Autoreactive T cells induce necrosis and not BCL-2-regulated or death receptor-mediated apoptosis or RIPK3-dependent necroptosis of transplanted islets in a mouse model of type 1 diabetes
- Author(s)
- Zhao, Y; Scott, NA; Fynch, S; Elkerbout, L; Wong, WW; Mason, KD; Strasser, A; Huang, DC; Kay, TW; Thomas, HE;
- Details
- Publication Year 2014-10-10,Volume 58,Issue #1,Page 140-148
- Journal Title
- Diabetologia
- Publication Type
- Journal Article
- Abstract
- AIMS/HYPOTHESIS: Type 1 diabetes results from T cell-mediated destruction of pancreatic beta cells. The mechanisms of beta cell destruction in vivo, however, remain unclear. We aimed to test the relative roles of the main cell death pathways: apoptosis, necrosis and necroptosis, in beta cell death in the development of CD4+ T cell-mediated autoimmune diabetes. METHODS: We altered expression levels of critical cell death proteins in mouse islets and tested their ability to survive CD4+ T cell-mediated attack using an in vivo graft model. RESULTS: Loss of the B cell leukaemia/lymphoma 2 (BCL-2) homology domain 3-only proteins BIM, PUMA or BID did not protect beta cells from this death. Overexpression of the anti-apoptotic protein BCL-2 or combined deficiency of the pro-apoptotic multi-BCL2 homology domain proteins BAX and BAK also failed to prevent beta cell destruction. Furthermore, loss of function of the death receptor Fas or its essential downstream signalling molecule Fas-associated death domain (FADD) in islets was also not protective. Using electron microscopy we observed that dying beta cells showed features of necrosis. However, islets deficient in receptor-interacting serine/threonine protein kinase 3 (RIPK3), a critical initiator of necroptosis, were still normally susceptible to CD4+ T cell-mediated destruction. Remarkably, simultaneous inhibition of apoptosis and necroptosis by combining loss of RIPK3 and overexpression of BCL-2 in islets did not protect them against immune attack either. CONCLUSIONS/INTERPRETATION: Collectively, our data indicate that beta cells die by necrosis in autoimmune diabetes and that the programmed cell death pathways apoptosis and necroptosis are both dispensable for this process.
- Publisher
- Springer
- Research Division(s)
- Molecular Genetics Of Cancer; Cancer And Haematology
- PubMed ID
- 25301392
- Publisher's Version
- https://doi.org/10.1007/s00125-014-3407-5
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2014-11-20 10:16:04
Last Modified: 2018-03-26 02:31:27