Zou, FangSchafer, NadjaPalesch, DavidBrucken, RuthBeck, AlexanderSienczyk, MarcinKalbacher, HubertSun, ZiLinBoehm, Bernhard O.Burster, TimoHerrath, Matthias G.2018-08-202018-08-202011-08-05Zou F, Scha¨fer N, Palesch D, Bru¨ cken R, Beck A, et al. (2011) Regulation of Cathepsin G Reduces the Activation of Proinsulin-Reactive T Cells from Type 1 Diabetes Patients. PLoS ONE 6(8): e22815. doi:10.1371/journal.pone.0022815http://nur.nu.edu.kz/handle/123456789/3386Autoantigenic 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.enAttribution-NonCommercial-ShareAlike 3.0 United StatesDiabetes PatientsDiabetesArticle