title: Urban particulate matter suppresses priming of T helper type 1 cells by granulocyte/macrophage colony-stimulating factor-activated human dendritic cells.
abstract: Urban particulate matter (UPM) exacerbates asthmatic lung inflammation and depresses lung immunity. Lung dendritic cells (DCs) react to airway particulates, and have a critical role in linking innate and adaptive immunity, but the direct effects of UPM on DCs, that have been activated by granulocyte/macrophage colony-stimulating factor (GM-CSF), a product of stimulated normal human bronchial epithelial cells, has not been investigated. Human blood CD1c(+) DCs were purified and activated with UPM in the presence or absence of GM-CSF with and without LPS, and DC maturation was assessed by flow cytometry. DC stimulatory capacity and priming of 5-(and -6)-carboxyfluorescein diacetate succinimidyl ester-labeled naive CD4 T cells was investigated using the allogeneic mixed lymphocyte reaction. T cell proliferation and effector function were assessed using flow cytometry and secreted cytokines were measured by combined bead array. UPM enhanced DC maturation in an LPS-independent manner. DCs activated by UPM plus GM-CSF (UPM + GM-CSF DCs) induced higher naive CD4 T cell proliferation in the allogeneic mixed lymphocyte reaction than DCs pretreated by GM-CSF alone (GM-CSF DCs), and elicited both substantially lower levels of IFN-γ, IL-13, and IL-5 secretion, and lower frequencies of alloantigen-specific T helper (Th) type 1 effector cells than naive CD4 T cells primed by GM-CSF DCs. UPM-stimulated DCs produced IL-6 and TNF-α. Neutralization of IL-6 decreased naive CD4 T cell proliferation stimulated by UPM + GM-CSF DCs, and significantly increased the frequency of alloantigen-specific Th1 effector cells, but did not reverse UPM-induced inhibition of IFN-γ secretion. We conclude that UPM enhances GM-CSF-induced DC maturation and stimulatory capacity, but inhibits the generation of Th1 cells. Thus, UPM exposure may impair Th1 responses to pulmonary pathogens.
authors.affiliation: 1 Division of Asthma, Allergy and Lung Biology, Medical Research Council (MRC)-Asthma United Kingdom Centre for Allergic Mechanisms of Asthma, Guy's Hospital, King's College London, United Kingdom.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Matthews
authors.forename: Alex
authors.initials: A
authors.lastname: Faith
authors.forename: Paul
authors.initials: P
authors.lastname: Pfeffer
authors.forename: Haw
authors.initials: H
authors.lastname: Lu
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kelly
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hawrylowicz
authors.forename: Tak H
authors.initials: TH
authors.lastname: Lee
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000494:pharmacology*; D052638:Particulate Matter / Q000276:immunology / Q000494:pharmacology*; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C578095:IL13 protein, human; C508599:IL5 protein, human; C508600:IL6 protein, human; D018793:Interleukin-13; D015848:Interleukin-5; D015850:Interleukin-6; D052638:Particulate Matter; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor