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

Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):8553-8. doi: 10.1073/pnas.1408048111. Epub 2014 May 27.


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.

Keywords: MHC presentation; genetic susceptibility; metal hypersensitivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / genetics
  • Adaptive Immunity / immunology
  • Animals
  • Berylliosis / genetics
  • Berylliosis / immunology*
  • Beryllium / immunology
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoalveolar Lavage Fluid / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Disease Models, Animal*
  • Enzyme-Linked Immunospot Assay
  • Flow Cytometry
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism
  • Granuloma / genetics
  • Granuloma / immunology*
  • HLA-DP beta-Chains / genetics
  • HLA-DP beta-Chains / immunology*
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology*
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Transgenic
  • Spleen / immunology
  • Spleen / metabolism
  • Spleen / pathology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • HLA-DP beta-Chains
  • HLA-DPw2 antigen
  • Interleukin-2
  • beryllium oxide
  • Interferon-gamma
  • Beryllium