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Deficient and dysfunctional regulatory T cells in the lungs of chronic beryllium disease subjects.

ABSTRACT: Chronic beryllium disease (CBD) is a CD4(+) T cell-mediated disorder characterized by persistent lung inflammation. Naturally occurring regulatory T (T(reg)) cells modulate adaptive immune responses. The role of this T-cell subset in beryllium-induced lung disease is unknown.The aim of this study was to determine whether dysfunctional T(reg) cells in the lung contribute to the "unchecked" inflammatory response that characterizes CBD.Using blood and bronchoalveolar lavage (BAL) cells from normal control subjects and individuals with beryllium-induced disease, we determined the frequency and function of naturally occurring T(reg) cells.A significantly decreased percentage and expression of FoxP3 in BAL CD4(+) T cells from CBD patients compared with beryllium-sensitized subjects was seen, and the percentage of FoxP3-expressing CD4(+) T(reg) cells in BAL inversely correlated with disease severity. In contrast to blood T(reg) cells derived from beryllium-sensitized subjects and patients with CBD that completely suppressed blood responder T-cell proliferation, BAL FoxP3-expressing T(reg) cells from patients with CBD are unable to suppress anti-CD3-mediated BAL T-cell proliferation. Mixing studies showed that blood T(reg) cells are capable of suppressing autologous BAL responder T cells. Conversely, BAL CD4(+) T(reg) cells are incapable of suppressing blood T cells, confirming that the failure of BAL T(reg) cells to suppress T-cell proliferation is caused by a dysfunctional T(reg) cell subset and not by resistance of BAL effector T cells to suppression.These findings suggest that the deficient and dysfunctional T(reg) cells in the lung of patients with CBD contribute to the persistent inflammatory response in this disease.

SUBMITTER: Mack DG

PROVIDER: S-EPMC2891494 | biostudies-other | 2010 Jun

REPOSITORIES: biostudies-other

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Deficient and dysfunctional regulatory T cells in the lungs of chronic beryllium disease subjects.

Mack Douglas G DG Lanham Allison M AM Falta Michael T MT Palmer Brent E BE Maier Lisa A LA Fontenot Andrew P AP

American journal of respiratory and critical care medicine 20100318 11

<h4>Rationale</h4>Chronic beryllium disease (CBD) is a CD4(+) T cell-mediated disorder characterized by persistent lung inflammation. Naturally occurring regulatory T (T(reg)) cells modulate adaptive immune responses. The role of this T-cell subset in beryllium-induced lung disease is unknown.<h4>Objectives</h4>The aim of this study was to determine whether dysfunctional T(reg) cells in the lung contribute to the "unchecked" inflammatory response that characterizes CBD.<h4>Methods</h4>Using bloo ...[more]

PMID: 20299529

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Project description:RationaleOccupational exposure to beryllium (Be) can result in chronic granulomatous inflammation characterized by the presence of Be-specific CD4+ T cells. Studies show that oxidative stress plays a role in the pathogenesis of chronic inflammatory disorders.ObjectivesWe hypothesized that Be-induced oxidative stress modulates the proliferation of Be-specific CD4+ T cells.MethodsThirty-three subjects with chronic beryllium disease (CBD), 15 subjects with beryllium sensitization, and 28 healthy normal control subjects were consecutively enrolled from the Occupational and Environmental Health Clinic of the National Jewish Medical and Research Center.Measurements and main resultsAll studies were performed with Ficoll-Hypaque-isolated peripheral blood mononuclear cells from subsets of the study subjects. Decreased intracellular levels of the thiol antioxidants, glutathione and cysteine, were observed in peripheral blood mononuclear cells from subjects with beryllium sensitization and CBD, as compared with healthy control subjects. Beryllium stimulation decreased intracellular thiol antioxidants by more than 40%, accompanied by increased reactive oxygen species levels and the proliferation of Be-specific blood CD4+ T cells from subjects with CBD. Be-induced T-cell proliferation was inhibited by treatment with the thiol antioxidant N-acetylcysteine or the catalytic antioxidant manganese(III) 5,10,15,20-tetrakis(4-benzoic acid)porphyrin (MnTBAP). MnTBAP treatment also inhibited T-cell proliferation in response to the unrelated, MHC class II-restricted antigen tetanus toxoid. Treatment of CBD blood lymphocytes, but not antigen-presenting cells, with MnTBAP decreased Be-induced T-cell proliferation by more than 40%.ConclusionsBeryllium can mediate a thiol imbalance leading to oxidative stress that may modulate the proliferation and clonal expansion of Be-specific blood CD4+ T cells. These data suggest that Be-induced oxidative stress plays a role in the pathogenesis of granulomatous inflammation in CBD.

Dataset Information

Deficient and dysfunctional regulatory T cells in the lungs of chronic beryllium disease subjects.

Publications

Deficient and dysfunctional regulatory T cells in the lungs of chronic beryllium disease subjects.

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