Type 1 Diabetes (T1D) is a chronic autoimmune disease in which pancreatic beta cells are selectively destroyed by autoreactive CD8+ cytotoxic T lymphocytes (CTLs). The identification of the epitopes presented by “diabetogenic” HLA molecules to these CTLs constitutes a major research target to understand how beta cells are killed. Preproinsulin (PPI) has emerged as a key autoantigen in T1D: a surprising finding made in the host laboratory is that the dominant HLA-A2.1-restricted-PPI epitope, PPI 15-24, localizes to the signal peptide (SP), being an unusual finding for self-, or indeed microbial antigens. The processing of PPI to derive such epitope is also highly unconventional in being proteasome and transporter associated with processing(TAP) independent. Preliminary studies in the host lab have identified more antigenic PPI-SP epitopes restricted to other “diabetogenic” HLA molecules and the existence of a common cleavage motif among them within the intramembrane SP portion. This suggests the involvement of an intramembrane cleaving protease (I-CLiP) in generating these disease-related epitopes.
The hypothesis is that the generation of disease-associated PPI-SP epitopes involves novel I-CLiP-dependent processing and presentation pathway(s). This will be studied via: (i) generation of CD8 T-cell clones specific for each PPI-SP-epitope/HLA; (ii) determination of TAP and proteasome roles in the generation of PPI-SP epitopes(other than PPI 15-24) by specific inhibitor strategies; and (iii) determination of the role of ER proteases and I-CLiPs in the generation of PPI 15-24 and other TAP/proteasome-independent PPI-SP epitopes-potentially identified in (ii) using RNAi strategies. Thus, this proposal aims to unravel the molecular mechanisms leading to the generation of these important epitopes, potentially offering novel immunobiological insights and opening new fields of therapeutic interventions, while at the same time strengthening the ERA excellence in T1D research
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