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Diabetes with the Development of Autoimmune VTCN1 (B7-H4

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Diabetes with the Development of Autoimmune VTCN1 (B7-H4 Loss of Peripheral Protection in Pancreatic Islets by Proteolysis-Driven Impairment of VTCN1 (B7-H4) Presentation Is Associated with the Development of Autoimmune This information is current as Diabetes of October 1, 2021. Ilian A. Radichev, Lilia V. Maneva-Radicheva, Christina Amatya, Maryam Salehi, Camille Parker, Jacob Ellefson, Paul Burn and Alexei Y. Savinov J Immunol published online 15 January 2016 Downloaded from http://www.jimmunol.org/content/early/2016/01/15/jimmun ol.1403251 Supplementary http://www.jimmunol.org/content/suppl/2016/01/15/jimmunol.140325 http://www.jimmunol.org/ Material 1.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published January 15, 2016, doi:10.4049/jimmunol.1403251 The Journal of Immunology Loss of Peripheral Protection in Pancreatic Islets by Proteolysis-Driven Impairment of VTCN1 (B7-H4) Presentation Is Associated with the Development of Autoimmune Diabetes Ilian A. Radichev,* Lilia V. Maneva-Radicheva,* Christina Amatya,* Maryam Salehi,* Camille Parker,* Jacob Ellefson,* Paul Burn,* and Alexei Y. Savinov*,† 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 do- main–containing T cell activation inhibitor 1 (VTCN1) protein on APCs, is shared between diabetes-susceptible NOD mice Downloaded from and human T1D patients. In this study, we show that a similar process takes place in the target organ, as both a and b 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 http://www.jimmunol.org/ 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. The Journal of Immunology, 2016, 196: 000–000. ype 1 diabetes (T1D) is a life-threatening disease of an possess several protective mechanisms capable of downregulation autoimmune nature, for which the only currently available of autoimmune attack (3, 4). One of such mechanisms is at the treatment is continuous insulin administration. Clinical center of our investigation. T by guest on October 1, 2021 T1D arises as a consequence of the cytotoxic destruction of insulin- V-set domain–containing T cell activation inhibitor 1 (VTCN1), producing b cells by abnormally activated autoreactive T cells also known as B7-H4, B7S1, B7X, is a negative costimulatory specific for multiple islet cells’ Ags (1, 2). Accumulating evi- molecule, representing one of the newly discovered members of dence, however, suggests that islet cells do not merely play a role the B7 family (5–7). VTCN1 acts through a not yet identified of plain targets of autoimmune destruction, but, on the contrary, receptor on T cells, inhibiting T cell activation, proliferation, and cytokine production (5, 6, 8, 9). The persistence of autoreactive T cell responses during T1D prompted several experimental at- *The Sanford Project, Children’s Health Research Center, Sanford Research, Sioux Falls, SD 57104; and †Department of Pediatrics, University of South Dakota School tempts to alleviate diabetogenic autoimmunity via artificial en- of Medicine, Sioux Falls, SD 57105 richment of VTCN1-mediated coinhibition. Accordingly, matrix ORCIDs: 0000-0001-9585-8453 (I.A.R.); 0000-0003-4030-2399 (C.A.); 0000-0002- surface–bound VTCN1-Ig fusion protein suppressed the prolifer- 8493-8543 (C.P.); 0000-0002-7861-3355 (A.Y.S.). ation of islet-specific T cell clones derived from T1D patients. Received for publication January 5, 2015. Accepted for publication December 5, Furthermore, the treatment of diabetes-susceptible NOD mice 2015. with VTCN1-Ig protein significantly attenuated T1D (10). This work was supported by Sanford Research start-up funds, Juvenile Diabetes Unlike classical costimulatory molecules (B7-1 and B7-2), Research Foundation Grant 47-2013-522, and National Institutes of Health Subcontract UC4 DK104194 (all to A.Y.S.). Support was also received by Sanford Research’s Im- whose natural expression and action are strictly limited to APCs aging and Flow Cytometry core facilities funded by National Institutes of Health Centers (11, 12), VTCN1 is also expressed in several nonlymphoid organs of Biomedical Research Excellence Grants P20 GM103548 and P20 GM103620. and, most importantly, in pancreatic islets (6, 7, 9, 13–15). Con- Address correspondence and reprint requests to Dr. Alexei Y. Savinov, The Sanford sequently, VTCN1 has been hypothesized to not only inhibit Project, Children’s Health Research Center, Sanford Research, 2310 East 60th Street North, Sioux Falls, SD 57104. E-mail address: [email protected] classical T cell activation by APCs in the lymphoid compartment, The online version of this article contains supplemental material. but also to induce T cell tolerance within peripheral target tissues. Supporting this suggestion, upregulated VTCN1 expression was Abbreviations used in this article: 7-AAD, 7-aminoactinomycin D; BM, bone mar- row; EdU, 5-ethynyl-29-deoxyuridine; Mf, macrophage; NRD1, N-arginine dibasic detected in multiple neoplasms (7, 13, 16–18), where it was as- convertase 1; PCSK1/2, proprotein convertase subtilisin/kexin type 1/2; PD-1, pro- sociated with tumor-protective downregulation of antitumor T cell grammed cell death-1 protein; PD-L1, programmed cell death–ligand 1; PLN, pan- creatic lymph node; RA, rheumatoid arthritis; RT-qPCR, real-time quantitative PCR; responses (19). sVTCN1, soluble V set domain–containing T cell activation inhibitor 1; T1D, type 1 In the T1D setting, transfection of the VTCN1-Ig construct into diabetes; Treg, T regulatory cell; VTCN1, V-set domain–containing T cell activation human primary islet cells protected them from diabetogenic T inhibitor 1. cell clones isolated from T1D patients (14). Additionally, ex vivo Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 VTCN1 overexpression in mouse islets shielded them from T cell– www.jimmunol.org/cgi/doi/10.4049/jimmunol.1403251 2 T1D IS ASSOCIATED WITH VTCN1 LOSS FROM PANCREATIC ISLETS induced damage in transplantation experiments (20), whereas In vivo bestatin treatments in vivo b cell–specific VTCN1 overexpression protected against + + Female NOD mice at 6 wk of age were injected daily (i.p.) with either diabetes induced by both CD4 and CD8 islet-specific clonal vehicle or 10 mg/kg bestatin (see Fig. 3A). Two groups (n = 7/group) were T cells (9, 21). Therefore, the distinctive combination of T cell treated for 4 wk, the other two (n = 12–14/group) were treated until dia- coinhibitory function with expression on islet cells uniquely po- betes development. To analyze the proliferation of insulitis-forming cells, sitions VTCN1 at the interface of pancreatic islets and the immune all animals in the 4 wk treatment groups received i.p. injections of 2.5 mg/kg 5-ethynyl-29-deoxyuridine (EdU) for the last four consecutive days of system. treatments. Mice were then euthanized and Mfs, pancreatic lymph nodes Despite the growing number of functional studies utilizing ge- (PLNs), spleens, and pancreata were collected for analysis. From 12 wk of netically manipulated VTCN1 (overexpression and/or deletion), age, all mice were monitored daily for urine glucose using Diastix strips. the state of natural VTCN1 on either APCs or islet cells in con- Mice with urine glucose $250 mg/dl on 2 consecutive days were con- firmed diabetic by a blood glucose analysis and euthanized. Mfs were nection with T1D development is largely unknown. This is why we collected from diabetic mice. asked the question of whether a compromised function of en- dogenous VTCN1 can trigger enhanced vulnerability of islet tissue
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