Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease

Michael T. Falta, Clemencia Pinilla, Douglas G. Mack, Alex N. Tinega, Frances Crawford, Marc Giulianotti, Radleigh Santos, Gina M. Clayton, Yuxiao Wang, Xuewu Zhang, Lisa A. Maier, Philippa Marrack, John W. Kappler, Andrew P. Fontenot

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4+ T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP-restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4+ T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2-mimotope and HLA-DP2-plexin A4 tetramers detected high frequencies of CD4+ T cells specific for these ligands in all HLA-DP2+ CBD patients tested. Thus, our findings identify the first ligand for a CD4+ T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD.

Original languageEnglish (US)
Pages (from-to)1403-1418
Number of pages16
JournalJournal of Experimental Medicine
Volume210
Issue number7
DOIs
StatePublished - Jul 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Falta, M. T., Pinilla, C., Mack, D. G., Tinega, A. N., Crawford, F., Giulianotti, M., Santos, R., Clayton, G. M., Wang, Y., Zhang, X., Maier, L. A., Marrack, P., Kappler, J. W., & Fontenot, A. P. (2013). Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease. Journal of Experimental Medicine, 210(7), 1403-1418. https://doi.org/10.1084/jem.20122426