Nardilysin-dependent proteolysis of cell-associated VTCN1 (B7-H4) marks type 1 diabetes development.
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.
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.
Ilian A
IA
Radichev
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.
Lilia V
LV
Maneva-Radicheva
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.
Christina
C
Amatya
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.
Camille
C
Parker
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.
Jacob
J
Ellefson
Department of Pathology, College of Medicine, University of Florida, Gainesville, FL.
Clive
C
Wasserfall
Department of Pathology, College of Medicine, University of Florida, Gainesville, FL.
Mark
M
Atkinson
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.
Paul
P
Burn
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.
Alexei Y
AY
Savinov
D000293:Adolescent; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000378:metabolism*; D055815:Young Adult
D015415:Biomarkers; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; D008666:Metalloendopeptidases; C087976:nardilysin