Rationale: 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.
Objectives: 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.
Methods: 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.
Measurements and main results: 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.
Conclusions: 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.