Recombinant HLA-DP2 binds beryllium and tolerizes beryllium-specific pathogenic CD4+ T cells

Andrew P. Fontenot, Timothy S. Keizer, Mark McCleskey, Douglas G. Mack, Roberto Meza-Romero, Jianya Huan, David M. Edwards, Yuan K. Chou, Arthur A. Vandenbark, Brian Scott, Gregory Burrows

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Chronic beryllium disease is a lung disorder caused by beryllium exposure in the workplace and is characterized by granulomatous inflammation and the accumulation of beryllium-specific, HLA-DP2-restricted CD4+ T lymphocytes in the lung that proliferate and secrete Th1-type cytokines. To characterize the interaction among HLA-DP2, beryllium, and CD4+ T cells, we constructed rHLA-DP2 and rHLA-DP4 molecules consisting of the α-1 and β-1 domains of the HLA-DP molecules genetically linked into single polypeptide chains. Peptide binding to rHLA-DP2 and rHLA-DP4 was consistent with previously published peptide-binding motifs for these MHC class II molecules, with peptide binding dominated by aromatic residues in the P1 pocket. 9Be nuclear magnetic resonance spectroscopy showed that beryllium binds to the HLA-DP2-derived molecule, with no binding to the HLA-DP4 molecule that differs from DP2 by four amino acid residues. Using beryllium-specific CD4+ T cell lines derived from the lungs of chronic beryllium disease patients, beryllium presentation to those cells was independent of Ag processing because fixed APCs were capable of presenting BeSO4 and inducing T cell proliferation. Exposure of beryllium-specific CD4+ T cells to BeSO4-pulsed, plate-bound rHLA-DP2 molecules induced IFN-γ secretion. In addition, pretreatmeat of beryllium-specific CD4+ T cells with BeSO 4-pulsed, plate-bound HLA-DP2 blocked proliferation and EL-2 secretion upon re-exposure to beryllium presented by APCs. Thus, the rHLA-DP2 molecules described herein provide a template for engineering variants that retain the ability to tolerize pathogenic CD4+ T cells, but do so in the absence of the beryllium Ag.

Original languageEnglish (US)
Pages (from-to)3874-3883
Number of pages10
JournalJournal of Immunology
Volume177
Issue number6
DOIs
StatePublished - Sep 15 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Fontenot, A. P., Keizer, T. S., McCleskey, M., Mack, D. G., Meza-Romero, R., Huan, J., Edwards, D. M., Chou, Y. K., Vandenbark, A. A., Scott, B., & Burrows, G. (2006). Recombinant HLA-DP2 binds beryllium and tolerizes beryllium-specific pathogenic CD4+ T cells. Journal of Immunology, 177(6), 3874-3883. https://doi.org/10.4049/jimmunol.177.6.3874