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 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.

• Authors: Natalie A Bowerman, Michael T Falta, Douglas G Mack, Fabian Wehrmann, Frances Crawford, Margaret M Mroz, Lisa A Maier, John W Kappler, Andrew P Fontenot
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 10 Pg. 4571-80 (May 15 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24719461 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-DP beta-Chains
• HLA-DPw2 antigen
• Receptors, Antigen, T-Cell, alpha-beta

Topics

• Base Sequence
• Berylliosis (genetics, immunology, metabolism)
• CD4-Positive T-Lymphocytes (immunology, metabolism, pathology)
• Chronic Disease
• Female
• Gene Expression Regulation (immunology)
• HLA-DP beta-Chains (biosynthesis, genetics, immunology)
• Humans
• Lung (immunology, metabolism, pathology)
• Male
• Molecular Sequence Data
• Receptors, Antigen, T-Cell, alpha-beta (biosynthesis, genetics, immunology)