title: Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease.
abstract: Susceptibility to chronic beryllium disease (CBD) is linked to certain HLA-DP molecules, including HLA-DP2. To elucidate the molecular basis of this association, we exposed mice transgenic (Tg) for HLA-DP2 to beryllium oxide (BeO) via oropharyngeal aspiration. As opposed to WT mice, BeO-exposed HLA-DP2 Tg mice developed mononuclear infiltrates in a peribronchovascular distribution that were composed of CD4(+) T cells and included regulatory T (Treg) cells. Beryllium-responsive, HLA-DP2-restricted CD4(+) T cells expressing IFN-γ and IL-2 were present in BeO-exposed HLA-DP2 Tg mice and not in WT mice. Using Be-loaded HLA-DP2-peptide tetramers, we identified Be-specific CD4(+) T cells in the mouse lung that recognize identical ligands as CD4(+) T cells derived from the human lung. Importantly, a subset of HLA-DP2 tetramer-binding CD4(+) T cells expressed forkhead box P3, consistent with the expansion of antigen-specific Treg cells. Depletion of Treg cells in BeO-exposed HLA-DP2 Tg mice exacerbated lung inflammation and enhanced granuloma formation. These findings document, for the first time to our knowledge, the development of a Be-specific adaptive immune response in mice expressing HLA-DP2 and the ability of Treg cells to modulate the beryllium-induced granulomatous immune response.
authors.affiliation: Departments of Medicine and.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Mack
authors.affiliation: Departments of Medicine and.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Falta
authors.affiliation: Departments of Medicine and.
authors.forename: Amy S
authors.initials: AS
authors.lastname: McKee
authors.affiliation: Departments of Medicine and.
authors.forename: Allison K
authors.initials: AK
authors.lastname: Martin
authors.affiliation: Departments of Medicine and.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Simonian
authors.affiliation: Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206.
authors.forename: Frances
authors.initials: F
authors.lastname: Crawford
authors.affiliation: Department of Environmental Medicine, New York University, Tuxedo, NY 10987;
authors.forename: Terry
authors.initials: T
authors.lastname: Gordon
authors.affiliation: National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV 26505; and.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Mercer
authors.affiliation: National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV 26505; and.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Hoover
authors.affiliation: Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206.
authors.forename: Philippa
authors.initials: P
authors.lastname: Marrack
authors.affiliation: Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206 kapplerj@njhealth.org andrew.fontenot@ucdenver.edu.
authors.forename: John W
authors.initials: JW
authors.lastname: Kappler
authors.affiliation: Departments of Medicine and.
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.affiliation: Departments of Medicine andImmunology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; kapplerj@njhealth.org andrew.fontenot@ucdenver.edu.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fontenot
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology; D000818:Animals; D001607:Berylliosis / Q000235:genetics / Q000276:immunology*; D001608:Beryllium / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006099:Granuloma / Q000235:genetics / Q000276:immunology*; D059868:HLA-DP beta-Chains / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D059868:HLA-DP beta-Chains; C083176:HLA-DPw2 antigen; D007376:Interleukin-2; C032777:beryllium oxide; D007371:Interferon-gamma; D001608:Beryllium
keywords: MHC presentation; genetic susceptibility; metal hypersensitivity