Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease

Abstract

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.

Blockade of the Programmed Death-1 Pathway Restores Sarcoidosis CD4+ T-Cell Proliferative Capacity

“…PD-1 up-regulation has been described in other granulomatous diseases, such as on beryllium-specific CD4 1 T cells in CBD. In the subjects with CBD, PD-1 expression correlated with the severity of the T-cell alveolitis (17). PD-1 has also been investigated specifically in the context of immune regulation, using PD-1 2/2 gene disrupted M. tuberculosis-infected mice (41).…”

“…When PD-1 is engaged, Src homology phosphatase-1 and -2 block phosphatidylinositol 3 kinase/Akt (PI3K/Akt) activation and induce both CD3-and CD28-mediated alterations to the T-cell transcriptome leading to reduced T-cell activation (15,16). Blockade of the PD-1 pathway restores T-cell function in granulomatous diseases, such as chronic beryllium disease (CBD) (17). Blockade of the PD-1 pathway also leads to clinical improvement of lung cancers (18,19).…”

Lymphocytic Alveolitis Is Associated with the Accumulation of Functionally Impaired HIV-Specific T Cells in the Lung of Antiretroviral Therapy–Naive Subjects

“…PBMCs and BAL cells were stimulated, washed, incubated with FcR-blocking reagent (Miltenyi Biotec, Bergisch Gladbach, Germany), stained, and analyzed as detailed in the online supplement. In certain experiments, PBMCs and BAL cells were labeled with Celltrace Violet (Life Technologies, Carlsbad, CA) as previously described (12,19), and HIV-1 gag-specific T-cell proliferation was determined as detailed in the online supplement.…”

“…These findings, although from liver and lymph node, illustrate that differences in immune regulation of T cells exist in different body compartments. Beryllium-specific CD4 1 T cells in BAL of patients with chronic beryllium disease have significantly higher PD-1 expression than their counterparts in blood, and blockade of the PD-1 pathway augmented beryllium-induced T-cell proliferation (19).…”

Deficient and Dysfunctional Regulatory T Cells in the Lungs of Chronic Beryllium Disease Subjects

“…Cells were washed and resuspended in 1% formaldehyde. Intracellular cytokine staining was performed as previously described (32). The lymphocyte population was identified using forward and 90-degree light scatter patterns, and fluorescence intensity was analyzed using a FACSCalibur flow cytometer (BD) (32).…”