T cell recognition of beryllium

•CBD is a classic example of a disorder resulting from a gene–environment interaction.•HLA-DP2 is linked for the generation of beryllium-induced hypersensitivity.•HLA-DP2 possesses unique structural features, including a beryllium-binding site.•Beryllium's binding to MHCII-peptide generates an abnormal landscape for TCR interaction.

Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by a hypersensitivity to beryllium and characterized by the accumulation of beryllium-specific CD4+ T cells in the lung. Genetic susceptibility to beryllium-induced disease is strongly associated with HLA-DP alleles possessing a glutamic acid at the 69th position of the β-chain (βGlu69). The structure of HLA-DP2, the most prevalent βGlu69-containing molecule, revealed a unique solvent-exposed acidic pocket that includes βGlu69 and represents the putative beryllium-binding site. The delineation of mimotopes and endogenous self-peptides that complete the αβTCR ligand for beryllium-specific CD4+ T cells suggests a unique role of these peptides in metal ion coordination and the generation of altered self-peptides, blurring the distinction between hypersensitivity and autoimmunity.