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

Falta, MT, Pinilla, C, Mack, DG et al. (2013). Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease . JOURNAL OF EXPERIMENTAL MEDICINE, 210(7), 1403-1418. 10.1084/jem.20122426

cited authors

  • Falta, MT; Pinilla, C; Mack, DG; Tinega, AN; Crawford, F; Giulianotti, M; Santos, R; Clayton, GM; Wang, Y; Zhang, X; Maier, LA; Marrack, P; Kappler, JW; Fontenot, AP

authors

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. © 2013 Falta et al.

publication date

  • July 1, 2013

published in

Digital Object Identifier (DOI)

start page

  • 1403

end page

  • 1418

volume

  • 210

issue

  • 7