title: Airway infiltration of CD4+ CCR6+ Th17 type cells associated with chronic cigarette smoke induced airspace enlargement.
abstract: Recently, patients with tobacco smoke induced emphysema have been shown to exhibit classical signs of T cell mediated autoimmunity characterized by autoantibody production and Th1 type responses. As the recently described Th17 type subset has been found to play a role in the pathogenesis of a number of autoimmune diseases previously considered to be Th1 driven, we sought to examine whether a Th17 type response was associated with airspace enlargement in a murine model of emphysema. Six to eight months exposure of mice to inhalation of mainstream cigarette smoke led to progressive airspace enlargement as defined by morphometric analysis. Flow cytometric analysis of the bronchoalveolar lavage (BAL) from these mice demonstrated a significant increase in the overall number of both CD4+ and CD8+ T cells present. These cells were subsequently examined for skewing towards a Th1, Th2 or Th17 phenotype by intracellular cytokine analysis. Distinct populations of BAL CD4+ T cells were found to express IFN-gamma or IL-17 demonstrating the presence of both a Th1 and Th17 type response. No expression of the Th2 associated cytokine IL-4 was detected. Further analysis of this Th17 subset demonstrated that the majority of cells with this effector phenotype express the chemokine receptor CCR6. Together these data identify a novel T cell subset associated with pulmonary inflammation as a result of cigarette smoke exposure. Given the reported roles of CCR6 and IL-17 in promoting pulmonary inflammation, this subset may play an important role in the pathogenesis of cigarette smoke induced autoimmunity.
authors.affiliation: Respiratory Center of Excellence for Drug Discovery, GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Harrison
authors.forename: Joseph
authors.initials: J
authors.lastname: Foley
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bolognese
authors.forename: Edward
authors.initials: E
authors.lastname: Long
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Podolin
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Walsh
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011656:Pulmonary Emphysema / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D054399:Receptors, CCR6 / Q000276:immunology / Q000378:metabolism; D012907:Smoking / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: C498126:CCR6 protein, mouse; D020381:Interleukin-17; D054399:Receptors, CCR6; D015847:Interleukin-4; D007371:Interferon-gamma