title: Loss of Peripheral Protection in Pancreatic Islets by Proteolysis-Driven Impairment of VTCN1 (B7-H4) Presentation Is Associated with the Development of Autoimmune Diabetes.
abstract: Ag-specific activation of T cells is an essential process in the control of effector immune responses. Defects in T cell activation, particularly in the costimulation step, have been associated with many autoimmune conditions, including type 1 diabetes (T1D). Recently, we demonstrated that the phenotype of impaired negative costimulation, due to reduced levels of V-set domain-containing T cell activation inhibitor 1 (VTCN1) protein on APCs, is shared between diabetes-susceptible NOD mice and human T1D patients. In this study, we show that a similar process takes place in the target organ, as both α and β cells within pancreatic islets gradually lose their VTCN1 protein during autoimmune diabetes development despite upregulation of the VTCN1 gene. Diminishment of functional islet cells' VTCN1 is caused by the active proteolysis by metalloproteinase N-arginine dibasic convertase 1 (NRD1) and leads to the significant induction of proliferation and cytokine production by diabetogenic T cells. Inhibition of NRD1 activity, alternatively, stabilizes VTCN1 and dulls the anti-islet T cell responses. Therefore, we suggest a general endogenous mechanism of defective VTCN1 negative costimulation, which affects both lymphoid and peripheral target tissues during T1D progression and results in aggressive anti-islet T cell responses. This mechanism is tied to upregulation of NRD1 expression and likely acts in two synergistic proteolytic modes: cell-intrinsic intracellular and cell-extrinsic systemic. Our results highlight an importance of VTCN1 stabilization on cell surfaces for the restoration of altered balance of immune control during T1D.
authors.affiliation: The Sanford Project, Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104; and.
authors.forename: Ilian A
authors.identifier: http://orcid.org/0000-0001-9585-8453
authors.initials: IA
authors.lastname: Radichev
authors.affiliation: The Sanford Project, Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104; and.
authors.forename: Lilia V
authors.initials: LV
authors.lastname: Maneva-Radicheva
authors.affiliation: The Sanford Project, Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104; and.
authors.forename: Christina
authors.identifier: http://orcid.org/0000-0003-4030-2399
authors.initials: C
authors.lastname: Amatya
authors.affiliation: The Sanford Project, Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104; and.
authors.forename: Maryam
authors.initials: M
authors.lastname: Salehi
authors.affiliation: The Sanford Project, Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104; and.
authors.forename: Camille
authors.identifier: http://orcid.org/0000-0002-8493-8543
authors.initials: C
authors.lastname: Parker
authors.affiliation: The Sanford Project, Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104; and.
authors.forename: Jacob
authors.initials: J
authors.lastname: Ellefson
authors.affiliation: The Sanford Project, Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104; and.
authors.forename: Paul
authors.initials: P
authors.lastname: Burn
authors.affiliation: The Sanford Project, Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104; and Department of Pediatrics, University of South Dakota School of Medicine, Sioux Falls, SD 57105 Alexei.Savinov@sanfordhealth.org.
authors.forename: Alexei Y
authors.identifier: http://orcid.org/0000-0002-7861-3355
authors.initials: AY
authors.lastname: Savinov
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000503:physiopathology; D050416:Glucagon-Secreting Cells / Q000276:immunology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016688:Mice, Inbred NOD; D059748:Proteolysis; D013601:T-Lymphocytes / Q000276:immunology; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; C475824:Vtcn1 protein, mouse; D008666:Metalloendopeptidases; C087976:nardilysin