The role of Fas in autoimmune diabetes.
Immunologically privileged sites express Fas ligand (FasL), which protects them from attack by activated T cells that express Fas and die upon contact with FasL. In an attempt to protect nonobese diabetic mice (NOD) from autoimmune diabetes, we made FasL transgenic NOD mice using the beta cell-specific rat insulin-1 promoter. Surprisingly, these transgenic mice showed heightened sensitivity to diabetogenic T cells, which was due to self-destruction of beta cells upon T cell-mediated induction of Fas. Fas-negative NOD(lpr/lpr) animals were resistant to diabetogenic T cells and to spontaneous diabetes. Thus, induction of Fas expression on beta cells and their subsequent destruction constitutes the main pathogenic mechanism in autoimmune diabetes.
Chervonsky
A V
AV
Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Wang
Y
Y
Wong
F S
FS
Visintin
I
I
Flavell
R A
RA
Janeway
C A
CA
Matis
L A
LA
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000503:physiopathology*; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007328:Insulin / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000276:immunology; D051381:Rats; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D019076:Transgenes / Q000276:immunology
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D007328:Insulin; D008024:Ligands; D008562:Membrane Glycoproteins