Loss of Peripheral Protection in Pancreatic Islets by Proteolysis-Driven Impairment of VTCN1 (B7-H4) Presentation Is Associated with the Development of Autoimmune Diabetes

The Journal of Immunology : Official Journal of the American Association of Immunologists
Ilian A RadichevAlexei Y Savinov

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 ...Continue Reading

References

May 3, 1996·Cell·R Tisch, H McDevitt
Mar 11, 1998·Current Opinion in Immunology·P LuP S Linsley
Nov 21, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·A Y SavinovA V Chervonsky
Dec 5, 2002·Essays in Biochemistry·Nabil G Seidah, Annik Prat
Jun 24, 2003·Immunity·Gabriel L SicaLieping Chen
Jun 24, 2003·Immunity·Durbaka V R PrasadChen Dong
Jul 9, 2003·The Journal of Experimental Medicine·Mohammed Javeed I AnsariMohamed H Sayegh
Aug 16, 2003·Proceedings of the National Academy of Sciences of the United States of America·Xingxing ZangJames P Allison
Oct 22, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·In-Hak ChoiLieping Chen
Jun 23, 2005·Frontiers in Bioscience : a Journal and Virtual Library·Masao Ichikawa, Lieping Chen
Aug 10, 2005·Proceedings of the National Academy of Sciences of the United States of America·Jian WangTasuku Honjo
Apr 12, 2006·The Journal of Experimental Medicine·Ilona KryczekWeiping Zou
Apr 12, 2006·The Journal of Experimental Medicine·Mary E KeirArlene H Sharpe
Jun 20, 2006·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Yuping SunXiongbiao Wang
Jun 21, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ilona KryczekWeiping Zou
Jun 27, 2006·Proceedings of the National Academy of Sciences of the United States of America·Amy E KrambeckEugene D Kwon
Nov 29, 2007·Proceedings of the National Academy of Sciences of the United States of America·Xingxing ZangJames P Allison
Nov 8, 2008·Journal of Visualized Experiments : JoVE·Gregory L SzotJeffrey A Bluestone
Jan 6, 2009·Annals of the New York Academy of Sciences·Emanuela MartinuzziRoberto Mallone
Apr 9, 2009·Nature Reviews. Endocrinology·Décio L EizirikFernanda Ortis
Apr 14, 2009·Transplant Immunology·Chun-Lei YuanFei-Li Gong
Dec 15, 2010·Nature Immunology·Jan H KesslerCornelis J M Melief
Mar 8, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Dagmar QuandtBarbara Seliger
Jul 6, 2011·The Journal of Experimental Medicine·Joyce WeiJames P Allison
Sep 21, 2011·Cell Transplantation·Xiaojie WangGarth L Warnock
Oct 21, 2011·Clinical & Developmental Immunology·Changjun HeXueying Sun
Jul 10, 2012·Diabetes·Vineeth VaranasiAlexander V Chervonsky
Sep 14, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jun Sik LeeXingxing Zang
May 21, 2013·Journal of Autoimmunity·Joseph R PodojilStephen D Miller
Dec 12, 2013·Pancreas·Susan S C CheungGarth L Warnock
Jun 21, 2014·World Journal of Surgical Oncology·Hongbing ShiJingting Jiang
Sep 27, 2014·PloS One·Lilia Maneva-RadichevaAlexei Y Savinov

❮ Previous
Next ❯

Citations

Mar 5, 2017·Immunological Reviews·Joseph R Podojil, Stephen D Miller
Oct 3, 2019·Cancers·Theodoulakis ChristofiApostolos Zaravinos
Feb 9, 2018·Oncotarget·Ji-Xin ZhongLihua Duan
Mar 23, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Heather L MacGregor, Pamela S Ohashi
Nov 18, 2019·Cellular Immunology·Jia-Yu Wang, Wei-Peng Wang
Nov 5, 2019·Trends in Pharmacological Sciences·Peter JohnXingxing Zang
May 7, 2021·Clinical Medicine Insights. Endocrinology and Diabetes·Marina Yuryevna YukinaDiana Arshaluysovna Dimitrova

❮ Previous
Next ❯

Related Concepts

Related Feeds

Autoimmune Diabetes & Tolerance

Patients with type I diabetes lack insulin-producing beta cells due to the loss of immunological tolerance and autoimmune disease. Discover the latest research on targeting tolerance to prevent diabetes.

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.