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Published ahead of print on February 19, 2004, doi:10.1165/rcmb.2003-0336OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 31, pp. 122-130, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.2003-0336OC

Original Article

Beryllium-Induced Tumor Necrosis Factor-{alpha} Production by CD4+ T Cells Is Mediated by HLA-DP

Richard T. Sawyer, Charles E. Parsons, Andrew P. Fontenot, Lisa A. Maier, May M. Gillespie, E. Brigitte Gottschall, Lori Silveira and Lee S. Newman

Department of Medicine, Hollis Laboratory of Environmental and Occupational Health, National Jewish Medical and Research Center, Denver; and Department of Medicine, Division of Pulmonary Science and Critical Care Medicine, Department of Immunology, and Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado

Address for correspondence: Dr. Richard T. Sawyer, Division of Environmental and Occupational Health Sciences, Hollis Laboratory of Environmental and Occupational Health, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: sawyerr{at}njc.org

Beryllium (Be) presentation to CD4+ T cells from patients with chronic beryllium disease (CBD) results in T cell activation, and these Be-specific CD4+ T cells undergo clonal proliferation and T-helper 1-type cytokine production. In exposed workers, genetic susceptibility to this granulomatous disorder is associated with particular HLA-DPB1 alleles. We hypothesized that these HLA-DP molecules could mediate Be-stimulated tumor necrosis factor-{alpha} (TNF-{alpha}) messenger RNA (mRNA) and protein production. Using intracellular cytokine staining, we found that treatment with an anti–HLA-DP, but not anti–HLA-DR, monoclonal antibody inhibited Be-stimulated TNF-{alpha} expression in lung CD3+ CD4+ T cells. This monoclonal antibody also blocked Be-specific T cell proliferation, increased production of TNF-{alpha} mature-mRNA transcripts, and increased TNF-{alpha} protein production by Be-stimulated CBD peripheral blood mononuclear cells and bronchoalveolar lavage (BAL) cells. The Be-stimulated upregulation of TNF-{alpha} mature-mRNA levels with TNF-{alpha} protein production was a unique property of CBD BAL cells, and did not occur in BAL cells from Be-sensitized patients without CBD, or sarcoidosis BAL cells. This study identifies HLA-DP as a regulatory component in the activation of T cell receptors on Be-specific CD4+ T cells from CBD patients resulting in proliferation and proinflammatory cytokine production.

Abbreviations: B cell receptor, BCR • beryllium, Be • beryllium-lymphocyte proliferation test, BeLPT • beryllium sensitization, BeS • bronchoalveolar lavage, BAL • chronic beryllium disease, CBD • counts per minute, cpm • immunoglobulin, Ig • interferon, IFN • interleuken, IL • lipopolysaccharide, LPS • monoclonal antibody, mAb • major histocompatibility complex, MHC • reverse transcription polymerase chain reaction, RT-PCR • peripheral blood mononuclear cells, PBMC • standard error of the mean, SEM • Staphylococcal enterotoxin B, SEB • stimulation index, SI • T cell receptor, TCR • tumor necrosis factor-{alpha}, TNF-{alpha}




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