title: T-cell receptor-HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis.
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.
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine, Solna and CMM, Karolinska Institutet and Karolinska University Hospital, Solna, Sweden johan.grunewald@ki.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Grunewald
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine, Solna and CMM, Karolinska Institutet and Karolinska University Hospital, Solna, Sweden.
authors.forename: Ylva
authors.initials: Y
authors.lastname: Kaiser
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine, Solna and CMM, Karolinska Institutet and Karolinska University Hospital, Solna, Sweden.
authors.forename: Mahyar
authors.initials: M
authors.lastname: Ostadkarampour
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine, Solna and CMM, Karolinska Institutet and Karolinska University Hospital, Solna, Sweden.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Rivera
authors.affiliation: Science for Life Laboratory (SciLifeLab), Dept of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vezzi
authors.affiliation: Science for Life Laboratory (SciLifeLab), Dept of Biosciences and Nutrition, Karolinska Institutet, Solna, Sweden.
authors.forename: Britta
authors.initials: B
authors.lastname: Lötstedt
authors.affiliation: Science for Life Laboratory (SciLifeLab), Dept of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Remi-André
authors.initials: RA
authors.lastname: Olsen
authors.affiliation: Science for Life Laboratory (SciLifeLab), Dept of Biosciences and Nutrition, Karolinska Institutet, Solna, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Sylwan
authors.affiliation: Science for Life Laboratory (SciLifeLab), Royal Institute of Technology (KTH), Gene Technology, Solna, Sweden.
authors.forename: Sverker
authors.initials: S
authors.lastname: Lundin
authors.affiliation: Science for Life Laboratory (SciLifeLab), Royal Institute of Technology (KTH), Gene Technology, Solna, Sweden.
authors.forename: Max
authors.initials: M
authors.lastname: Käller
authors.affiliation: Science for Life Laboratory (SciLifeLab), Dept of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Sandalova
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine, Solna and CMM, Karolinska Institutet and Karolinska University Hospital, Solna, Sweden.
authors.forename: Kerstin M
authors.initials: KM
authors.lastname: Ahlgren
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine, Solna and CMM, Karolinska Institutet and Karolinska University Hospital, Solna, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Wahlström
authors.affiliation: Science for Life Laboratory (SciLifeLab), Dept of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Adnane
authors.initials: A
authors.lastname: Achour
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine, Solna and CMM, Karolinska Institutet and Karolinska University Hospital, Solna, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ronninger
authors.affiliation: Respiratory Medicine Unit, Dept of Medicine, Solna and CMM, Karolinska Institutet and Karolinska University Hospital, Solna, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Eklund
mesh_terms: D000328:Adult; D001992:Bronchoalveolar Lavage Fluid; D001999:Bronchoscopy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D059811:HLA-DRB1 Chains / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D017565:Sarcoidosis, Pulmonary / Q000276:immunology*; D013548:Sweden
chemical_list: D059811:HLA-DRB1 Chains; D011948:Receptors, Antigen, T-Cell