title: Impaired function of CTLA-4 in the lungs of patients with chronic beryllium disease contributes to persistent inflammation.
abstract: Chronic beryllium disease (CBD) is an occupational lung disorder characterized by granulomatous inflammation and the accumulation of beryllium-responsive CD4(+) T cells in the lung. These differentiated effector memory T cells secrete IL-2, IFN-γ, and TNF-α upon in vitro activation. Beryllium-responsive CD4(+) T cells in the lung are CD28 independent and have increased expression of the coinhibitory receptor, programmed death 1, resulting in Ag-specific T cells that proliferate poorly yet retain the ability to express Th1-type cytokines. To further investigate the role of coinhibitory receptors in the beryllium-induced immune response, we examined the expression of CTLA-4 in blood and bronchoalveolar lavage cells from subjects with CBD. CTLA-4 expression was elevated on CD4(+) T cells from the lungs of study subjects compared with blood. Furthermore, CTLA-4 expression was greatest in the beryllium-responsive subset of CD4(+) T cells that retained the ability to proliferate and express IL-2. Functional assays show that the induction of CTLA-4 signaling in blood cells inhibited beryllium-induced T cell proliferation while having no effect on the proliferative capacity of beryllium-responsive CD4(+) T cells in the lung. Collectively, our findings suggest a dysfunctional CTLA-4 pathway in the lung and its potential contribution to the persistent inflammatory response that characterizes CBD.
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Chain
authors.forename: Allison K
authors.initials: AK
authors.lastname: Martin
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Mack
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Maier
authors.forename: Brent E
authors.initials: BE
authors.lastname: Palmer
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fontenot
mesh_terms: D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000235:genetics; D001607:Berylliosis / Q000097:blood / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D060908:CTLA-4 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D002455:Cell Division; D002908:Chronic Disease; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007376:Interleukin-2 / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D018448:Models, Immunological; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007376:Interleukin-2; D008222:Lymphokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma