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 | Douglas G Mack, Michael T Falta, Amy S McKee, Allison K Martin, Philip L Simonian, Frances Crawford, Terry Gordon, Robert R Mercer, Mark D Hoover, Philippa Marrack, John W Kappler, Rubin M Tuder, Andrew P Fontenot |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 111
Issue 23
Pg. 8553-8
(Jun 10 2014)
ISSN: 1091-6490 [Electronic] United States |
PMID | 24912188
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Forkhead Transcription Factors
- Foxp3 protein, mouse
- HLA-DP beta-Chains
- HLA-DPw2 antigen
- Interleukin-2
- beryllium oxide
- Interferon-gamma
- Beryllium
|
Topics |
- Adaptive Immunity
(genetics, immunology)
- Animals
- Berylliosis
(genetics, immunology)
- Beryllium
(immunology)
- Bronchoalveolar Lavage Fluid
(cytology, immunology)
- CD4-Positive T-Lymphocytes
(immunology, metabolism)
- Disease Models, Animal
- Enzyme-Linked Immunospot Assay
- Flow Cytometry
- Forkhead Transcription Factors
(immunology, metabolism)
- Granuloma
(genetics, immunology)
- HLA-DP beta-Chains
(genetics, immunology)
- Humans
- Inflammation
(genetics, immunology)
- Interferon-gamma
(immunology, metabolism)
- Interleukin-2
(immunology, metabolism)
- Lung
(immunology, metabolism, pathology)
- Mice
- Mice, Transgenic
- Spleen
(immunology, metabolism, pathology)
- T-Lymphocytes, Regulatory
(immunology, metabolism)
|