Original Article

Natural Interferon /ß–producing Cells Link Innate and Adaptive Immunity

Correspondence to: Yong-Jun Liu, DNAX Research Institute, 901 California Ave., Palo Alto, CA 94304. Tel:650-496-1157 Fax:650-496-1200 E-mail:yliu{at}dnax.org.

Innate immune responses to pathogens critically impact the development of adaptive immune responses. However, it is not completely understood how innate immunity controls the initiation of adaptive immunities or how it determines which type of adaptive immunity will be induced to eliminate a given pathogen. Here we show that viral stimulation not only triggers natural interferon (IFN)-/ß–producing cells (IPCs) to produce vast amounts of antiviral IFN-/ß but also induces these cells to differentiate into dendritic cells (DCs). IFN-/ß and tumor necrosis factor produced by virus-activated IPCs act as autocrine survival and DC differentiation factors, respectively. The virus-induced DCs stimulate naive CD4⁺ T cells to produce IFN- and interleukin (IL)-10, in contrast to IL-3–induced DCs, which stimulate naive CD4⁺ T cells to produce T helper type 2 cytokines IL-4, IL-5, and IL-10. Thus, IPCs may play two master roles in antiviral immune responses: directly inhibiting viral replication by producing large amounts of IFN-/ß, and subsequently triggering adaptive T cell–mediated immunity by differentiating into DCs. IPCs constitute a critical link between innate and adaptive immunity.

Key Words: dendritic cells, interferon /ß–producing cells, innate immunity, adaptive immunity, T cells

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• Dai, J., Megjugorac, N. J., Amrute, S. B., Fitzgerald-Bocarsly, P. (2004). Regulation of IFN Regulatory Factor-7 and IFN-{alpha} Production by Enveloped Virus and Lipopolysaccharide in Human Plasmacytoid Dendritic Cells. J. Immunol. 173: 1535-1548 [Abstract] [Full Text]  
• Teleshova, N., Kenney, J., Jones, J., Marshall, J., Van Nest, G., Dufour, J., Bohm, R., Lifson, J. D., Gettie, A., Pope, M. (2004). CpG-C Immunostimulatory Oligodeoxyribonucleotide Activation of Plasmacytoid Dendritic Cells in Rhesus Macaques to Augment the Activation of IFN-{gamma}-Secreting Simian Immunodeficiency Virus-Specific T Cells. J. Immunol. 173: 1647-1657 [Abstract] [Full Text]  
• Salek-Ardakani, S., Lyons, S. A., Arrand, J. R. (2004). Epstein-Barr Virus Promotes Human Monocyte Survival and Maturation through a Paracrine Induction of IFN-{alpha}. J. Immunol. 173: 321-331 [Abstract] [Full Text]  
• Hubert, F.-X., Voisine, C., Louvet, C., Heslan, M., Josien, R. (2004). Rat Plasmacytoid Dendritic Cells Are an Abundant Subset of MHC Class II+ CD4+CD11b-OX62- and Type I IFN-Producing Cells That Exhibit Selective Expression of Toll-Like Receptors 7 and 9 and Strong Responsiveness to CpG. J. Immunol. 172: 7485-7494 [Abstract] [Full Text]  
• Teleshova, N., Jones, J., Kenney, J., Purcell, J., Bohm, R., Gettie, A., Pope, M. (2004). Short-term Flt3L treatment effectively mobilizes functional macaque dendritic cells. J. Leukoc. Biol. 75: 1102-1110 [Abstract] [Full Text]  
• Senechal, B., Boruchov, A. M., Reagan, J. L., Hart, D. N. J., Young, J. W. (2004). Infection of mature monocyte-derived dendritic cells with human cytomegalovirus inhibits stimulation of T-cell proliferation via the release of soluble CD83. Blood 103: 4207-4215 [Abstract] [Full Text]  
• Reddy, V., Iturraspe, J. A., Tzolas, A. C., Meier-Kriesche, H.-U., Schold, J., Wingard, J. R. (2004). Low dendritic cell count after allogeneic hematopoietic stem cell transplantation predicts relapse, death, and acute graft-versus-host disease. Blood 103: 4330-4335 [Abstract] [Full Text]  
• Fonteneau, J.-F., Larsson, M., Beignon, A.-S., McKenna, K., Dasilva, I., Amara, A., Liu, Y.-J., Lifson, J. D., Littman, D. R., Bhardwaj, N. (2004). Human Immunodeficiency Virus Type 1 Activates Plasmacytoid Dendritic Cells and Concomitantly Induces the Bystander Maturation of Myeloid Dendritic Cells. J. Virol. 78: 5223-5232 [Abstract] [Full Text]  
• Mazzoni, A., Segal, D. M. (2004). Controlling the Toll road to dendritic cell polarization. J. Leukoc. Biol. 75: 721-730 [Abstract] [Full Text]  
• Bjorck, P. (2004). Dendritic Cells Exposed to Herpes Simplex Virus In Vivo Do Not Produce IFN-{alpha} after Rechallenge with Virus In Vitro and Exhibit Decreased T Cell Alloreactivity. J. Immunol. 172: 5396-5404 [Abstract] [Full Text]  
• Dillon, S., Agrawal, A., Van Dyke, T., Landreth, G., McCauley, L., Koh, A., Maliszewski, C., Akira, S., Pulendran, B. (2004). A Toll-Like Receptor 2 Ligand Stimulates Th2 Responses In Vivo, via Induction of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and c-Fos in Dendritic Cells. J. Immunol. 172: 4733-4743 [Abstract] [Full Text]  
• Pichyangkul, S., Yongvanitchit, K., Kum-arb, U., Hemmi, H., Akira, S., Krieg, A. M., Heppner, D. G., Stewart, V. A., Hasegawa, H., Looareesuwan, S., Shanks, G. D., Miller, R. S. (2004). Malaria Blood Stage Parasites Activate Human Plasmacytoid Dendritic Cells and Murine Dendritic Cells through a Toll-Like Receptor 9-Dependent Pathway. J. Immunol. 172: 4926-4933 [Abstract] [Full Text]  
• Ito, T., Amakawa, R., Inaba, M., Hori, T., Ota, M., Nakamura, K., Takebayashi, M., Miyaji, M., Yoshimura, T., Inaba, K., Fukuhara, S. (2004). Plasmacytoid Dendritic Cells Regulate Th Cell Responses through OX40 Ligand and Type I IFNs. J. Immunol. 172: 4253-4259 [Abstract] [Full Text]  
• Van Krinks, C. H., Matyszak, M. K., Hill Gaston, J. S. (2004). Characterization of plasmacytoid dendritic cells in inflammatory arthritis synovial fluid. Rheumatology (Oxford) 43: 453-460 [Abstract] [Full Text]  
• Chen, W., Antonenko, S., Sederstrom, J. M., Liang, X., Chan, A. S. H., Kanzler, H., Blom, B., Blazar, B. R., Liu, Y.-J. (2004). Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors. Blood 103: 2547-2553 [Abstract] [Full Text]  

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