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


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 HLADP2+ 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.

SUBMITTER: Falta MT 

PROVIDER: S-EPMC3698527 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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

Falta Michael T MT   Pinilla Clemencia C   Mack Douglas G DG   Tinega Alex N AN   Crawford Frances F   Giulianotti Marc M   Santos Radleigh R   Clayton Gina M GM   Wang Yuxiao Y   Zhang Xuewu X   Maier Lisa A LA   Marrack Philippa P   Kappler John W JW   Fontenot Andrew P AP  

The Journal of experimental medicine 20130701 7


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 endoge  ...[more]

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