The early phase of influenza infection occurs in the upper respiratory tract and the trachea, but little is known about the initial events of virus recognition and control of viral dissemination by the immune system. Here, we report that inflammatory dendritic cells (IDCs) are recruited to the trachea shortly after influenza infection through type I interferon-mediated production of the chemokine CCL2. We further show that recruited IDCs express the C-type lectin receptor SIGN-R1, which mediates direct recognition of the virus by interacting with N-linked glycans present in glycoproteins of the virion envelope. Activation of IDCs via SIGN-R1 triggers the production of the chemokines CCL5, CXCL9 and CXCL10, which initiate the recruitment of protective natural killer (NK) cells in the infected trachea. In the absence of SIGN-R1, the recruitment and activation of NK cells is impaired, leading to uncontrolled viral proliferation. In sum, our results provide insight into the orchestration of the early cellular and molecular events involved in immune protection against influenza.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
All data from this study are available from the corresponding author upon request.
Eichelberger, M., Allan, W., Zijlstra, M., Jaenisch, R. & Doherty, P. C. Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J. Exp. Med. 174, 875–880 (1991).
Pulendran, B. & Maddur, M. S. Innate immune sensing and response to influenza. Life Sci. J. 6, 23–71 (2014).
Rello, J. & Pop-Vicas, A. Clinical review: primary influenza viral pneumonia. Crit. Care 13, 235 (2009).
Wikstrom, M. E. & Stumbles, P. A. Mouse respiratory tract dendritic cell subsets and the immunological fate of inhaled antigens. Immunol. Cell Biol. 85, 182–188 (2007).
GeurtsvanKessel, C. H. et al. Clearance of influenza virus from the lung depends on migratory langerin+CD11b− but not plasmacytoid dendritic cells. J. Exp. Med. 205, 1621–1634 (2008).
Brimnes, M. K., Bonifaz, L., Steinman, R. M. & Moran, T. M. Influenza virus–induced dendritic cell maturation is associated with the induction of strong T cell immunity to a coadministered, normally nonimmunogenic protein. J. Exp. Med. 198, 133–144 (2003).
Geurtsvankessel, C. H. & Lambrecht, B. N. Division of labor between dendritic cell subsets of the lung. Mucosal Immunol. 1, 442–450 (2008).
Serbina, N. V., Salazar-Mather, T. P., Biron, C. A., Kuziel, W. A. & Pamer, E. G. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59–70 (2003).
Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5, 987–995 (2004).
Monteiro, J. & Lepenies, B. Myeloid C-type lectin receptors in viral recognition and antiviral immunity. Viruses 9, 59 (2017).
Kang, Y. et al. The C-type lectin SIGN-R1 mediates uptake of the capsular polysaccharide of Streptococcus pneumoniae in the marginal zone of mouse spleen. Proc. Natl Acad. Sci. USA 101, 215–220 (2004).
Gonzalez, S. F. et al. Capture of influenza by medullary dendritic cells via SIGN-R1 is essential for humoral immunity in draining lymph nodes. Nat. Immunol. 11, 427–434 (2010).
Taylor, P. R. et al. The role of SIGNR1 and the β-glucan receptor (dectin-1) in the nonopsonic recognition of yeast by specific macrophages. J. Immunol. 172, 1157–1162 (2004).
Parent, S. A. et al. Molecular characterization of the murine SIGNR1 gene encoding a C-type lectin homologous to human DC-SIGN and DC-SIGNR. Gene 293, 33–46 (2002).
Davies, L. C., Jenkins, S. J., Allen, J. E. & Taylor, P. R. Tissue-resident macrophages. Nat. Immunol. 14, 986–995 (2013).
Auffray, C., Sieweke, M. H. & Geissmann, F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu. Rev. Immunol. 27, 669–692 (2009).
McKean, D. et al. Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. Proc. Natl Acad. Sci. USA 81, 3180–3184 (1984).
Corti, D. et al. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 333, 850–856 (2011).
Khan, W. H., Shrungaram, R. V. L. N., Broor, S. & Parveen, S. Glycosylation studies of G protein of group B human respiratory syncytial virus (hRSV) in eukaryotic system. Int. J. Curr. Microbiol. Appl. Sci. 3, 107–113 (2014).
Yang, C. F. et al. Human metapneumovirus G protein is highly conserved within but not between genetic lineages. Arch. Virol. 158, 1245–1252 (2013).
Gregoire, C. et al. The trafficking of natural killer cells. Immunol. Rev. 220, 169–182 (2007).
Turner, M. D., Nedjai, B., Hurst, T. & Pennington, D. J. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim. Biophys. Acta Mol. Cell Res. 1843, 2563–2582 (2014).
Deshmane, S. L., Kremlev, S., Amini, S. & Sawaya, B. E. Monocyte chemoattractant protein-1 (MCP-1): an overview. J. Interf. Cytokine Res. 29, 313–326 (2009).
Jia, T. et al. Additive roles for MCP-1 and MCP-3 in CCR2-mediated recruitment of inflammatory monocytes during Listeria monocytogenes infection. J. Immunol. 180, 6846–6853 (2008).
Nakano, H. et al. Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute TH1 immune responses. Nat. Immunol. 10, 394–402 (2009).
Herold, S. et al. Alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: impact of chemokines and adhesion molecules. J. Immunol. 177, 1817–1824 (2006).
Pattison, M. J., MacKenzie, K. F., Elcombe, S. E. & Arthur, J. S. C. IFNβ autocrine feedback is required to sustain TLR induced production of MCP-1 in macrophages. FEBS Lett. 587, 1496–1503 (2013).
Chatziandreou, N. et al. Macrophage death following influenza vaccination initiates the inflammatory response that promotes dendritic cell function in the draining lymph node. Cell Rep. 18, 2427–2440 (2017).
Tate, M. D. & Hertzog, P. J. P109 The role of the type I interferon receptor during influenza virus infection. Cytokine 59, 554–555 (2012).
Helft, J. et al. Cross-presenting CD103+ dendritic cells are protected from influenza virus infection. J. Clin. Invest. 122, 4037–4047 (2012).
Geijtenbeek, T. B. H. & Gringhuis, S. I. Signalling through C-type lectin receptors: shaping immune responses. Nat. Rev. Immunol. 9, 465–479 (2009).
Tanne, A. et al. A murine DC-SIGN homologue contributes to early host defense against Mycobacterium tuberculosis. J. Exp. Med. 206, 2205–2220 (2009).
Schroder, K., Hertzog, P. J., Ravasi, T. & Hume, D. A. Interferon-γ: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 75, 163–189 (2004).
Taub, D. D. et al. Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J. Exp. Med. 177, 1809–1814 (1993).
Hickman, H. D. et al. CXCR3 Chemokine receptor enables local CD8+ T cell migration for the destruction of virus-infected cells. Immunity 42, 524–537 (2015).
Biron, C. A., Byron, K. S. & Sullivan, J. L. Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320, 1731–1735 (1989).
Stein-Streilein, J. & Guffee, J. In vivo treatment of mice and hamsters with antibodies to asialo GM1 increases morbidity and mortality to pulmonary influenza infection. J. Immunol. 136, 1435–1441 (1986).
Jost, S. & Altfeld, M. Control of human viral infections by natural killer cells. Annu. Rev. Immunol. 31, 163–194 (2013).
He, X.-S. et al. T cell-dependent production of IFN-γ by NK cells in response to influenza A virus. J. Clin. Invest. 114, 1812–1819 (2004).
Ge, M. Q. et al. NK cells regulate CD8+ T cell priming and dendritic cell migration during influenza A Infection by IFN- and perforin-dependent mechanisms. J. Immunol. 189, 2099–2109 (2012).
Hwang, I. et al. Activation mechanisms of natural killer cells during influenza virus infection. PLoS ONE 7, e51858 (2012).
Verbist, K. C., Rose, D. L., Cole, C. J., Field, M. B. & Klonowski, K. D. IL-15 Participates in the respiratory innate immune response to influenza virus infection. PLoS ONE 7, e37539 (2012).
Chaix, J. et al. Cutting edge: priming of NK cells by IL-18. J. Immunol. 181, 1627–1631 (2008).
Haeberlein, S., Sebald, H., Bogdan, C. & Schleicher, U. IL-18, but not IL-15, contributes to the IL-12-dependent induction of NK-cell effector functions by Leishmania infantum in vivo. Eur. J. Immunol. 40, 1708–1717 (2010).
Dawson, T. C., Beck, M. A., Kuziel, W. A., Henderson, F. & Maeda, N. Contrasting effects of CCR5 and CCR2 deficiency in the pulmonary inflammatory response to influenza A virus TL-156. Am. J. Pathol. 156, 1951–1959 (2000).
Rimmelzwaan, G. F., Baars, M. M., de Lijster, P., Fouchier, R. A. & Osterhaus, A. D. Inhibition of influenza virus replication by nitric oxide. J. Virol. 73, 8880–8883 (1999).
Seo, S. H. & Webster, R. G. Tumor necrosis factor alpha exerts powerful anti-influenza virus effects in lung epithelial cells. J. Virol. 76, 1071–1076 (2002).
Lin, K. L., Suzuki, Y., Nakano, H., Ramsburg, E. & Gunn, M. D. CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J. Immunol. 180, 2562–2572 (2008).
Lin, S.-J. et al. The pathological effects of CCR2+ inflammatory monocytes are amplified by an IFNAR1-triggered chemokine feedback loop in highly pathogenic influenza infection. J. Biomed. Sci. 21, 99 (2014).
Pamer, E. G. Tipping the balance in favor of protective immunity during influenza virus infection. Proc. Natl Acad. Sci. USA 106, 4961–4962 (2009).
Lindquist, R. L. et al. Visualizing dendritic cell networks in vivo. Nat. Immunol. 5, 1243–1250 (2004).
Boring, L. et al. Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. J. Clin. Invest. 100, 2552–2561 (1997).
Müller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994).
Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).
Palomino-Segura, M. et al. Imaging cell interaction in tracheal mucosa during influenza virus infection using two-photon intravital microscopy. J. Vis. Exp. 138, e58355 (2018).
Gonzalez, S. F., Jayasekera, J. P. & Carroll, M. C. Complement and natural antibody are required in the long-term memory response to influenza virus. Vaccine 26, I86–I93 (2008).
Harris, P. et al. Double-stranded RNA induces molecular and inflammatory signatures that are directly relevant to COPD. Mucosal Immunol. 6, 474–484 (2013).
Pfaffl, M. W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001).
We thank D. Jarrossay for the provision of technical support and M. Uguccioni for critical discussion of the manuscript; J. Paulson (The Scripps Research Institute) for initially providing KO mice; D. Corti (Humabs) for providing the antibody FI6 and Core G of the Consortium for Functional Glycomics (S. Orr) for mouse phenotyping. This work was supported by the Swiss National Foundation grants, R’equipt (145038), Ambizione (148183) and grant 176124 to S.F.G., the European Commission Marie Curie Reintegration Grant (612742), and SystemsX.ch for a grant to D.U.P. (2013/124). This work was partly supported by Center for Research on Influenza Pathogenesis and National Institute of Allergy and Infectious Diseases-funded Center of Excellence on Influenza Research and Pathogenesis (contract number HHSN272201400008C).
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Palomino-Segura, M., Perez, L., Farsakoglu, Y. et al. Protection against influenza infection requires early recognition by inflammatory dendritic cells through C-type lectin receptor SIGN-R1. Nat Microbiol 4, 1930–1940 (2019). https://doi.org/10.1038/s41564-019-0506-6
Journal of Hematology & Oncology (2020)