HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.
AuthorsDouglas 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
JournalProceedings 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
PMID24912188 (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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: