Frequency of beryllium-specific, T1-type cytokine-expressing CD4 T cells in patients with beryllium-induced disease

Pott, Gregory B.; Palmer, Brent E.; Sullivan, Andrew; Silviera, Lori; Maier, Lisa A.; Newman, Lee S.; Kotzin, Brian L.; Fontenot, Andrew P.

doi:10.1016/j.jaci.2005.01.019

Cited by 39 publications

(55 citation statements)

References 29 publications

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“…Although corticosteroid treatment provides symptomatic relief, it does not result in a significant drop in the number of CD4 ϩ T cells in the lung or the number of circulating berylliumspecific CD4 ϩ T cells (29,42). This study clearly demonstrates that PD-1 expression on beryllium-specific CD4 ϩ T cells is upregulated and that the pathway is active.…”

Section: Discussionmentioning

confidence: 73%

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

Palmer¹,

Mack²,

Martin³

et al. 2008

The Journal of Immunology

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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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Section: Discussionmentioning

confidence: 73%

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

Palmer¹,

Mack²,

Martin³

et al. 2008

The Journal of Immunology

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“…Similar to the human disease, these findings confirm the presence of lymphocytic alveolitis in BeOexposed HLA-DP2 Tg mice with a predominance of CD4 + T cells. To document an adaptive immune response to Be, we used IFN-γ and IL-2 enzyme-linked immunosorbent spot (ELISPOT) assays as a measure of T-cell response (10,11). Be-responsive, IL-2-secreting T cells [median, 54 spot forming units (SFUs); range, 9.3-217] were only present in the lung of HLA-DP2 Tg mice exposed to BeO ( Fig.…”

Section: Hla-dp2 Tg Mice Develop Peribronchovascular Mononuclear Infimentioning

confidence: 99%

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

Mack¹,

Falta²,

McKee³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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 (T reg ) 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 T reg cells. Depletion of T reg 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 T reg cells to modulate the beryllium-induced granulomatous immune response.metal hypersensitivity | MHC presentation | genetic susceptibility

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“…The BAL of our subjects with CBD contained Ͼ 100 million total WBC with ‫ف‬ 31% lymphocytes, consistent with our previous observations (2, 6, 7, 14, 18). Moreover, Be exposure activates these T cells, resulting in proliferation and clonal expansion into an effector-memory T cell population (2), and studies show that these T cells upregulate proinflammatory cytokines skewed toward a Th1-type phenotype (24). The signal driving this Be-specific T cell activation is MHC class II restricted, and an interesting aspect of these activated CD4 ϩ T cells is their ability to also produce high levels of TNF-␣ (7).…”

Section: Discussionmentioning

confidence: 99%

“…To date, studies demonstrating the precise cellular source of these various cytokines and chemokines in PBMC and BAL cells from patients with CBD have been limited. Fontenot and his coworkers used intracellular cytokine staining (2,20) and ELISPOT analysis (24) to demonstrate that CD4 ϩ T cells from blood and BAL of subjects with CBD upregulate TNF-␣ and IFN-␥. Sawyer and colleagues (7) demonstrated that Be stimulation does not upregulate TNF-␣ production by CBD BAL macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…Future studies will include sufficient patient numbers to perform a more detailed analysis using nuclear run-on transcription assays or RNA Pol II ChIP assays to provide formal biochemical proof that Be-stimulation induces TNF-␣ gene transcription. Due to this limitation, it is reasonable to suggest that some, or all, of these transcription factors could mediate the activation of genes encoding other Be-stimulated proteins produced by CBD BAL CD4 ϩ T cells-for example, IFN-␥, IL-2, IL-6, and IL-10 (7,(24)(25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

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Beryllium-Induced TNF-α Production Is Transcription-Dependent in Chronic Beryllium Disease

Sawyer

Fontenot

Barnes

et al. 2007

Am J Respir Cell Mol Biol

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Beryllium (Be)-antigen presentation to Be-specific CD4 ϩ T cells from the lungs of patients with chronic beryllium disease (CBD) results in T cell proliferation and TNF-␣ secretion. We tested the hypothesis that Be-induced, CBD bronchoalveolar lavage (BAL) T cell, transcription-dependent, TNF-␣ secretion was accompanied by specific transcription factor upregulation. After 6 h of Be stimulation, CBD BAL cells produced a median of 883 pg/ml TNF-␣ (range, 608-1,275 pg/ml) versus 198 pg/ml (range, 116-245 pg/ml) by unstimulated cells. After 12 h CBD BAL cells produced a median of 2,963 pg/ml (range, 99-9,424 pg/ml) TNF-␣ versus 55 pg/ml (range, 0-454) by unstimulated cells. Using real-time RT-PCR, Be-stimulated TNF-␣ production at 6 h was preceded by a 5-fold increase in TNF-␣ premRNA copy number:␤-actin copy number (Be median ratio 0.21; unstimulated median ratio 0.04). The median ratio of mature TNF-␣ mRNA:␤-actin mRNA was upregulated 1.4-fold (Be median ratio 0.17; unstimulated median ratio 0.12). Be exposure in the presence of the transcription inhibitor pentoxifylline (PTX) decreased CBD BAL cell TNF-␣ pre-mRNA levels Ͼ 60%, whereas treatment with the mRNA splicing inhibitor 2-aminopurine (2AP) decreased levels 40% relative to Be exposure alone. PTX treatment decreased mature TNF-␣ mRNA levels 50% while 2AP decreased levels Ͼ 80%, relative to Be exposure alone. Beryllium exposure specifically upregulated transcription factors AP-1 and NF-B. The data suggest that Be exposure induces transcription-dependent TNF-␣ production, potentially due to upregulation of specific transcription factors.

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Frequency of beryllium-specific, T1-type cytokine-expressing CD4 T cells in patients with beryllium-induced disease

Cited by 39 publications

References 29 publications

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

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

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

Beryllium-Induced TNF-α Production Is Transcription-Dependent in Chronic Beryllium Disease

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