Regulation of Cathepsin G Reduces the Activation of Proinsulin-Reactive T Cells from Type 1 Diabetes Patients
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Date
2011-08-05
Authors
Zou, Fang
Schafer, Nadja
Palesch, David
Brucken, Ruth
Beck, Alexander
Sienczyk, Marcin
Kalbacher, Hubert
Sun, ZiLin
Boehm, Bernhard O.
Burster, Timo
Journal Title
Journal ISSN
Volume Title
Publisher
PLoS ONE
Abstract
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.
Description
Keywords
Diabetes Patients, Diabetes
Citation
Zou 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.0022815