Аннотация:
Autoantigenic peptides resulting from self-proteins such as proinsulin are important players in the development of type 1
diabetes mellitus (T1D). Self-proteins can be processed by cathepsins (Cats) within endocytic compartments and loaded to
major histocompatibility complex (MHC) class II molecules for CD4+ T cell inspection. However, the processing and presentation
of proinsulin by antigen-presenting cells (APC) in humans is only partially understood. Here we demonstrate that the processing
of proinsulin by B cell or myeloid dendritic cell (mDC1)-derived lysosomal cathepsins resulted in several proinsulin-derived
intermediates. These intermediates were similar to those obtained using purified CatG and, to a lesser extent, CatD, S, and V in
vitro. Some of these intermediates polarized T cell activation in peripheral blood mononuclear cells (PBMC) from T1D patients
indicative for naturally processed T cell epitopes. Furthermore, CatG activity was found to be elevated in PBMC from T1D
patients and abrogation of CatG activity resulted in functional inhibition of proinsulin-reactive T cells. Our data suggested the
notion that CatG plays a critical role in proinsulin processing and is important in the activation process of diabetogenic T cells.