Identification of Multiple Public T Cell Receptor Repertoires in Chronic Beryllium Disease1

• Published in: The Journal of immunology (1950) Vol. 192; no. 10; pp. 4571 - 4580
• Main Authors: Bowerman, Natalie A., Falta, Michael T., Mack, Douglas G., Wehrmann, Fabian, Crawford, Frances, Mroz, Margaret M., Maier, Lisa A., Kappler, John W., Fontenot, Andrew P.
• Format: Journal Article
• Language: English
• Published: 09.04.2014
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1400007

Chronic beryllium disease (CBD) is a granulomatous lung disease characterized by the accumulation of beryllium (Be)-specific CD4 + T cells in bronchoalveolar lavage (BAL). These expanded CD4 + T cells are composed of oligoclonal T cell subsets, suggesting their recruitment to the lung in response to conventional antigen. In the present study, we noted that all BAL-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 Vβ5.1with 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.