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.