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Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease.

Mack-DG; Falta-MT; McKee-AS; Martin-AK; Simonian-PL; Crawford-F; Gordon-T; Mercer-RR; Hoover-MD; Marrack-P; Kappler-JW; Tudera-RM; Fontenot-AP
Proc Natl Acad Sci U.S.A. 2014 Jun; 111(23):8553-8558
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-? 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. Chronic beryllium disease (CBD) is a granulomatous lung disorder that occurs in susceptible individuals exposed to beryllium (Be) in the workplace. Genetic susceptibility to CBD has been linked to major histocompatibility complex class II (MHCII) alleles, particularly HLA-DP. HLA-DPB1 alleles with a glutamic acid at position 69 of the ▀-chain (▀Glu69), which includes DPB1*02:01, are strongly associated with disease susceptibility. Functional studies have shown that the HLA-DP molecules that mediate Be presentation to T cells match those implicated in disease susceptibility. An HLA-DP2 crystal structure revealed a unique solvent-exposed acidic pocket located between the peptide backbone and the HLA-DP2 ▀-chain a-helix, formed by three glutamic acid residues from the ▀-chain, including ▀Glu69. Mutagenesis of any of these residues resulted in loss of the ability of HLA-DP2 to present Be to T cells establishing that the HLA contribution to the development of CBD is due to the ability of ▀Glu69-containing HLA-DP molecules to bind and present Be to pathogenic CD4+ T cells. Regulatory T (Treg) cells play a key role in maintaining peripheral T-cell tolerance, in particular, by suppressing the activation and expansion of effector T cells. We have previously shown that there is variation in the frequency of Treg cells in the bronchoalveolar lavage (BAL) of CBD patients and that the frequency of forkhead box P3 (FoxP3)-expressing Treg cells in the lung is inversely associated with disease severity (8). However, the lack of a viable animal model has precluded study of whether this T-cell subset participates in the regulation of disease severity as well as a determination of the factors that contribute to their presence in the lung. Here, we exposed mice transgenic (Tg) for HLA-DP2 (the most prevalent ▀Glu69-containing molecule) to Be oxide (BeO), a form of the metal that is used in the workplace. BeO-exposed HLA-DP2-expressing mice developed mononuclear infiltrates in the lung, a Be-specific adaptive immune response in lung and spleen, and an expansion of Treg cells in the lung. Depletion of Treg cells exacerbated the Be-specific CD4+ T-cell alveolitis and converted the peribronchovascular mononuclear cell infiltrates into well-formed granulomas. Our findings strongly suggest that expression of the correct MHCII molecule in mice accompanied by an environmental exposure drives disease development, and identify an important role for Treg cells in modulating the Be-induced granulomatous response.
Beryllium-disease; Disinfectants; Molecular-structure; Humans; Men; Respiration; Respiratory-irritants; Respiratory-system-disorders; Pulmonary-system; Pulmonary-system-disorders; Pulmonary-function; Pulmonary-disorders; Animals; Laboratory-animals; Cellular-structures; Cell-function; Exposure-levels; Risk-factors; Author Keywords: Beryllium disease; Toxicopathology; Immunotoxicology; Immune reaction
John W. Kappler, Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206
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Proceedings of the National Academy of Sciences of the United States of America