Format

Send to

Choose Destination
Diabetes. 2014 Oct;63(10):3470-82. doi: 10.2337/db14-0213. Epub 2014 May 21.

Nardilysin-dependent proteolysis of cell-associated VTCN1 (B7-H4) marks type 1 diabetes development.

Author information

1
Sanford Project/Children's Health Research Center at Sanford Research, Sioux Falls, SD Department of Pediatrics, University of South Dakota School of Medicine, Sioux Falls, SD.
2
Department of Pathology, College of Medicine, University of Florida, Gainesville, FL.
3
Sanford Project/Children's Health Research Center at Sanford Research, Sioux Falls, SD Department of Pediatrics, University of South Dakota School of Medicine, Sioux Falls, SD alexei.savinov@sanfordhealth.org.

Abstract

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 costimulatory protein, V-set domain-containing T-cell activation inhibitor-1 (VTCN1), 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 hyperproliferation of diabetogenic T cells. Mechanistically, we demonstrate that the loss of membrane-tethered VTCN1 is linked to proteolytic cleavage mediated by the metalloproteinase nardilysin. The cleaved sVTCN1 fragment was detected at high levels in the peripheral blood of 53% T1D patients compared with 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 nardilysin as a potential therapeutic target.

PMID:
24848066
PMCID:
PMC4171653
DOI:
10.2337/db14-0213
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center