Regulation of TLR7/9 signaling in plasmacytoid dendritic cells

Abstract

Plasmacytoid dendritic cells (pDCs), also known as type I interferon (IFN)-producing cells, are specialized immune cells characterized by their extraordinary capabilities of mounting rapid and massive type I IFN response to nucleic acids derived from virus, bacteria or dead cells. PDCs selectively express endosomal Toll-like receptor (TLR) 7 and TLR9, which sense viral RNA and DNA respectively. Following type I IFN and cytokine responses, pDCs differentiate into antigen presenting cells and acquire the ability to regulate T cell-mediated adaptive immunity. The functions of pDCs have been implicated not only in antiviral innate immunity but also in immune tolerance, inflammation and tumor microenvironments. In this review, we will focus on TLR7/9 signaling and their regulation by pDC-specific receptors.

Keywords

plasmacytoid dendritic cells / Toll-like receptors / immunoreceptor tyrosine-based activation motif / immunoreceptor tyrosine-based inhibitory motif / immunoglobulin-like transcript / BDCA2 / phospholipid scramblase 1 / protein kinase C and casein kinase substrate in neurons 1

References

[1] Akira, S., and Takeda, K. (2004). Toll-like receptor signalling. Nat Rev Immunol 4, 499-511 .10.1038/nri1391
[2] An, H., Hou, J., Zhou, J., Zhao, W., Xu, H., Zheng, Y., Yu, Y., Liu, S., and Cao, X. (2008). Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by+inhibiting the kinase IRAK1. Nat Immunol 9, 542-550 .10.1038/ni.1604
[3] An, H., Zhao, W., Hou, J., Zhang, Y., Xie, Y., Zheng, Y., Xu, H., Qian, C., Zhou, J., Yu, Y., . (2006). SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production. Immunity 25, 919-928 .10.1016/j.immuni.2006.10.014
[4] Arnon, T.I., Lev, M., Katz, G., Chernobrov, Y., Porgador, A., and Mandelboim, O. (2001). Recognition of viral hemagglutinins by NKp44 but not by NKp30. Eur J Immunol 31, 2680-2689 .10.1002/1521-4141(200109)31:9<2680::AID-IMMU2680>3.0.CO;2-A
[5] Bao, M., Hanabuchi, S., Facchinetti, V., Du, Q., Bover, L., Plumas, J., Chaperot, L., Cao, W., Qin, J., Sun, S.C., . (2012). CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl. J Immunol 189, 786-792 .10.4049/jimmunol.1200887
[6] Blasius, A.L., Arnold, C.N., Georgel, P., Rutschmann, S., Xia, Y., Lin, P., Ross, C., Li, X., Smart, N.G., and Beutler, B. (2010). Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells. Proc Natl Acad Sci U S A 107, 19973-19978 .10.1073/pnas.1014051107
[7] Blasius, A.L., Cella, M., Maldonado, J., Takai, T., and Colonna, M. (2006). Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12. Blood 107, 2474-2476 .10.1182/blood-2005-09-3746
[8] Bonaccorsi, I., Cantoni, C., Carrega, P., Oliveri, D., Lui, G., Conte, R., Navarra, M., Cavaliere, R., Traggiai, E., Gattorno, M., . (2010). The immune inhibitory receptor LAIR-1 is highly expressed by plasmacytoid dendritic cells and acts complementary with NKp44 to control IFNalpha production. PLoS One 5, e15080.10.1371/journal.pone.0015080
[9] Brooks, J.C., Sun, W., Chiosis, G., and Leifer, C.A. (2012). Heat shock protein gp96 regulates Toll-like receptor 9 proteolytic processing and conformational stability. Biochem Biophys Res Commun 421, 780-784 .10.1016/j.bbrc.2012.04.083
[10] Brown, D., Trowsdale, J., and Allen, R. (2004). The LILR family: modulators of innate and adaptive immune pathways in health and disease. Tissue Antigens 64, 215-225 .10.1111/j.0001-2815.2004.00290.x
[11] Cao, W., Bover, L., Cho, M., Wen, X., Hanabuchi, S., Bao, M., Rosen, D.B., Wang, Y.H., Shaw, J.L., Du, Q., . (2009). Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction. J Exp Med 206, 1603-1614 .10.1084/jem.20090547
[12] Cao, W., Manicassamy, S., Tang, H., Kasturi, S.P., Pirani, A., Murthy, N., and Pulendran, B. (2008). Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol 9, 1157-1164 .10.1038/ni.1645
[13] Cao, W., Rosen, D.B., Ito, T., Bover, L., Bao, M., Watanabe, G., Yao, Z., Zhang, L., Lanier, L.L., and Liu, Y.J. (2006). Plasmacytoid dendritic cell-specific receptor ILT7-Fc epsilonRI gamma inhibits Toll-like receptor-induced interferon production. J Exp Med 203, 1399-1405 .10.1084/jem.20052454
[14] Cao, W., Zhang, L., Rosen, D.B., Bover, L., Watanabe, G., Bao, M., Lanier, L.L., and Liu, Y.J. (2007). BDCA2/Fc epsilon RI gamma complex signals through a novel BCR-like pathway in human plasmacytoid dendritic cells. PLoS Biol 5, e248.10.1371/journal.pbio.0050248
[15] Chevrier, N., Mertins, P., Artyomov, M.N., Shalek, A.K., Iannacone, M., Ciaccio, M.F., Gat-Viks, I., Tonti, E., DeGrace, M.M., Clauser, K.R., . (2011). Systematic discovery of TLR signaling components delineates viral-sensing circuits. Cell 147, 853-867 .10.1016/j.cell.2011.10.022
[16] Cisse, B., Caton, M.L., Lehner, M., Maeda, T., Scheu, S., Locksley, R., Holmberg, D., Zweier, C., den Hollander, N.S., Kant, S.G., . (2008). Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 135, 37-48 .10.1016/j.cell.2008.09.016
[17] Clark, G.J., Ju, X., Tate, C., and Hart, D.N. (2009). The CD300 family of molecules are evolutionarily significant regulators of leukocyte functions. Trends Immunol 30, 209-217 .10.1016/j.it.2009.02.003
[18] Colina, R., Costa-Mattioli, M., Dowling, R.J., Jaramillo, M., Tai, L.H., Breitbach, C.J., Martineau, Y., Larsson, O., Rong, L., Svitkin, Y.V., . (2008). Translational control of the innate immune response through IRF-7. Nature 452, 323-328 .10.1038/nature06730
[19] Daeron, M., Jaeger, S., Du Pasquier, L., and Vivier, E. (2008). Immunoreceptor tyrosine-based inhibition motifs: a quest in the past and future. Immunol Rev 224, 11-43 .10.1111/j.1600-065X.2008.00666.x
[20] Dai, P., Jeong, S.Y., Yu, Y., Leng, T., Wu, W., Xie, L., and Chen, X. (2009). Modulation of TLR signaling by multiple MyD88-interacting partners including leucine-rich repeat Fli-I-interacting proteins. J Immunol 182, 3450-3460 .10.4049/jimmunol.0802260
[21] Deng, L., Wang, C., Spencer, E., Yang, L., Braun, A., You, J., Slaughter, C., Pickart, C., and Chen, Z.J. (2000). Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103, 351-361 .10.1016/S0092-8674(00)00126-4
[22] Dikic, I. (2002). CIN85/CMS family of adaptor molecules. FEBS Lett 529, 110-115 .10.1016/S0014-5793(02)03188-5
[23] Enesa, K., Ordureau, A., Smith, H., Barford, D., Cheung, P.C., Patterson-Kane, J., Arthur, J.S., and Cohen, P. (2012). Pellino1 Is Required for Interferon Production by Viral Double-stranded RNA. J Biol Chem 287, 34825-34835 .10.1074/jbc.M112.367557
[24] Esashi, E., Bao, M., Wang, Y.H., Cao, W., and Liu, Y.J. (2012). PACSIN1 regulates the TLR7/9-mediated type I interferon response in plasmacytoid dendritic cells. Eur J Immunol 42, 573-579 .10.1002/eji.201142045
[25] Ewald, S.E., Engel, A., Lee, J., Wang, M., Bogyo, M., and Barton, G.M. (2011). Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase. J Exp Med 208, 643-651 .10.1084/jem.20100682
[26] Ewald, S.E., Lee, B.L., Lau, L., Wickliffe, K.E., Shi, G.P., Chapman, H.A., and Barton, G.M. (2008). The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456, 658-662 .10.1038/nature07405
[27] Fuchs, A., Cella, M., Kondo, T., and Colonna, M. (2005). Paradoxic inhibition of human natural interferon-producing cells by the activating receptor NKp44. Blood 106, 2076-2082 .10.1182/blood-2004-12-4802
[28] Ghosh, H.S., Cisse, B., Bunin, A., Lewis, K.L., and Reizis, B. (2010). Continuous expression of the transcription factor e2-2 maintains the cell fate of mature plasmacytoid dendritic cells. Immunity 33, 905-916 .10.1016/j.immuni.2010.11.023
[29] Gilliet, M., Cao, W., and Liu, Y.J. (2008). Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol 8, 594-606 .10.1038/nri2358
[30] Gotoh, K., Tanaka, Y., Nishikimi, A., Nakamura, R., Yamada, H., Maeda, N., Ishikawa, T., Hoshino, K., Uruno, T., Cao, Q., . (2010). Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation. J Exp Med 207, 721-730 .10.1084/jem.20091776
[31] Guiducci, C., Ott, G., Chan, J.H., Damon, E., Calacsan, C., Matray, T., Lee, K.D., Coffman, R.L., and Barrat, F.J. (2006). Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. J Exp Med 203, 1999-2008 .10.1084/jem.20060401
[32] Hacker, H., Redecke, V., Blagoev, B., Kratchmarova, I., Hsu, L.C., Wang, G.G., Kamps, M.P., Raz, E., Wagner, H., Hacker, G., . (2006). Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439, 204-207 .10.1038/nature04369
[33] Hacker, H., Tseng, P.H., and Karin, M. (2011). Expanding TRAF function: TRAF3 as a tri-faced immune regulator. Nat Rev Immunol 11, 457-468 .10.1038/nri2998
[34] Hacker, H., Vabulas, R.M., Takeuchi, O., Hoshino, K., Akira, S., and Wagner, H. (2000). Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J Exp Med 192, 595-600 .10.1084/jem.192.4.595
[35] Hamerman, J.A., and Lanier, L.L. (2006). Inhibition of immune responses by ITAM-bearing receptors. Sci STKE 2006, re1.10.1126/stke.3202006re1
[36] Han, K.J., Su, X., Xu, L.G., Bin, L.H., Zhang, J., and Shu, H.B. (2004). Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways. J Biol Chem 279, 15652-15661 .10.1074/jbc.M311629200
[37] Hemmi, H., Kaisho, T., Takeuchi, O., Sato, S., Sanjo, H., Hoshino, K., Horiuchi, T., Tomizawa, H., Takeda, K., and Akira, S. (2002). Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3, 196-200 .10.1038/ni758
[38] Hida, S., Ogasawara, K., Sato, K., Abe, M., Takayanagi, H., Yokochi, T., Sato, T., Hirose, S., Shirai, T., Taki, S., . (2000). CD8(+) T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-alpha/beta signaling. Immunity 13, 643-655 .10.1016/S1074-7613(00)00064-9
[39] Higgs, R., Lazzari, E., Wynne, C., Ni Gabhann, J., Espinosa, A., Wahren-Herlenius, M., and Jefferies, C.A. (2010). Self protection from anti-viral responses--Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors. PLoS One 5, e11776.10.1371/journal.pone.0011776
[40] Honda, K., Ohba, Y., Yanai, H., Negishi, H., Mizutani, T., Takaoka, A., Taya, C., and Taniguchi, T. (2005a). Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035-1040 .10.1038/nature03547
[41] Honda, K., Yanai, H., Negishi, H., Asagiri, M., Sato, M., Mizutani, T., Shimada, N., Ohba, Y., Takaoka, A., Yoshida, N., . (2005b). IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772-777 .10.1038/nature03464
[42] Horvath, C.M., Stark, G.R., Kerr, I.M., and Darnell, J.E., Jr. (1996). Interactions between STAT and non-STAT proteins in the interferon-stimulated gene factor 3 transcription complex. Mol Cell Biol 16, 6957-6964 .
[43] Hoshino, K., Sugiyama, T., Matsumoto, M., Tanaka, T., Saito, M., Hemmi, H., Ohara, O., Akira, S., and Kaisho, T. (2006). IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9. Nature 440, 949-953 .10.1038/nature04641
[44] Into, T., Inomata, M., Niida, S., Murakami, Y., and Shibata, K. (2010). Regulation of MyD88 aggregation and the MyD88-dependent signaling pathway by sequestosome 1 and histone deacetylase 6. J Biol Chem 285, 35759-35769 .10.1074/jbc.M110.126904
[45] Israel, A. (2010). The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol 2, a000158.10.1101/cshperspect.a000158
[46] Ivashkiv, L.B. (2011). How ITAMs inhibit signaling. Sci Signal 4, pe20.10.1126/scisignal.2001917
[47] Iwasaki, H., Takeuchi, O., Teraguchi, S., Matsushita, K., Uehata, T., Kuniyoshi, K., Satoh, T., Saitoh, T., Matsushita, M., Standley, D.M., . (2011). The IkappaB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1. Nat Immunol 12, 1167-1175 .10.1038/ni.2137
[48] Jounai, N., Takeshita, F., Kobiyama, K., Sawano, A., Miyawaki, A., Xin, K.Q., Ishii, K.J., Kawai, T., Akira, S., Suzuki, K., . (2007). The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci U S A 104, 14050-14055 .10.1073/pnas.0704014104
[49] Ju, X., Zenke, M., Hart, D.N., and Clark, G.J. (2008). CD300a/c regulate type I interferon and TNF-alpha secretion by human plasmacytoid dendritic cells stimulated with TLR7 and TLR9 ligands. Blood 112, 1184-1194 .10.1182/blood-2007-12-127951
[50] Kadowaki, N., Ho, S., Antonenko, S., Malefyt, R.W., Kastelein, R.A., Bazan, F., and Liu, Y.J. (2001). Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194, 863-869 .10.1084/jem.194.6.863
[51] Kawagoe, T., Sato, S., Jung, A., Yamamoto, M., Matsui, K., Kato, H., Uematsu, S., Takeuchi, O., and Akira, S. (2007). Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling. J Exp Med 204, 1013-1024 .10.1084/jem.20061523
[52] Kawagoe, T., Sato, S., Matsushita, K., Kato, H., Matsui, K., Kumagai, Y., Saitoh, T., Kawai, T., Takeuchi, O., and Akira, S. (2008). Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat Immunol 9, 684-691 .10.1038/ni.1606
[53] Kawai, T., Sato, S., Ishii, K.J., Coban, C., Hemmi, H., Yamamoto, M., Terai, K., Matsuda, M., Inoue, J., Uematsu, S., . (2004). Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5, 1061-1068 .10.1038/ni1118
[54] Kayagaki, N., Phung, Q., Chan, S., Chaudhari, R., Quan, C., O'Rourke, K.M., Eby, M., Pietras, E., Cheng, G., Bazan, J.F., . (2007). DUBA: a deubiquitinase that regulates type I interferon production. Science 318, 1628-1632 .10.1126/science.1145918
[55] Kim, T.W., Staschke, K., Bulek, K., Yao, J., Peters, K., Oh, K.H., Vandenburg, Y., Xiao, H., Qian, W., Hamilton, T., . (2007). A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity. J Exp Med 204, 1025-1036 .10.1084/jem.20061825
[56] Kim, Y.M., Brinkmann, M.M., Paquet, M.E., and Ploegh, H.L. (2008). UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature 452, 234-238 .10.1038/nature06726
[57] Kobayashi, K., Hernandez, L.D., Galan, J.E., Janeway, C.A., Jr.,Medzhitov, R., and Flavell, R.A. (2002). IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110, 191-202 .10.1016/S0092-8674(02)00827-9
[58] Lanier, L.L. (2006). Viral immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling in cell transformation and cancer. Trends Cell Biol 16, 388-390 .10.1016/j.tcb.2006.06.004
[59] Lee, H.K., Lund, J.M., Ramanathan, B., Mizushima, N., and Iwasaki, A. (2007). Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science 315, 1398-1401 .10.1126/science.1136880
[60] Li, S., Strelow, A., Fontana, E.J., and Wesche, H. (2002). IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci U S A 99, 5567-5572 .10.1073/pnas.082100399
[61] Li, S., Wang, L., Berman, M., Kong, Y.Y., and Dorf, M.E. (2011). Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. Immunity 35, 426-440 .10.1016/j.immuni.2011.06.014
[62] Li, Y., Dai, J., Song, M., Fitzgerald-Bocarsly, P., and Kiledjian, M. (2012). Dcp2 decapping protein modulates mRNA stability of the critical interferon regulatory factor (IRF) IRF-7. Mol Cell Biol 32, 1164-1172 .10.1128/MCB.06328-11
[63] Liang, Q., Deng, H., Li, X., Wu, X., Tang, Q., Chang, T.H., Peng, H., Rauscher, F.J., 3 rd , Ozato, K., and Zhu, F. (2011). Tripartite motif-containing protein 28 is a small ubiquitin-related modifier E3 ligase and negative regulator of IFN regulatory factor 7. J Immunol 187, 4754-4763 .10.4049/jimmunol.1101704
[64] Lin, S.C., Lo, Y.C., and Wu, H. (2010). Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465, 885-890 .10.1038/nature09121
[65] Litvak, V., Ratushny, A.V., Lampano, A.E., Schmitz, F., Huang, A.C., Raman, A., Rust, A.G., Bergthaler, A., Aitchison, J.D., and Aderem, A. (2012). A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature 490, 421-425 .10.1038/nature11428
[66] Lo, C.C., Schwartz, J.A., Johnson, D.J., Yu, M., Aidarus, N., Mujib, S., Benko, E., Hyrcza, M., Kovacs, C., and Ostrowski, M.A. (2012). HIV Delays IFN-alpha Production from Human Plasmacytoid Dendritic Cells and Is Associated with SYK Phosphorylation. PLoS One 7, e37052.10.1371/journal.pone.0037052
[67] Martinelli, E., Cicala, C., Van Ryk, D., Goode, D.J., Macleod, K., Arthos, J., and Fauci, A.S. (2007). HIV-1 gp120 inhibits TLR9-mediated activation and IFN-{alpha} secretion in plasmacytoid dendritic cells. Proc Natl Acad Sci U S A 104, 3396-3401 .10.1073/pnas.0611353104
[68] Matsushita, K., Takeuchi, O., Standley, D.M., Kumagai, Y., Kawagoe, T., Miyake, T., Satoh, T., Kato, H., Tsujimura, T., Nakamura, H., . (2009). Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458, 1185-1190 .10.1038/nature07924
[69] Mitchell, A., Rentero, C., Endoh, Y., Hsu, K., Gaus, K., Geczy, C., McNeil, H.P., Borges, L., and Tedla, N. (2008). LILRA5 is expressed by synovial tissue macrophages in rheumatoid arthritis, selectively induces pro-inflammatory cytokines and IL-10 and is regulated by TNF-alpha, IL-10 and IFN-gamma. Eur J Immunol 38, 3459-3473 .10.1002/eji.200838415
[70] Moynagh, P.N. (2009). The Pellino family: IRAK E3 ligases with emerging roles in innate immune signalling. Trends Immunol 30, 33-42 .10.1016/j.it.2008.10.001
[71] Nagasawa, M., Schmidlin, H., Hazekamp, M.G., Schotte, R., and Blom, B. (2008). Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix-loop-helix factor E2-2 and the Ets factor Spi-B. Eur J Immunol 38, 2389-2400 .10.1002/eji.200838470
[72] Nakahashi-Oda, C., Tahara-Hanaoka, S., Shoji, M., Okoshi, Y., Nakano-Yokomizo, T., Ohkohchi, N., Yasui, T., Kikutani, H., Honda, S.I., Shibuya, K., . (2012). Apoptotic cells suppress mast cell inflammatory responses via the CD300a immunoreceptor. J Exp Med. (In Press) .10.1084/jem.20120096
[73] Nakajima, H., Samaridis, J., Angman, L., and Colonna, M. (1999). Human myeloid cells express an activating ILT receptor (ILT1) that associates with Fc receptor gamma-chain. J Immunol 162, 5-8 .
[74] Nakhaei, P., Mesplede, T., Solis, M., Sun, Q., Zhao, T., Yang, L., Chuang, T.H., Ware, C.F., Lin, R., and Hiscott, J. (2009). The E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation. PLoS Pathog 5, e1000650.10.1371/journal.ppat.1000650
[75] Negishi, H., Ohba, Y., Yanai, H., Takaoka, A., Honma, K., Yui, K., Matsuyama, T., Taniguchi, T., and Honda, K. (2005). Negative regulation of Toll-like-receptor signaling by IRF-4. Proc Natl Acad Sci U S A 102, 15989-15994 .10.1073/pnas.0508327102
[76] Ning, S., Campos, A.D., Darnay, B.G., Bentz, G.L., and Pagano, J.S. (2008). TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1. Mol Cell Biol 28, 6536-6546 .10.1128/MCB.00785-08
[77] Ninomiya-Tsuji, J., Kishimoto, K., Hiyama, A., Inoue, J., Cao, Z., and Matsumoto, K. (1999). The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature 398, 252-256 .10.1038/18465
[78] Oganesyan, G., Saha, S.K., Guo, B., He, J.Q., Shahangian, A., Zarnegar, B., Perry, A., and Cheng, G. (2006). Critical role of TRAF3 in the Toll-like receptor-dependent and-independent antiviral response. Nature 439, 208-211 .10.1038/nature04374
[79] Osawa, Y., Iho, S., Takauji, R., Takatsuka, H., Yamamoto, S., Takahashi, T., Horiguchi, S., Urasaki, Y., Matsuki, T., and Fujieda, S. (2006). Collaborative action of NF-kappaB and p38 MAPK is involved in CpG DNA-induced IFN-alpha and chemokine production in human plasmacytoid dendritic cells. J Immunol 177, 4841-4852 .
[80] Pasquier, B., Launay, P., Kanamaru, Y., Moura, I.C., Pfirsch, S., Ruffie, C., Henin, D., Benhamou, M., Pretolani, M., Blank, U., . (2005). Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM. Immunity 22, 31-42 .
[81] Pauls, E., Shpiro, N., Peggie, M., Young, E.R., Sorcek, R.J., Tan, L., Choi, H.G., and Cohen, P. (2012). Essential Role for IKKbeta in Production of Type 1 Interferons by Plasmacytoid Dendritic Cells. J Biol Chem 287, 19216-19228 .10.1074/jbc.M112.345405
[82] Pfirsch-Maisonnas, S., Aloulou, M., Xu, T., Claver, J., Kanamaru, Y., Tiwari, M., Launay, P., Monteiro, R.C., and Blank, U. (2011). Inhibitory ITAM signaling traps activating receptors with the phosphatase SHP-1 to form polarized "inhibisome" clusters. Sci Signal 4, ra24.10.1126/scisignal.2001309
[83] Pillai, S., Netravali, I.A., Cariappa, A., and Mattoo, H. (2012). Siglecs and immune regulation. Annu Rev Immunol 30, 357-392 .10.1146/annurev-immunol-020711-075018
[84] Rock, J., Schneider, E., Grun, J.R., Grutzkau, A., Kuppers, R., Schmitz, J., and Winkels, G. (2007). CD303 (BDCA-2) signals in plasmacytoid dendritic cells via a BCR-like signalosome involving Syk, Slp65 and PLCgamma2. Eur J Immunol 37, 3564-3575 .10.1002/eji.200737711
[85] Rosental, B., Brusilovsky, M., Hadad, U., Oz, D., Appel, M.Y., Afergan, F., Yossef, R., Rosenberg, L.A., Aharoni, A., Cerwenka, A., . (2011). Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44. J Immunol 187, 5693-5702 .10.4049/jimmunol.1102267
[86] Saitoh, T., and Akira, S. (2010). Regulation of innate immune responses by autophagy-related proteins. J Cell Biol 189, 925-935 .10.1083/jcb.201002021
[87] Saitoh, T., Satoh, T., Yamamoto, N., Uematsu, S., Takeuchi, O., Kawai, T., and Akira, S. (2011). Antiviral protein Viperin promotes Toll-like receptor 7- and Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells. Immunity 34, 352-363 .10.1016/j.immuni.2011.03.010
[88] Sasai, M., Linehan, M.M., and Iwasaki, A. (2010). Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3. Science 329, 1530-1534 .10.1126/science.1187029
[89] Sato, M., Hata, N., Asagiri, M., Nakaya, T., Taniguchi, T., and Tanaka, N. (1998). Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7. FEBS Lett 441, 106-110 .10.1016/S0014-5793(98)01514-2
[90] Schnare, M., Holt, A.C., Takeda, K., Akira, S., and Medzhitov, R. (2000). Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Curr Biol 10, 1139-1142 .10.1016/S0960-9822(00)00700-4
[91] Schroeder, J.T., Bieneman, A.P., Xiao, H., Chichester, K.L., Vasagar, K., Saini, S., and Liu, M.C. (2005). TLR9- and FcepsilonRI-mediated responses oppose one another in plasmacytoid dendritic cells by down-regulating receptor expression. J Immunol 175, 5724-5731 .
[92] Shah, K.M., Stewart, S.E., Wei, W., Woodman, C.B., O'Neil, J.D., Dawson, C.W., and Young, L.S. (2009). The EBV-encoded latent membrane proteins, LMP2A and LMP2B, limit the actions of interferon by targeting interferon receptors for degradation. Oncogene 28, 3903-3914 .10.1038/onc.2009.249
[93] Shinohara, M.L., Lu, L., Bu, J., Werneck, M.B., Kobayashi, K.S., Glimcher, L.H., and Cantor, H. (2006). Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells. Nat Immunol 7, 498-506 .10.1038/ni1327
[94] Siednienko, J., Jackson, R., Mellett, M., Delagic, N., Yang, S., Wang, B., Tang, L.S., Callanan, J.J., Mahon, B.P., and Moynagh, P.N. (2012). Pellino3 targets the IRF7 pathway and facilitates autoregulation of TLR3- and viral-induced expression of type I interferons. Nat Immunol. (In Press) .10.1038/ni.2429
[95] Simhadri, V.R., Andersen, J.F., Calvo, E., Choi, S.C., Coligan, J.E., and Borrego, F. (2012). Human CD300a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells. Blood 119, 2799-2809 .10.1182/blood-2011-08-372425
[96] Su, X., Li, S., Meng, M., Qian, W., Xie, W., Chen, D., Zhai, Z., and Shu, H.B. (2006). TNF receptor-associated factor-1 (TRAF1) negatively regulates Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-mediated signaling. Eur J Immunol 36, 199-206 .10.1002/eji.200535415
[97] Suzuki, N., Suzuki, S., Duncan, G.S., Millar, D.G., Wada, T., Mirtsos, C., Takada, H., Wakeham, A., Itie, A., Li, S., . (2002). Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416, 750-756 .10.1038/nature736
[98] Tai, L.H., Goulet, M.L., Belanger, S., Toyama-Sorimachi, N., Fodil-Cornu, N., Vidal, S.M., Troke, A.D., McVicar, D.W., and Makrigiannis, A.P. (2008). Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC. J Exp Med 205, 3187-3199 .10.1084/jem.20080718
[99] Tailor, P., Tamura, T., Kong, H.J., Kubota, T., Kubota, M., Borghi, P., Gabriele, L., and Ozato, K. (2007). The feedback phase of type I interferon induction in dendritic cells requires interferon regulatory factor 8. Immunity 27, 228-239 .10.1016/j.immuni.2007.06.009
[100] Takaoka, A., Yanai, H., Kondo, S., Duncan, G., Negishi, H., Mizutani, T., Kano, S., Honda, K., Ohba, Y., Mak, T.W., . (2005). Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434, 243-249 .10.1038/nature03308
[101] Takeshita, F., Ishii, K.J., Kobiyama, K., Kojima, Y., Coban, C., Sasaki, S., Ishii, N., Klinman, D.M., Okuda, K., Akira, S., . (2005). TRAF4 acts as a silencer in TLR-mediated signaling through the association with TRAF6 and TRIF. Eur J Immunol 35, 2477-2485 .10.1002/eji.200526151
[102] Takeuchi, O., and Akira, S. (2010). Pattern recognition receptors and inflammation. Cell 140, 805-820 .10.1016/j.cell.2010.01.022
[103] Tal, M.C., Sasai, M., Lee, H.K., Yordy, B., Shadel, G.S., and Iwasaki, A. (2009). Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc Natl Acad Sci U S A 106, 2770-2775 .10.1073/pnas.0807694106
[104] Talukder, A.H., Bao, M., Kim, T.W., Facchinetti, V., Hanabuchi, S., Bover, L., Zal, T., and Liu, Y.J. (2012). Phospholipid Scramblase 1 regulates Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells. Cell Res 22, 1129-1139 .10.1038/cr.2012.45
[105] Tamura, T., Tailor, P., Yamaoka, K., Kong, H.J., Tsujimura, H., O'Shea, J.J., Singh, H., and Ozato, K. (2005). IFN regulatory factor-4 and-8 govern dendritic cell subset development and their functional diversity. J Immunol 174, 2573-2581 .
[106] Taniguchi, T., Ogasawara, K., Takaoka, A., and Tanaka, N. (2001). IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 19, 623-655 .10.1146/annurev.immunol.19.1.623
[107] Tsujimura, H., Tamura, T., and Ozato, K. (2003). Cutting edge: IFN consensus sequence binding protein/IFN regulatory factor 8 drives the development of type I IFN-producing plasmacytoid dendritic cells. J Immunol 170, 1131-1135 .
[108] Tun-Kyi, A., Finn, G., Greenwood, A., Nowak, M., Lee, T.H., Asara, J.M., Tsokos, G.C., Fitzgerald, K., Israel, E., Li, X., . (2011). Essential role for the prolyl isomerase Pin1 in Toll-like receptor signaling and type I interferon-mediated immunity. Nat Immunol 12, 733-741 .10.1038/ni.2069
[109] Uematsu, S., Sato, S., Yamamoto, M., Hirotani, T., Kato, H., Takeshita, F., Matsuda, M., Coban, C., Ishii, K.J., Kawai, T., . (2005). Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. J Exp Med 201, 915-923 .10.1084/jem.20042372
[110] Wan, Y., Kim, T.W., Yu, M., Zhou, H., Yamashita, M., Kang, Z., Yin, W., Wang, J.A., Thomas, J., Sen, G.C., . (2011). The dual functions of IL-1 receptor-associated kinase 2 in TLR9-mediated IFN and proinflammatory cytokine production. J Immunol 186, 3006-3014 .10.4049/jimmunol.1003217
[111] Wang, C., Chen, T., Zhang, J., Yang, M., Li, N., Xu, X., and Cao, X. (2009). The E3 ubiquitin ligase Nrdp1 'preferentially' promotes TLR-mediated production of type I interferon. Nat Immunol 10, 744-752 .10.1038/ni.1742
[112] Wang, R.P., Zhang, M., Li, Y., Diao, F.C., Chen, D., Zhai, Z., and Shu, H.B. (2008). Differential regulation of IKK alpha-mediated activation of IRF3/7 by NIK. Mol Immunol 45, 1926-1934 .10.1016/j.molimm.2007.10.034
[113] Watarai, H., Sekine, E., Inoue, S., Nakagawa, R., Kaisho, T., and Taniguchi, M. (2008). PDC-TREM, a plasmacytoid dendritic cell-specific receptor, is responsible for augmented production of type I interferon. Proc Natl Acad Sci U S A 105, 2993-2998 .10.1073/pnas.0710351105
[114] Yan, D., Wang, X., Luo, L., Cao, X., and Ge, B. (2012). Inhibition of TLR signaling by a bacterial protein containing immunoreceptor tyrosine-based inhibitory motifs. Nat Immunol. (In Press) .10.1038/ni.2417
[115] Yang, Y., Liu, B., Dai, J., Srivastava, P.K., Zammit, D.J., Lefrancois, L., and Li, Z. (2007). Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity 26, 215-226 .10.1016/j.immuni.2006.12.005
[116] Yoshizaki, M., Tazawa, A., Kasumi, E., Sasawatari, S., Itoh, K., Dohi, T., Sasazuki, T., Inaba, K., Makrigiannis, A.P., and Toyama-Sorimachi, N. (2009). Spatiotemporal regulation of intracellular trafficking of Toll-like receptor 9 by an inhibitory receptor, Ly49Q. Blood 114, 1518-1527 .10.1182/blood-2008-12-192344
[117] Yu, Y., and Hayward, G.S. (2010). The ubiquitin E3 ligase RAUL negatively regulates type i interferon through ubiquitination of the transcription factors IRF7 and IRF3. Immunity 33, 863-877 .10.1016/j.immuni.2010.11.027
[118] Zhang, J., Xu, L.G., Han, K.J., Wei, X., and Shu, H.B. (2004). PIASy represses TRIF-induced ISRE and NF-kappaB activation but not apoptosis. FEBS Lett 570, 97- 101.10.1016/j.febslet.2004.05.081