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.

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