T-cell receptor-HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis
Number of Authors: 16
2016 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 47, no 3, 898-909 p.Article in journal (Refereed) Published
In pulmonary sarcoidosis, CD4(+) T-cells expressing T-cell receptor V alpha 2.3 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 alpha and beta chains of CD4(+) T-cells were analysed by flow cytometry, DNA-sequenced, and three-dimensional molecular models of T-cell receptor-HLA-DRB1*03 complexes generated. Simultaneous expression of V alpha 2.3 with the V beta 22 chain was identified in the lungs of all HLA-DRB1*03(+) patients. Accumulated V alpha 2.3/V beta 22-expressing T-cells were highly clonal, with identical or near-identical V alpha 2.3 chain sequences and inter-patient similarities in V beta 22 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 V alpha 2.3/V beta 22 T-cell receptor-expressing CD4(+) T-cells in the lungs of HLA-DRB1*03(+) sarcoidosis patients. Several distinct contact points between V alpha 2.3/V beta 22 receptors and HLA-DRB1*03 molecules suggest presentation of prototypic vimentin-derived peptides.
Place, publisher, year, edition, pages
2016. Vol. 47, no 3, 898-909 p.
Biological Sciences Immunology in the medical area
IdentifiersURN: urn:nbn:se:su:diva-136225DOI: 10.1183/13993003.01209-2015ISI: 000385950700026PubMedID: 26585430OAI: oai:DiVA.org:su-136225DiVA: diva2:1056666