T-cell receptor-HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis
2016 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 47, no 3, 898-909 p.Article in journal (Refereed) PublishedText
In pulmonary sarcoidosis, CD4+; T-cells expressing T-cell receptor Vα2.3 accumulate in the lungs of HLA-DRB1∗03+; patients. To investigate T-cell receptor-HLA-DRB1∗03 interactions underlying recognition of hitherto unknown antigens, we performed detailed analyses of T-cell receptor expression on bronchoalveolar lavage fluid CD4+; T-cells from sarcoidosis patients. Pulmonary sarcoidosis patients (n=43) underwent bronchoscopy with bronchoalveolar lavage. T-cell receptor α and β chains of CD4+; T-cells were analysed by flow cytometry, DNA-sequenced, and threedimensional molecular models of T-cell receptor-HLA-DRB1∗03 complexes generated. Simultaneous expression of Vα2.3 with the Vβ22 chain was identified in the lungs of all HLADRB1∗ 03+; patients. Accumulated Vα2.3/Vβ22-expressing T-cells were highly clonal, with identical or near-identical Vα2.3 chain sequences and inter-patient similarities in Vβ22 chain amino acid distribution. Molecular modelling revealed specific T-cell receptor-HLA-DRB1∗03-peptide interactions, with a previously identified, sarcoidosis-associated vimentin peptide, (Vim)429-443 DSLPLVDTHSKRTLL, matching both the HLA peptide-binding cleft and distinct T-cell receptor features perfectly. We demonstrate, for the first time, the accumulation of large clonal populations of specific Vα2.3/Vβ22 T-cell receptor-expressing CD4+; T-cells in the lungs of HLA-DRB1∗03+; sarcoidosis patients. Several distinct contact points between Vα2.3/Vβ22 receptors and HLA-DRB1∗03 molecules suggest presentation of prototypic vimentin-derived peptides.
Place, publisher, year, edition, pages
European Respiratory Society , 2016. Vol. 47, no 3, 898-909 p.
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:kth:diva-187288DOI: 10.1183/13993003.01209-2015ScopusID: 2-s2.0-84959901141OAI: oai:DiVA.org:kth-187288DiVA: diva2:929552
FunderScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
QC 201605192016-05-192016-05-192016-05-19Bibliographically approved