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4-1BB Enhances Proliferation of Beryllium-Specific T Cells in the Lung of Subjects with Chronic Beryllium Disease¹

Douglas G. Mack^*, Allison K. Lanham^*, Brent E. Palmer^*, Lisa A. Maier^*,, Tania H. Watts and Andrew P. Fontenot^*,,2

^* Department of Medicine and Department of Immunology, University of Colorado Denver, Denver, CO 80262; Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206; and Department of Immunology, University of Toronto, Toronto, Ontario, Canada

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--producing CD4⁺ T cells in blood coexpress CD28 and 4-1BB. Conversely, a significant fraction of IFN--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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by National Institute of Health Grants HL62410 and ES11810 to A.P.F., Canadian Institutes of Health Grant MOP-74492 to T.H.W., and the General Clinical Research Center Grant M01-RR-0051 from the Division of Research Resources.

² Address correspondence and reprint requests to Dr. Andrew P. Fontenot, Division of Clinical Immunology (B164), University of Colorado Denver, 4200 East Ninth Avenue, Denver, CO 80262. E-mail address: andrew.fontenot{at}uchsc.edu

³ Abbreviations used in this paper: BAL, bronchoalveolar lavage; CBD, chronic beryllium disease; 7-AAD, 7-aminoactinomycin D; BeS, beryllium sensitized; BeSO₄, beryllium sulfate; CD40L, CD40 ligand; MFI, median fluorescence intensity; MOI, multiplicity of infection; OX-40L, OX-40 ligand; PD-1, programmed death-1; T_EM cells, effector memory T cells.

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