SUMMARY T cell-mediated hypersensitivity to metal cations is common in humans. How the T cell antigen receptor (TCR) recognizes these cations bound to a major histocompatibility complex (MHC) protein and self-peptide is unknown. Individuals carrying the MHCII allele, HLA-DP2, are at risk for chronic beryllium disease (CBD), a debilitating inflammatory lung condition caused by the reaction of CD4 T cells to inhaled beryllium. We show here that the T cell ligand is created when a Be2+ cation becomes buried in an HLA-DP2/peptide complex, where it is coordinated by both MHC and peptide acidic amino acids. Surprisingly, the TCR does not interact with the Be2+ itself, but rather with surface changes induced by the firmly bound Be2+ and an accompanying Na+ cation. Thus, CBD, by creating a new antigen by indirectly modifying the structure of pre-existing self MHC-peptide complex, lies on the border between allergic hypersensitivity and autoimmunity.

SignificanceInsulin is a target of CD4 T cells in type 1 diabetes in mice and humans. Why the major epitope in the insulin B chain is presented poorly to the diabetogenic CD4 T cells by the disease-associated major histocompatibility class II (MHCII) alleles has been highly debated. Here we present high-resolution mouse and human MHCII structures and T-cell functional data to show that C-terminal modifications of this epitope are required for binding and presentation in the appropriate position in the MHCII binding groove. These results suggest that pancreas-specific posttranslational modifications of this peptide may play a role in the induction of diabetes and explain how the pathogenic T cells escape deletion in the thymus.

In type 1 diabetes (T1D), proinsulin is a major autoantigen and the insulin B:9–23 peptide contains epitopes for CD4 T cells in both mice and humans. This peptide requires C-terminal mutations for uniform binding in the proper position within the mouse IAg7 or human DQ8 MHCII peptide grooves and for strong CD4 T cell stimulation. Here we present structures showing how these mutations control CD4 T cell receptor (TCR) binding to these MHCII-peptide complexes. Our data reveal striking similarities between mouse and human CD4 TCRs in their interactions with these ligands. We also show how fusions between fragments of B:9–23 and of proinsulin C-peptide create chimeric peptides with activities as strong or stronger than the mutated insulin peptides. We propose transpeptidation in the lysosome as a mechanism that could accomplish these fusions in vivo, similar to the creation fused peptide epitopes for MHCI presentation shown to occur by transpeptidation in the proteasome. Were this mechanism unique to the pancreas and absent in the thymus, it could provide an explanation for how diabetogenic T cells escape negative selection during development but find their modified target antigens in the pancreas to cause T1D.

The structural study revealed that TGR functions are achieved not only through a mobile Sec-containing redox center but also by rotation of the Grx domain and distinct binding sites for Grx domain and thioredoxin. The conserved Cys and Cys residues targeted by gold assist catalysis through stabilization of the Sec-containing redox center. Antioxid. Redox Signal. 27, 1491-1504.