Virally induced inflammation triggers fratricide of Fas-ligand-expressing beta-cells.
Tissue-specific expression of Fas-ligand (Fas-L) can provide immune privilege by inducing apoptosis of "invading" lymphocytes expressing Fas. However, accelerated diabetes has been reported in transgenic mice expressing Fas-L in islets (RIP-Fas-L) as a result of Fas-dependent fratricide of beta-cells after transfer of diabetogenic clones. Here we studied whether Fas-L could protect islets from autoaggressive CD8 lymphocytes in a transgenic model of virally induced diabetes (RIP-LCMV-NP transgenic mice), in which the autoaggressive response is directed to a viral nucleoprotein (NP) expressed as a transgene in beta-cells. Indeed, disease incidence after viral (lymphocytic choriomeningitis virus [LCMV]) infection was reduced by approximately 30%, which was associated with a decrease of autoaggressive CD8 NP-specific lymphocytes in islets and pancreatic draining lymph nodes. However, surprisingly, a high degree (50%) of diabetes was seen in mice that expressed only Fas-L but not the viral transgene (NP) in beta-cells after infection with LCMV. This was due to induction of Fas on beta-cells after LCMV infection of the pancreas, resulting in Fas/Fas-L-mediated fratricide. Thus, although Fas-L can lend some immune privilege to islet cells, local virus-induced inflammation will induce Fas on beta-cells, leading to their mutual destruction if Fas-L is present. Expression of Fas-L therefore might not be protective in situations in which viral inflammation can be expected, resulting in Fas induction on the targeted cell itself.
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California, USA.
Urs
U
Christen
Rima
R
Darwiche
Helen E
HE
Thomas
Tom
T
Wolfe
Evelyn
E
Rodrigo
Alexander
A
Chervonsky
Richard A
RA
Flavell
Matthias G
MG
von Herrath
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003433:Crosses, Genetic; D053222:Fas Ligand Protein; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000821:virology; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D008217:Lymphocytic choriomeningitis virus; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D013154:Spleen / Q000276:immunology
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins