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* Department of Medicine and
Department of Immunology, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262; and
Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206
Chronic beryllium disease (CBD) is caused by workplace exposure to beryllium and is characterized by the accumulation of memory CD4+ T cells in the lung. These cells respond vigorously to beryllium salts in culture by producing proinflammatory Th1-type cytokines. The presence of these inflammatory cytokines leads to the recruitment of alveolar macrophages, alveolitis, and subsequent granuloma development. It has been shown that chronic exposure to conventional Ags leads to up-regulation in the expression of negative regulators of T cells such as programmed death-1 (PD-1). Due to the persistence of beryllium in the lung after the cessation of exposure, aberrant regulation of the PD-1 pathway may play an important role in CBD development. In the present study, PD-1 expression was measured on blood and bronchoalveolar lavage (BAL) CD4+ T cells from beryllium-sensitized and CBD subjects. PD-1 expression was significantly higher on BAL CD4+ T cells compared with those cells in blood, with the highest expression on the beryllium-specific T cell subset. In addition, the expression of PD-1 on BAL CD4+ T cells directly correlated with the severity of the T cell alveolitis. Increased expression of the PD-1 ligands, PD-L1 and PD-L2, on BAL CD14+ cells compared with blood was also seen. The addition of anti-PD-1 ligand mAbs augmented beryllium-induced CD4+ T cell proliferation, and an inverse correlation was seen between PD-1 expression on beryllium-specific CD4+ T cells and beryllium-induced proliferation. Thus, the PD-1 pathway is active in beryllium-induced disease and plays a key role in controlling beryllium-induced T cell proliferation.
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1 This work was supported by the following National Institutes of Health Grants: HL62410 and ES011810 (to A.P.F.), and the General Clinical Research Center (M01-RR00051) from the Division of Research Resources.
2 Address correspondence and reprint requests to Dr. Andrew P. Fontenot, Division of Clinical Immunology, University of Colorado at Denver and Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262. E-mail address: andrew.fontenot{at}uchsc.edu
3 Abbreviations used in this paper: CBD, chronic beryllium disease; BAL, bronchoalveolar lavage; TEM cell, effector memory T cell; PD-1, programmed death-1; BeS, beryllium sensitized; SEB, staphylococcal enterotoxin B; MFI, mean fluorescence intensity; WBC, white blood cell; TCM, central memory T cell.
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D. G. Mack, A. K. Lanham, B. E. Palmer, L. A. Maier, T. H. Watts, and A. P. Fontenot 4-1BB Enhances Proliferation of Beryllium-Specific T Cells in the Lung of Subjects with Chronic Beryllium Disease J. Immunol., September 15, 2008; 181(6): 4381 - 4388. [Abstract] [Full Text] [PDF]
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