title: Regulation of cathepsin G reduces the activation of proinsulin-reactive T cells from type 1 diabetes patients.
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.
authors.affiliation: Division of Endocrinology and Diabetes, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany.
authors.forename: Fang
authors.initials: F
authors.lastname: Zou
authors.forename: Nadja
authors.initials: N
authors.lastname: Schäfer
authors.forename: David
authors.initials: D
authors.lastname: Palesch
authors.forename: Ruth
authors.initials: R
authors.lastname: Brücken
authors.forename: Alexander
authors.initials: A
authors.lastname: Beck
authors.forename: Marcin
authors.initials: M
authors.lastname: Sienczyk
authors.forename: Hubert
authors.initials: H
authors.lastname: Kalbacher
authors.forename: ZiLin
authors.initials: Z
authors.lastname: Sun
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.forename: Timo
authors.initials: T
authors.lastname: Burster
mesh_terms: D015153:Blotting, Western; D002352:Carrier Proteins / Q000494:pharmacology; D056649:Cathepsin G / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057846:Cell-Penetrating Peptides; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D010436:Pepstatins / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011384:Proinsulin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D010436:Pepstatins; D011384:Proinsulin; C414409:penetratin; D056649:Cathepsin G; D007930:Leucine; C108192:aloxistatin; C031375:pepstatin