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.
Christen
Urs
U
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California, USA.
Darwiche
Rima
R
Thomas
Helen E
HE
Wolfe
Tom
T
Rodrigo
Evelyn
E
Chervonsky
Alexander
A
Flavell
Richard A
RA
von Herrath
Matthias G
MG
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