Regulation of cathepsin G reduces the activation of proinsulin-reactive T cells from type 1 diabetes patients

Fang Zou, Nadja Schäfer, David Palesch, Ruth Brücken, Alexander Beck, Marcin Sienczyk, Hubert Kalbacher, ZiLin Sun, Bernhard O Boehm, Timo Burster

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)e22815
JournalPLoS One
Volume6
Issue number8
DOIs
Publication statusPublished - 2011

Fingerprint

cathepsin G
proinsulin
Cathepsin G
Proinsulin
T-cells
insulin-dependent diabetes mellitus
Medical problems
Type 1 Diabetes Mellitus
T-lymphocytes
Chemical activation
T-Lymphocytes
cathepsins
Cathepsins
mononuclear leukocytes
Blood Cells
Reactive Inhibition
Blood
Processing
CD4 Antigens
T-Lymphocyte Epitopes

Keywords

  • Blotting, Western
  • Carrier Proteins
  • Cathepsin G
  • Cells, Cultured
  • Diabetes Mellitus, Type 1
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Leucine
  • Pepstatins
  • Polymerase Chain Reaction
  • Proinsulin
  • T-Lymphocytes
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Regulation of cathepsin G reduces the activation of proinsulin-reactive T cells from type 1 diabetes patients. / Zou, Fang; Schäfer, Nadja; Palesch, David; Brücken, Ruth; Beck, Alexander; Sienczyk, Marcin; Kalbacher, Hubert; Sun, ZiLin; Boehm, Bernhard O; Burster, Timo.

In: PLoS One, Vol. 6, No. 8, 2011, p. e22815.

Research output: Contribution to journalArticle

Zou, F, Schäfer, N, Palesch, D, Brücken, R, Beck, A, Sienczyk, M, Kalbacher, H, Sun, Z, Boehm, BO & Burster, T 2011, 'Regulation of cathepsin G reduces the activation of proinsulin-reactive T cells from type 1 diabetes patients', PLoS One, vol. 6, no. 8, pp. e22815. https://doi.org/10.1371/journal.pone.0022815
Zou, Fang ; Schäfer, Nadja ; Palesch, David ; Brücken, Ruth ; Beck, Alexander ; Sienczyk, Marcin ; Kalbacher, Hubert ; Sun, ZiLin ; Boehm, Bernhard O ; Burster, Timo. / Regulation of cathepsin G reduces the activation of proinsulin-reactive T cells from type 1 diabetes patients. In: PLoS One. 2011 ; Vol. 6, No. 8. pp. e22815.
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