Identification of multiple public TCR repertoires in chronic beryllium disease.
Chronic beryllium disease (CBD) is a granulomatous lung disease characterized by the accumulation of beryllium (Be)-specific CD4(+) T cells in bronchoalveolar lavage. These expanded CD4(+) T cells are composed of oligoclonal T cell subsets, suggesting their recruitment to the lung in response to conventional Ag. In the current study, we noted that all bronchoalveolar lavage-derived T cell lines from HLA-DP2-expressing CBD patients contained an expansion of Be-responsive Vβ5.1(+) CD4(+) T cells. Using Be-loaded HLA-DP2-peptide tetramers, the majority of tetramer-binding T cells also expressed Vβ5.1 with a highly conserved CDR3β motif. Interestingly, Be-specific, Vβ5.1-expressing CD4(+) T cells displayed differential HLA-DP2-peptide tetramer staining intensity, and sequence analysis of the distinct tetramer-binding subsets showed that the two populations differed by a single conserved amino acid in the CDR3β motif. TCR Vα-chain analysis of purified Vβ5.1(+) CD4(+) T cells based on differential tetramer-binding intensity showed differing TCR Vα-chain pairing requirements, with the high-affinity population having promiscuous Vα-chain pairing and the low-affinity subset requiring restricted Vα-chain usage. Importantly, disease severity, as measured by loss of lung function, was inversely correlated with the frequency of tetramer-binding CD4(+) T cells in the lung. Our findings suggest the presence of a dominant Be-specific, Vβ5.1-expressing public T cell repertoire in the lungs of HLA-DP2-expressing CBD patients using promiscuous Vα-chain pairing to recognize an identical HLA-DP2-peptide/Be complex. Importantly, the inverse relationship between expansion of CD4(+) T cells expressing these public TCRs and disease severity suggests a pathogenic role for these T cells in CBD.
Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045;
Natalie A
NA
Bowerman
Michael T
MT
Falta
Douglas G
DG
Mack
Fabian
F
Wehrmann
Frances
F
Crawford
Margaret M
MM
Mroz
Lisa A
LA
Maier
John W
JW
Kappler
Andrew P
AP
Fontenot
D001483:Base Sequence; D001607:Berylliosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D059868:HLA-DP beta-Chains / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
D059868:HLA-DP beta-Chains; C083176:HLA-DPw2 antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta