title: OX40 ligand and programmed cell death 1 ligand 2 expression on inflammatory dendritic cells regulates CD4 T cell cytokine production in the lung during viral disease.
abstract: CD4 Th differentiation is influenced by costimulatory molecules expressed on conventional dendritic cells (DCs) in regional lymph nodes and results in specific patterns of cytokine production. However, the function of costimulatory molecules on inflammatory (CD11b(+)) DCs in the lung during recall responses is not fully understood, but it is important for development of novel interventions to limit immunopathological responses to infection. Using a mouse model in which vaccination with vaccinia virus vectors expressing the respiratory syncytial virus (RSV) fusion protein (rVVF) or attachment protein (rVVG) leads to type 1- or type 2-biased cytokine responses, respectively, upon RSV challenge, we found expression of CD40 and OX40 ligand (OX40L) on lung inflammatory DCs was higher in rVVF-primed mice than in rVVG-primed mice early after RSV challenge, whereas the reverse was observed later in the response. Conversely, programmed cell death 1 ligand 2 (PD-L2) was higher in rVVG-primed mice throughout. Inflammatory DCs isolated at the resolution of inflammation revealed that OX40L on type 1-biased DCs promoted IL-5, whereas OX40L on type 2-biased DCs enhanced IFN-γ production by Ag-reactive Th cells. In contrast, PD-L2 promoted IFN-γ production, irrespective of conditions, suppressing IL-5 only if expressed on type 1-biased DCs. Thus, OX40L and PD-L2 expressed on DCs differentially regulate cytokine production during recall responses in the lung. Manipulation of these costimulatory pathways may provide a novel approach to controlling pulmonary inflammatory responses.
authors.affiliation: Center for Respiratory Infections, National Heart and Lung Institute, St. Mary's Campus, Imperial College London, London W2 1PG, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Wythe
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Dodd
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Openshaw
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schwarze
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D053278:OX40 Ligand; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000096:biosynthesis* / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000473:pathology; D022261:Respiratory Syncytial Virus Vaccines / Q000276:immunology; D012136:Respiratory Syncytial Viruses / Q000235:genetics / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000096:biosynthesis* / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics; D014760:Viral Fusion Proteins / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D015848:Interleukin-5; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C556978:Pdcd1lg2 protein, mouse; D061027:Programmed Cell Death 1 Ligand 2 Protein; D022261:Respiratory Syncytial Virus Vaccines; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D014760:Viral Fusion Proteins; D007371:Interferon-gamma