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.