title: Role of increased CD8/CD28(null) T cells and alternative co-stimulatory molecules in chronic obstructive pulmonary disease.
abstract: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease; it is a leading cause of death and existing treatments have no proven disease-modifying effect. The mechanisms underlying this resistance are largely unknown, but suggest the presence of some self-maintaining pathogenic process, possibly initiated by cigarette smoking, that prevents the normal resolution of inflammation. We have previously reported increased production of proinflammatory cytokines and granzyme b by CD8(+) T cells in COPD; costimulatory receptor/ligand interactions required include CD80:86/CD28, B7-1/CTLA4, 4-1BB/1BBL and OX40/OX40L. We hypothesized that a dysregulated expression/function of these molecules may play a role in inflammatory/autoimmune components of COPD. We analysed T cell co-stimulatory molecules in blood from 34 controls, 15 smokers and 48 COPD subjects. We assessed the potential functional relevance of CD8/CD28(null) cells in COPD by measuring their production of proinflammatory cytokines, co-stimulatory molecules, granzyme and perforin. A smoke-exposed murine model was applied to investigate the relative expression of CD8/CD28(null) T cells in blood, lung tissue and airway. CD8/CD28(null) cells were increased in both current- and ex-smoker COPD groups; these cells expressed significantly more interferon (IFN)-γ, OX40, 4-1BB, CTLA4, granzyme and perforin when stimulated than CD8/CD28(+) T cells. There were no changes in CD4/CD28(null) T cells. In mice exposed to cigarette smoke for 12 weeks, CD8/CD28(null) T cells were significantly increased in the airway with a trend for an increase in lung tissue and blood. Increased production of proinflammatory cytokines and expression of alternative co-stimulatory molecules by CD8/CD28(null) T cells may play a role in inflammatory or autoimmune responses in COPD and identify therapeutic targets.
authors.affiliation: Lung Research Laboratory, Hanson Institute and Department of Thoracic Medicine, Royal Adelaide Hospital and University of Adelaide, Adelaide, South Australia, Australia. greg.hodge@health.sa.gov.au
authors.forename: G
authors.initials: G
authors.lastname: Hodge
authors.forename: V
authors.initials: V
authors.lastname: Mukaro
authors.forename: P N
authors.initials: PN
authors.lastname: Reynolds
authors.forename: S
authors.initials: S
authors.lastname: Hodge
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism*; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008215:Lymphocytes, Null / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D054353:Perforin / Q000235:genetics / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000473:pathology; D012907:Smoking; D015854:Up-Regulation
chemical_list: D018106:CD28 Antigens; D015704:CD4 Antigens; D016207:Cytokines; D054353:Perforin; D053804:Granzymes