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Diabetes 53:591-596, 2004
© 2004 by the American Diabetes Association, Inc.

Virally Induced Inflammation Triggers Fratricide of Fas-Ligand–Expressing ß-Cells

Urs Christen1, Rima Darwiche2, Helen E. Thomas2, Tom Wolfe1, Evelyn Rodrigo1, Alexander Chervonsky3, Richard A. Flavell3, and Matthias G. von Herrath1

1 Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California
2 St. Vincent’s Institute, Fitzroy, Victoria, Australia
3 Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut

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 ß-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 ß-cells. Indeed, disease incidence after viral (lymphocytic choriomeningitis virus [LCMV]) infection was reduced by ~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 ß-cells after infection with LCMV. This was due to induction of Fas on ß-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 ß-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.

Address correspondence and reprint requests to Matthias G. von Herrath, MD, Division of Developmental Immunology, DI-3, La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. E-mail: matthias{at}liai.org


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.