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

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14 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

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

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  • Cite this

    Zou, F., Schäfer, N., Palesch, D., Brücken, R., Beck, A., Sienczyk, M., Kalbacher, H., Sun, Z., Boehm, B. O., & Burster, T. (2011). Regulation of cathepsin G reduces the activation of proinsulin-reactive T cells from type 1 diabetes patients. PLoS One, 6(8), e22815. https://doi.org/10.1371/journal.pone.0022815