title: 4-1BB enhances proliferation of beryllium-specific T cells in the lung of subjects with chronic beryllium disease.
abstract: In contrast to naive T cells, reactivation of memory cells is less dependent on CD28-mediated costimulation. We have shown that circulating beryllium-specific CD4(+) T cells from chronic beryllium disease patients remain CD28-dependent, while those present in the lung no longer require CD28 for T cell activation. In the present study, we analyzed whether other costimulatory molecules are essential for beryllium-induced T cell function in the lung. Enhanced proliferation of a beryllium-responsive, HLA-DP2-restricted T cell line was seen after the induction of 4-1BB ligand expression on the surface of HLA-DP2-expressing fibroblasts. Following beryllium exposure, CD4(+) T cells from blood and bronchoalveolar lavage of chronic beryllium disease patients up-regulate 4-1BB expression, and the majority of beryllium-responsive, IFN-gamma-producing CD4(+) T cells in blood coexpress CD28 and 4-1BB. Conversely, a significant fraction of IFN-gamma-producing bronchoalveolar lavage (BAL) T cells express 4-1BB in the absence of CD28. In contrast to blood, inhibition of the 4-1BB ligand-4-1BB interaction partially blocked beryllium-induced proliferation of BAL CD4(+) T cells, and a lack of 4-1BB expression on BAL T cells was associated with increased beryllium-induced cell death. Taken together, these findings suggest an important role of 4-1BB in the costimulation of beryllium-responsive CD4(+) T cells in the target organ.
authors.affiliation: Department of Medicine, University of Colorado Denver, Denver, CO 80262, USA.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Mack
authors.forename: Allison K
authors.initials: AK
authors.lastname: Lanham
authors.forename: Brent E
authors.initials: BE
authors.lastname: Palmer
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Maier
authors.forename: Tania H
authors.initials: TH
authors.lastname: Watts
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fontenot