Type 1 Diabetes (T1D) is a chronic autoimmune disease where immune responses destroy insulin-producing pancreatic beta cells. Increasing evidence indicates that the autoreactive CD8 cytotoxic T lymphocytes (CTLs) recognise specific autoantigens such as preproinsulin (PPI). PPI constitutes the primary form of insulin and contains a signal peptide at one end. Interestingly, the epitope recognised by T1D CTLs localises on the PPI signal peptide but the processing of PPI to derive such epitope remains elusive. The primary objective of the EU-funded DIABICLIPS (Unravelling the unconventional processing and presentation of preproinsulin to the immune system in human type 1 diabetes: the role of intramembrane-cleaving proteases) project was to investigate the molecular and cellular basis of processing of autoantigens in T1D. As a first step, researchers screened newly diagnosed T1D patients and matched healthy donors for their reactivity against several relevant autoantigens. Results indicated the presence of autoantigen-specific CD4+ T cells in both healthy individuals and T1D patients. However, these cells were present at higher frequency in T1D patients who also had a different phenotype/gene expression profile. In addition, scientists examined the T cell receptor repertoire in different T cell subsets and found differences in the diversity as well as several T1D-exclusive clonotypes in diabetic patients. The deep sequencing method they utilised could be further exploited as a new diagnostic/risk assessment tool for identifying antigen-specific T cells directly from blood bypassing the need for ex vivo cell culture. Collectively, the DIABICLIPS results advanced the current knowledge on the nature of the immune system and provided unprecedented information on diabetes disease mechanisms. Clinical exploitation of these findings could open the door to new, more specific and safer treatments for T1D.
Immune system, diabetes, T lymphocytes, preproinsulin, epitope, T cell receptor