Falta, M.T. et al. Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease. J. Exp. Med. 210, 1403-1418

Department of Medicine, University of Colorado, Denver, Aurora, CO 80045.
Journal of Experimental Medicine (Impact Factor: 12.52). 06/2013; 210(7). DOI: 10.1084/jem.20122426
Source: PubMed


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.

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Available from: Douglas G Mack, Mar 05, 2014
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    • "Despite this tilted conformation , the footprint of the AV22 TCR on DP2-M2 involves 280 atom-to-atom contacts (Table 1) and covers 1,288 A ˚ 2 , well within the range typically seen for CD4 T cell TCR contact with MHC-peptide ligands. Moreover, the TCR has a K D of 5 mM when binding to the complex (Falta et al., 2013) (Figures 2B and 2C), among the highest affinities seen for a TCR from a CD4 T cell. Table 1. "
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