Format

Send to

Choose Destination
Eur Respir J. 2016 Mar;47(3):898-909. doi: 10.1183/13993003.01209-2015. Epub 2015 Nov 19.

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

Author information

1
Respiratory Medicine Unit, Dept of Medicine, Solna and CMM, Karolinska Institutet and Karolinska University Hospital, Solna, Sweden johan.grunewald@ki.se.
2
Respiratory Medicine Unit, Dept of Medicine, Solna and CMM, Karolinska Institutet and Karolinska University Hospital, Solna, Sweden.
3
Science for Life Laboratory (SciLifeLab), Dept of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
4
Science for Life Laboratory (SciLifeLab), Dept of Biosciences and Nutrition, Karolinska Institutet, Solna, Sweden.
5
Science for Life Laboratory (SciLifeLab), Royal Institute of Technology (KTH), Gene Technology, Solna, Sweden.
6
Science for Life Laboratory (SciLifeLab), Dept of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.

Abstract

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.

PMID:
26585430
DOI:
10.1183/13993003.01209-2015
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center