Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease
| Autor: | Philippa Marrack, John W. Kappler, Andrew P. Fontenot, Radleigh G. Santos, Alex N. Tinega, Frances Crawford, Michael T. Falta, Gina M. Clayton, Yuxiao Wang, Xuewu Zhang, Marc A. Giulianotti, Lisa A. Maier, Clemencia Pinilla, Douglas G. Mack |
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| Rok vydání: | 2013 |
| Předmět: |
CD4-Positive T-Lymphocytes
T cell Immunology Peptide Receptors Cell Surface Human leukocyte antigen Article Cell Line 03 medical and health sciences Berylliosis Mice 0302 clinical medicine Peptide Library medicine Immunology and Allergy Cytotoxic T cell Animals Humans Amino Acid Sequence Antigen-presenting cell HLA-DP beta-Chains 030304 developmental biology chemistry.chemical_classification 0303 health sciences Binding Sites biology Ligand Plexin Molecular biology 3. Good health respiratory tract diseases medicine.anatomical_structure chemistry Chronic Disease biology.protein Beryllium Peptides 030215 immunology Beryllium Disease |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 |
| Popis: | Identification of peptides that form complexes with beryllium and class II HLA molecules and are recognized by CD4+ T cells from patients with chronic beryllium disease. 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. |
| Databáze: | OpenAIRE |
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