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Diabetes 53:2797-2803, 2004
© 2004 by the American Diabetes Association, Inc.

Fas Deficiency Prevents Type 1 Diabetes by Inducing Hyporesponsiveness in Islet ß-Cell–Reactive T-Cells

Luis Vence1,2,3, Christophe Benoist1,2,3, and Diane Mathis1,2,3

1 Section on Immunology and Immunogenetics, Joslin Diabetes Center, Boston, Massachusetts
2 Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
3 Harvard Medical School, Boston, Massachusetts

Type 1 diabetes is an autoimmune disease wherein autoreactive T-cells promote the specific destruction of pancreatic islet ß-cells. Evidence for a crucial role for Fas/FasL interactions in this destruction has been highly controversial because of the pleiotropic effects of Fas deficiency on the lymphoid and other systems. Fas-deficient mice are protected from spontaneous development of diabetes not because Fas has a role in the destruction of ß-cells, but rather because insulitis is abrogated. Fas may somehow be involved in the series of events provoking insulitis; for example, it may play a role in the physiological wave of ß-cell death believed to result in the export of pancreatic antigens to the pancreatic lymph nodes and, thereby, to circulating, naive, diabetogenic T-cells for the first time. To explore the implication of Fas in these events, we crossed the lpr mutation into the BDC2.5 model of type 1 diabetes to make it easier to monitor direct effects on the pathogenic specificity. We demonstrated that BDC2.5/NODlpr/lpr mice have qualitatively and quantitatively less aggressive insulitis than do BDC2.5/NOD mice. In vitro proliferation assays showed that BDC2.5/NODlpr/lpr splenocytes proliferated less vigorously than those from control mice in the presence of islet extracts, which reflects their inability to produce interleukin-2, resulting in weaker pathogenicity.

Address correspondence and reprint requests to Drs. Christophe Benoist and Diane Mathis, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: cbdm{at}joslin.harvard.edu


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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.