Mounting evidence suggests that β-cell-specific cytotoxic CD8+ T-cells are responsible for pancreatic β-cell destruction during Type 1 diabetes1. Discovery of disease relevant β-cell peptide epitopes and the T-cells that recognize them will be vital for understanding disease etiology. We have characterized a highly distinctive HLA A*0201-associated peptide epitope derived from the preproinsulin (PPI) signal peptide (residues 15-24) that exhibits glucose-dependent presentation on the surface of human β-cells and patient-derived T-cells that respond to this peptide2. X-ray crystallographic studies3 reveal a mechanism for how the T-cell receptor (TCR) from these cells enables them to recognize well over 1 million different peptides. Peptides that differ from the PPI15-24 ‘index’ sequence at 7 of 10 positions have been identified that are >100X more potent at activating these T-cells than the PPI-derived sequence4. This extensive TCR promiscuity provides wide scope for T-cell cross-reactivity via molecular mimicry being the root cause of disease. With this in mind, we have developed novel peptide-HLA multimer technologies for visualizing and phenotyping T-cells specific for several β-cell-specific peptides presented via T1D disease-risk HLA class I alleles and tested these reagents in patient and control cohorts. This work offers further insight into the autoimmune processes taking place in T1D and may also provide potential for disease diagnosis before the onset of symptoms.
1. Coppieters KT, von Herrath MG. Motifs for a deadly encounter. Nature Immunology 13, 197-198, 2012
2. Skowera A,et al. Glucose-regulated cytotoxic T-cell epitope of preproinsulin targets killing of beta-cells in human Type 1 diabetes. J Clin Invest. 118(10): 3390–340, 2008
3. Skowera A, Bulek AM, Cole DK,et al. Structural basis of human b-cell killing by preproinsulin-specific CD8+ T-cells in type 1 diabetes. Nature Immunology 13, 283-289, 2012
4. Ekeruche-Makinde J, et al. Peptide length determines the outcome of T cell receptor/peptide-MHCI engagement. Blood, Dec 18 2012