Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 23, Pages 8553-8558Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1408048111
Keywords
metal hypersensitivity; MHC presentation; genetic susceptibility
Categories
Funding
- National Institutes of Health [HL62410, HL111760, ES11810, ES011473, 212-2010-M-35006, DE-FG02-08ER64670]
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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 (T-reg) cells. Beryllium-responsive, HLA-DP2-restricted CD4(+) T cells expressing IFN-gamma 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 T-reg cells. Depletion of T-reg 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 T-reg cells to modulate the beryllium-induced granulomatous immune response.
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