Abstract
The non-obese diabetic mouse model of type 1 diabetes continues to be an important tool for delineating the role of T-cell-mediated destruction of pancreatic β-cells. However, little is known about the molecular mechanisms that enable this disease pathway. We show that insulin reactivity by a CD8(+) T-cell clone, known to induce type 1 diabetes, is characterized by weak T-cell antigen receptor binding to a relatively unstable peptide-MHC. The structure of the native 9- and 10-mer insulin epitopes demonstrated that peptide residues 7 and 8 form a prominent solvent-exposed bulge that could potentially be the main focus of T-cell receptor binding. The C terminus of the peptide governed peptide-MHC stability. Unexpectedly, we further demonstrate a novel mode of flexible peptide presentation in which the MHC peptide-binding groove is able to "open the back door" to accommodate extra C-terminal peptide residues.
Highlights
CD8ϩ T-cells play a central role in type 1 diabetes (T1D) by recognizing insulin peptides displayed by MHC
Substitution of Gly for Val at residue 9 in the G9V peptide, distal from the central bulge of the peptide that is usually involved in TCR contacts, increased activation markedly compared with the G9G peptide (Fig. 1)
The non-obese diabetic (NOD) mouse model of T1D is an important tool for investigating the role of T-cells in the destruction of islet -cells in the pancreas
Summary
CD8ϩ T-cells play a central role in type 1 diabetes (T1D) by recognizing insulin peptides displayed by MHC. It has been shown that epitopes within the insulin B chain have a prime role in the development of T1D, because substitution at position 16 of the B chain abolishes CD4ϩ [31] and CD8ϩ T-cell reactivity [8, 32] This region of the insulin B chain has been identified as an important autoantigen in humans [26, 33, 34], offering an important model system for investigating the human form of the disease. We solved the atomic structures of each of the peptides in complex with H-2Kd, demonstrating the peptide residues that interact with the MHC binding groove and identifying the solvent-exposed residues that are most likely to contact the TCR These data provide the first molecular insight into CD8ϩ T-cell-induced -cell destruction via recognition of the insulin B chain in this important disease model of T1D and demonstrate a novel flexible peptide-MHC binding mode that has broad implications for T-cell antigen presentation
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