Effective destruction of Fas-deficient insulin-producing beta cells in type 1 diabetes.
In type 1 diabetes, autoimmune T cells cause destruction of pancreatic beta cells by largely unknown mechanism. Previous analyses have shown that beta cell destruction is delayed but can occur in perforin-deficient nonobese diabetic (NOD) mice and that Fas-deficient NOD mice do not develop diabetes. However, because of possible pleiotropic functions of Fas, it was not clear whether the Fas receptor was an essential mediator of beta cell death in type 1 diabetes. To directly test this hypothesis, we have generated a beta cell-specific knockout of the Fas gene in a transgenic model of type 1 autoimmune diabetes in which CD4+ T cells with a transgenic TCR specific for influenza hemagglutinin (HA) are causing diabetes in mice that express HA under control of the rat insulin promoter. Here we show that the Fas-deficient mice develop autoimmune diabetes with slightly accelerated kinetics indicating that Fas-dependent apoptosis of beta cells is a dispensable mode of cell death in this disease.
Apostolou
Irina
I
Harvard Medical School, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Hao
Zhenyue
Z
Rajewsky
Klaus
K
von Boehmer
Harald
H
D000818:Animals; D017209:Apoptosis; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000473:pathology*; D007328:Insulin / Q000096:biosynthesis*; D019426:Integrases / Q000502:physiology; D007515:Islets of Langerhans / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D011506:Proteins / Q000502:physiology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D014764:Viral Proteins / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
D007328:Insulin; D011506:Proteins; D014764:Viral Proteins; D019014:fas Receptor; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C045073:Cre recombinase; D019426:Integrases