T-cell receptor-HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis.

Grunewald J, Kaiser Y, Ostadkarampour M, Rivera NV, Vezzi F, Lötstedt B, Olsen RA, Sylwan L, Lundin S, Käller M, Sandalova T, Ahlgren KM, Wahlström J, Achour A, Ronninger M, Eklund A

Eur. Respir. J. 47 (3) 898-909 [2016-03-00; online 2015-11-19]

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 three-dimensional 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 HLA-DRB1*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.

Bioinformatics Support for Computational Resources [Service]

NGI Stockholm (Genomics Applications) [Collaborative]

NGI Stockholm (Genomics Production) [Collaborative]

National Genomics Infrastructure [Collaborative]

PubMed 26585430

DOI 10.1183/13993003.01209-2015

Crossref 10.1183/13993003.01209-2015

pii: 13993003.01209-2015

Publications 9.5.0