Identification of multiple public TCR repertoires in chronic beryllium disease.

ABSTRACT: 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 V?5.1(+) CD4(+) T cells. Using Be-loaded HLA-DP2-peptide tetramers, the majority of tetramer-binding T cells also expressed V?5.1 with a highly conserved CDR3? motif. Interestingly, Be-specific, V?5.1-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 CDR3? motif. TCR V?-chain analysis of purified V?5.1(+) CD4(+) T cells based on differential tetramer-binding intensity showed differing TCR V?-chain pairing requirements, with the high-affinity population having promiscuous V?-chain pairing and the low-affinity subset requiring restricted V?-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, V?5.1-expressing public T cell repertoire in the lungs of HLA-DP2-expressing CBD patients using promiscuous V?-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.

SUBMITTER: Bowerman NA 

PROVIDER: S-EPMC4011988 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature