Fas deficiency prevents type 1 diabetes by inducing hyporesponsiveness in islet beta-cell-reactive T-cells.
Type 1 diabetes is an autoimmune disease wherein autoreactive T-cells promote the specific destruction of pancreatic islet beta-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 beta-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 beta-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/NOD(lpr/lpr) mice have qualitatively and quantitatively less aggressive insulitis than do BDC2.5/NOD mice. In vitro proliferation assays showed that BDC2.5/NOD(lpr/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.
Vence
Luis
L
Section on Immunology and Immunogenetics, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
Benoist
Christophe
C
Mathis
Diane
D
D000818:Animals; D002455:Cell Division; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D004912:Erythrocytes / Q000166:cytology / Q000502:physiology; D017353:Gene Deletion; D007515:Islets of Langerhans / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor