title: Respiratory syncytial virus infection, TLR3 ligands, and proinflammatory cytokines induce CD161 ligand LLT1 expression on the respiratory epithelium.
abstract: During respiratory-virus infection, excessive lymphocyte activation can cause pathology both in acute infection and in exacerbations of chronic respiratory diseases. The costimulatory molecule CD161 is expressed on lymphocyte subsets implicated in promoting respiratory inflammation, including Th2, Th17, mucosally associated invariant T (MAIT) cells, and type 2 innate lymphoid cells. We asked whether the CD161 ligand LLT1 could be expressed on respiratory epithelial cells following respiratory-virus infection as a mechanism by which respiratory-virus infection could promote activation of proinflammatory lymphocytes. In response to respiratory syncytial virus (RSV) infection, expression of LLT1 was upregulated in the BEAS-2B respiratory epithelial cell line and primary human bronchial epithelial cells. Imaging studies revealed that LLT1 expression increased in both RSV-infected and cocultured uninfected cells, suggesting that soluble factors produced during infection stimulate LLT1 expression. TLR3 and TLR2/6 ligands led to a rapid increase in LLT1 mRNA in respiratory epithelial cells, as did the proinflammatory cytokines type I interferons, interleukin 1β (IL-1β), and tumor necrosis factor alpha (TNF-α), which are produced early in respiratory-virus infection. Immunohistochemistry confirmed the increase in LLT1 protein on the epithelial cell surface, and live-cell confocal microscopy demonstrated accumulation of epithelial LLT1 at synapses formed with CD161(+) T lymphocytes. LLT1 expression by the respiratory epithelium in response to respiratory-virus infection and inflammatory cytokines represents a novel link between innate immunity and lymphocyte activation. As a regulator of CD161(+) proinflammatory lymphocytes, LLT1 could be a novel therapeutic target in inflammation caused by respiratory-virus infection.
  
  
  OBJECTIVE
  The immune response to respiratory-virus infection is essential for clearing the pathogen but, if excessive, can lead to tissue damage and obstruction of the airways. How viral infection activates immune cells in the lungs is not fully understood. Here, we show that LLT1 can be expressed in lung cells in response to infection. LLT1 triggers CD161, a receptor on inflammatory immune cells. This mechanism may promote activation of immune cells in the lungs in viral infection and could be a novel target for therapies aimed at reducing lung inflammation.
authors.affiliation: Department of Respiratory Medicine, Centre for Respiratory Infection, MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Stifani
authors.initials: S
authors.lastname: Satkunanathan
authors.forename: Naveenta
authors.initials: N
authors.lastname: Kumar
authors.forename: Monika
authors.initials: M
authors.lastname: Bajorek
authors.forename: Marco A
authors.initials: MA
authors.lastname: Purbhoo
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Culley
mesh_terms: D002460:Cell Line; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D037181:Lectins, C-Type / Q000235:genetics* / Q000378:metabolism; D008024:Ligands; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000821:virology*; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018113:Respiratory Syncytial Virus, Human / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D014779:Virus Replication
chemical_list: C400041:CLEC2D protein, human; D016207:Cytokines; D018836:Inflammation Mediators; D037181:Lectins, C-Type; D008024:Ligands; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3