Nardilysin-dependent proteolysis of cell-associated VTCN1 (B7-H4) marks type 1 diabetes development.
- Ilian A. Radichev1,
- Lilia V. Maneva-Radicheva1,
- Christina Amatya1,
- Camille Parker1,
- Jacob Ellefson1,
- Clive Wasserfall2,
- Mark Atkinson2,
- Paul Burn1 and
- Alexei Y. Savinov1⇑
- 1Sanford Project/Children’s Health Research Center at Sanford Research; Department of Pediatrics, University of South Dakota School of Medicine, Sioux Falls, South Dakota, USA
- 2Department of Pathology, University of Florida, College of Medicine, Gainesville, Florida, USA
- Corresponding author: Alexei Savinov, E-mail:
T cell responses directed against insulin-secreting pancreatic β cells are the key events highlighting type 1 diabetes (T1D). Therefore, a defective control of T cell activation is thought to underlie T1D development. Recent studies implicated a B7-like negative co-stimulatory protein, VTCN1 (V-set domain-containing T cell activation inhibitor-1), as a molecule capable of inhibiting T cell activation and, potentially, an important constituent in experimental models of T1D. Here, we unravel a general deficiency within the VTCN1 pathway that is shared between diabetes-prone mice and a subset of T1D patients. Gradual loss of membrane-tethered VTCN1 from antigen-presenting cells combined with an increased release of soluble VTCN1 (sVTCN1) occurs in parallel to natural T1D development, potentiating hyper-proliferation of diabetogenic T cells. Mechanistically, we demonstrate that the loss of membrane-tethered VTCN1 is linked to proteolytic cleavage mediated by the metalloproteinase nardilysin (NRD1). The cleaved sVTCN1 fragment was detected at high levels in the peripheral blood of 53% T1D patients compared to only 9% of the healthy subjects. Elevated blood sVTCN1 levels appeared early in the disease progression and correlated with the aggressive pace of disease, highlighting the potential use of sVTCN1 as a new T1D biomarker, and identifying NRD1 as a potential therapeutic target.
- Received February 6, 2014.
- Accepted May 13, 2014.
- © 2014 by the American Diabetes Association.
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