to C. albicans. Immunity (2013) 38(6):1176–86.10.1016/j.immuni.2013.05.010 PubMed DOI

Bourgeois C, Majer O, Frohner IE, Lesiak-Markowicz I, Hildering KS, Glaser W, et al. Conventional dendritic cells mount a type I IFN response against Candida spp. requiring novel phagosomal TLR7-mediated IFN-beta signaling. J Immunol (2011) 186(5):3104–12.10.4049/jimmunol.1002599 PubMed DOI

Chen CH, Floyd H, Olson NE, Magaletti D, Li C, Draves K, et al. Dendritic-cell-associated C-type lectin 2 (DCAL-2) alters dendritic-cell maturation and cytokine production. Blood (2006) 107(4):1459–67.10.1182/blood-2005-08-3264 PubMed DOI PMC

Meyer-Wentrup F, Cambi A, Joosten B, Looman MW, de Vries IJ, Figdor CG, et al. DCIR is endocytosed into human dendritic cells and inhibits TLR8-mediated cytokine production. J Leukoc Biol (2009) 85(3):518–25.10.1189/jlb.0608352 PubMed DOI

Joo H, Upchurch K, Zhang W, Ni L, Li D, Xue Y, et al. Opposing roles of dectin-1 expressed on human plasmacytoid dendritic cells and myeloid dendritic cells in Th2 polarization. J Immunol (2015) 195(4):1723–31.10.4049/jimmunol.1402276 PubMed DOI PMC

Sloan-Lancaster J, Shaw AS, Rothbard JB, Allen PM. Partial T cell signaling: altered phospho-zeta and lack of zap70 recruitment in APL-induced T cell anergy. Cell (1994) 79(5):913–22.10.1016/0092-8674(94)90080-9 PubMed DOI

Healy JI, Dolmetsch RE, Timmerman LA, Cyster JG, Thomas ML, Crabtree GR, et al. Different nuclear signals are activated by the B cell receptor during positive versus negative signaling. Immunity (1997) 6(4):419–28.10.1016/S1074-7613(00)80285-X PubMed DOI

Pasquier B, Launay P, Kanamaru Y, Moura IC, Pfirsch S, Ruffie C, et al. Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM. Immunity (2005) 22(1):31–42.10.1016/j.immuni.2004.11.017 PubMed DOI

Hamerman JA, Lanier LL. Inhibition of immune responses by ITAM-bearing receptors. Sci STKE (2006) 2006(320):re1.10.1126/stke.3202006re1 PubMed DOI

Turnbull IR, Colonna M. Activating and inhibitory functions of DAP12. Nat Rev Immunol (2007) 7(2):155–61.10.1038/nri2014 PubMed DOI

Wang L, Gordon RA, Huynh L, Su X, Park Min KH, Han J, et al. Indirect inhibition of toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins. Immunity (2010) 32(4):518–30.10.1016/j.immuni.2010.03.014 PubMed DOI PMC

Pfirsch-Maisonnas S, Aloulou M, Xu T, Claver J, Kanamaru Y, Tiwari M, et al. Inhibitory ITAM signaling traps activating receptors with the phosphatase SHP-1 to form polarized “inhibisome” clusters. Sci Signal (2011) 4(169):ra24.10.1126/scisignal.2001309 PubMed DOI

Huynh L, Wang L, Shi C, Park-Min KH, Ivashkiv LB. ITAM-coupled receptors inhibit IFNAR signaling and alter macrophage responses to TLR4 and Listeria monocytogenes. J Immunol (2012) 188(7):3447–57.10.4049/jimmunol.1102211 PubMed DOI PMC

Ben Mkaddem S, Hayem G, Jonsson F, Rossato E, Boedec E, Boussetta T, et al. Shifting FcgammaRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis. J Clin Invest (2014) 124(9):3945–59.10.1172/JCI74572 PubMed DOI PMC

Barrow AD, Trowsdale J. You say ITAM and I say ITIM, let’s call the whole thing off: the ambiguity of immunoreceptor signalling. Eur J Immunol (2006) 36(7):1646–53.10.1002/eji.200636195 PubMed DOI

Ivashkiv LB. PTPN22 in autoimmunity: different cell and different way. Immunity (2013) 39(1):91–3.10.1016/j.immuni.2013.07.007 PubMed DOI PMC

Kang YJ, Kusler B, Otsuka M, Hughes M, Suzuki N, Suzuki S, et al. Calcineurin negatively regulates TLR-mediated activation pathways. J Immunol (2007) 179(7):4598–607.10.4049/jimmunol.179.7.4598 PubMed DOI

Wang L, Tassiulas I, Park-Min KH, Reid AC, Gil-Henn H, Schlessinger J, et al. ‘Tuning’ of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages. Nat Immunol (2008) 9(2):186–93.10.1038/ni1548 PubMed DOI

Han C, Jin J, Xu S, Liu H, Li N, Cao X. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat Immunol (2010) 11(8):734–42.10.1038/ni.1908 PubMed DOI

Kirsch KH, Georgescu MM, Shishido T, Langdon WY, Birge RB, Hanafusa H. The adapter type protein CMS/CD2AP binds to the proto-oncogenic protein c-Cbl through a tyrosine phosphorylation-regulated Src homology 3 domain interaction. J Biol Chem (2001) 276(7):4957–63.10.1074/jbc.M005784200 PubMed DOI

Paolini R, Molfetta R, Beitz LO, Zhang J, Scharenberg AM, Piccoli M, et al. Activation of Syk tyrosine kinase is required for c-Cbl-mediated ubiquitination of Fc epsilon RI and Syk in RBL cells. J Biol Chem (2002) 277(40):36940–7.10.1074/jbc.M204948200 PubMed DOI

Molfetta R, Quatrini L, Gasparrini F, Zitti B, Santoni A, Paolini R. Regulation of fc receptor endocytic trafficking by ubiquitination. Front Immunol (2014) 5:449.10.3389/fimmu.2014.00449 PubMed DOI PMC

Lin YC, Huang DY, Chu CL, Lin WW. Anti-inflammatory actions of Syk inhibitors in macrophages involve non-specific inhibition of toll-like receptors-mediated JNK signaling pathway. Mol Immunol (2010) 47(7–8):1569–78.10.1016/j.molimm.2010.01.008 PubMed DOI

Rowland SL, Riggs JM, Gilfillan S, Bugatti M, Vermi W, Kolbeck R, et al. Early, transient depletion of plasmacytoid dendritic cells ameliorates autoimmunity in a lupus model. J Exp Med (2014) 211(10):1977–91.10.1084/jem.20132620 PubMed DOI PMC

Ananieva O, Darragh J, Johansen C, Carr JM, McIlrath J, Park JM, et al. The kinases MSK1 and MSK2 act as negative regulators of toll-like receptor signaling. Nat Immunol (2008) 9(9):1028–36.10.1038/ni.1644 PubMed DOI

Kim C, Sano Y, Todorova K, Carlson BA, Arpa L, Celada A, et al. The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nat Immunol (2008) 9(9):1019–27.10.1038/ni.1640 PubMed DOI PMC

Kaiser F, Cook D, Papoutsopoulou S, Rajsbaum R, Wu X, Yang HT, et al. TPL-2 negatively regulates interferon-beta production in macrophages and myeloid dendritic cells. J Exp Med (2009) 206(9):1863–71.10.1084/jem.20091059 PubMed DOI PMC

Arthur JS, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol (2013) 13(9):679–92.10.1038/nri3495 PubMed DOI

Rosadini CV, Zanoni I, Odendall C, Green ER, Paczosa MK, Philip NH, et al. A single bacterial immune evasion strategy dismantles both MyD88 and TRIF signaling pathways downstream of TLR4. Cell Host Microbe (2015) 18(6):682–93.10.1016/j.chom.2015.11.006 PubMed DOI PMC

Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH, et al. TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell (2000) 103(7):1071–83.10.1016/S0092-8674(00)00210-5 PubMed DOI

Mielke LA, Elkins KL, Wei L, Starr R, Tsichlis PN, O’Shea JJ, et al. Tumor progression locus 2 (Map3k8) is critical for host defense against Listeria monocytogenes and IL-1 beta production. J Immunol (2009) 183(12):7984–93.10.4049/jimmunol.0901336 PubMed DOI PMC

Jahn PS, Zanker KS, Schmitz J, Dzionek A. BDCA-2 signaling inhibits TLR-9-agonist-induced plasmacytoid dendritic cell activation and antigen presentation. Cell Immunol (2010) 265(1):15–22.10.1016/j.cellimm.2010.06.005 PubMed DOI

Cho M, Ishida K, Chen J, Ohkawa J, Chen W, Namiki S, et al. SAGE library screening reveals ILT7 as a specific plasmacytoid dendritic cell marker that regulates type I IFN production. Int Immunol (2008) 20(1):155–64.10.1093/intimm/dxm127 PubMed DOI

Martinelli E, Cicala C, Van Ryk D, Goode DJ, Macleod K, Arthos J, et al. HIV-1 gp120 inhibits TLR9-mediated activation and IFN-{alpha} secretion in plasmacytoid dendritic cells. Proc Natl Acad Sci U S A (2007) 104(9):3396–401.10.1073/pnas.0611353104 PubMed DOI PMC

Florentin J, Aouar B, Dental C, Thumann C, Firaguay G, Gondois-Rey F, et al. HCV glycoprotein E2 is a novel BDCA-2 ligand and acts as an inhibitor of IFN production by plasmacytoid dendritic cells. Blood (2012) 120(23):4544–51.10.1182/blood-2012-02-413286 PubMed DOI

Rosental B, Brusilovsky M, Hadad U, Oz D, Appel MY, Afergan F, et al. Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44. J Immunol (2011) 187(11):5693–702.10.4049/jimmunol.1102267 PubMed DOI PMC

Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol (2004) 5(2):190–8.10.1038/ni1028 PubMed DOI

Kim YM, Brinkmann MM, Paquet ME, Ploegh HL. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature (2008) 452(7184):234–8.10.1038/nature06726 PubMed DOI

Park B, Brinkmann MM, Spooner E, Lee CC, Kim YM, Ploegh HL. Proteolytic cleavage in an endolysosomal compartment is required for activation of toll-like receptor 9. Nat Immunol (2008) 9(12):1407–14.10.1038/ni.1669 PubMed DOI PMC

Avalos AM, Kirak O, Oelkers JM, Pils MC, Kim YM, Ottinger M, et al. Cell-specific TLR9 trafficking in primary APCs of transgenic TLR9-GFP mice. J Immunol (2013) 190(2):695–702.10.4049/jimmunol.1202342 PubMed DOI PMC

Jaehn PS, Zaenker KS, Schmitz J, Dzionek A. Functional dichotomy of plasmacytoid dendritic cells: antigen-specific activation of T cells versus production of type I interferon. Eur J Immunol (2008) 38(7):1822–32.10.1002/eji.200737552 PubMed DOI

Pellerin A, Otero K, Czerkowicz JM, Kerns HM, Shapiro RI, Ranger AM, et al. Anti-BDCA2 monoclonal antibody inhibits plasmacytoid dendritic cell activation through Fc-dependent and Fc-independent mechanisms. EMBO Mol Med (2015) 7(4):464–76.10.15252/emmm.201404719 PubMed DOI PMC

Aouar B, Kovarova D, Letard S, Font-Haro A, Florentin J, Weber J, et al. Dual role of the tyrosine kinase Syk in regulation of toll-like receptor signaling in plasmacytoid dendritic cells. PLoS One (2016) 11(6):e0156063.10.1371/journal.pone.0156063 PubMed DOI PMC

Bao M, Hanabuchi S, Facchinetti V, Du Q, Bover L, Plumas J, et al. CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl. J Immunol (2012) 189(2):786–92.10.4049/jimmunol.1200887 PubMed DOI PMC

Srivatsan S, Swiecki M, Otero K, Cella M, Shaw AS. CD2-associated protein regulates plasmacytoid dendritic cell migration, but is dispensable for their development and cytokine production. J Immunol (2013) 191(12):5933–40.10.4049/jimmunol.1300454 PubMed DOI PMC

Guilliams M, Bruhns P, Saeys Y, Hammad H, Lambrecht BN. The function of Fcgamma receptors in dendritic cells and macrophages. Nat Rev Immunol (2014) 14(2):94–108.10.1038/nri3582 PubMed DOI

Bauer M, Redecke V, Ellwart JW, Scherer B, Kremer JP, Wagner H, et al. Bacterial CpG-DNA triggers activation and maturation of human CD11c-, CD123+ dendritic cells. J Immunol (2001) 166(8):5000–7.10.4049/jimmunol.166.8.5000 PubMed DOI

Kerkmann M, Rothenfusser S, Hornung V, Towarowski A, Wagner M, Sarris A, et al. Activation with CpG-A and CpG-B oligonucleotides reveals two distinct regulatory pathways of type I IFN synthesis in human plasmacytoid dendritic cells. J Immunol (2003) 170(9):4465–74.10.4049/jimmunol.170.9.4465 PubMed DOI

Dental C, Florentin J, Aouar B, Gondois-Rey F, Durantel D, Baumert TF, et al. Hepatitis C virus fails to activate NF-kappaB signaling in plasmacytoid dendritic cells. J Virol (2011) 86(2):1090–6.10.1128/JVI.05444-11 PubMed DOI PMC

Tel J, Schreibelt G, Sittig SP, Mathan TS, Buschow SI, Cruz LJ, et al. Human plasmacytoid dendritic cells efficiently cross-present exogenous Ags to CD8+ T cells despite lower Ag uptake than myeloid dendritic cell subsets. Blood (2013) 121(3):459–67.10.1182/blood-2012-06-435644 PubMed DOI

Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP, Archambault JM, et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med (2011) 208(10):1989–2003.10.1084/jem.20101158 PubMed DOI PMC

Conrad C, Gregorio J, Wang YH, Ito T, Meller S, Hanabuchi S, et al. Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3+ T-regulatory cells. Cancer Res (2012) 72(20):5240–9.10.1158/0008-5472.CAN-12-2271 PubMed DOI PMC

Faget J, Bendriss-Vermare N, Gobert M, Durand I, Olive D, Biota C, et al. ICOS-ligand expression on plasmacytoid dendritic cells supports breast cancer progression by promoting the accumulation of immunosuppressive CD4+ T cells. Cancer Res (2012) 72(23):6130–41.10.1158/0008-5472.CAN-12-2409 PubMed DOI

Sisirak V, Faget J, Gobert M, Goutagny N, Vey N, Treilleux I, et al. Impaired IFN-alpha production by plasmacytoid dendritic cells favors regulatory T-cell expansion that may contribute to breast cancer progression. Cancer Res (2012) 72(20):5188–97.10.1158/0008-5472.CAN-11-3468 PubMed DOI

Sisirak V, Vey N, Goutagny N, Renaudineau S, Malfroy M, Thys S, et al. Breast cancer-derived TGF-beta and TNF-alpha compromise IFN-alpha production by tumor-associated plasmacytoid dendritic cells. Int J Cancer (2013) 133(3):771–8.10.1002/ijc.28072 PubMed DOI

Glitzner E, Korosec A, Brunner PM, Drobits B, Amberg N, Schonthaler HB, et al. Specific roles for dendritic cell subsets during initiation and progression of psoriasis. EMBO Mol Med (2014) 6(10):1312–27.10.15252/emmm.201404114 PubMed DOI PMC

Expression of TIM-3 on Plasmacytoid Dendritic Cells as a Predictive Biomarker of Decline in HIV-1 RNA Level during ART

The MEK1/2-ERK Pathway Inhibits Type I IFN Production in Plasmacytoid Dendritic Cells