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

Abstract

Type 1 diabetes is an autoimmune disease wherein autoreactive T-cells promote the specific destruction of pancreatic islet ␤-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 ␤-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 ␤-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.

Transgenic Expression of Dominant-Negative Fas-Associated Death Domain Protein in β Cells Protects against Fas Ligand-Induced Apoptosis and Reduces Spontaneous Diabetes in Nonobese Diabetic Mice

“…We found that Fas on ␤ cells played a minor role in ␤ cell death during the effector phase of diabetes, and this has been confirmed by others (13,14). In fact, the lack of infiltration into NODlpr islets may have more to do with the reduced proliferative ability of T cells, rather than a role for Fas on the islets themselves (15). Recently, better tools have been made to test the significance of Fas on ␤ cells without the complications brought about by the lpr mutation.…”

Distinct Effector Mechanisms in the Development of Autoimmune Neuropathy versus Diabetes in Nonobese Diabetic Mice

“…Although the analysis of the fas pathway in NOD mice was complicated by the abnormal immune phenotype observed in lpr mice, alternative models convincingly demonstrated a role for the fas-fas ligand pathway in autoimmune diabetes (26,50). Thus, it was surprising that perforin and fas deficiency were not necessary for tissue damage in NOD-B7-2KO mice.…”

“…Indeed, although blocking IFN-␥ by mAbs reduced the incidence of diabetes in NOD mice (54), NOD-IFN-␥KO mice develop diabetes with incidence similar to NOD mice and only slightly delayed kinetics (23,24). In contrast, whereas fas and perforin are involved in the development of autoimmune diabetes and islet destruction in NOD mice (21,22,26,50), both pathways were dispensable for autoimmune neuropathy. These results suggest that although both diabetes and neuropathy are T cell-mediated inflammatory autoimmune diseases occurring on the autoimmune-prone NOD background, the immune mechanisms underlying these diseases are distinct.…”

Deletion of Fas in the pancreatic β-cells leads to enhanced insulin secretion

“…Fas was initially thought to be critical in ␤-cell apoptosis in type 1 diabetes since NOD mice homozygous for the lpr mutation were protected from diabetes development (5,12). However, this is most likely a result of their dysregulated immune system from the lpr mutation rather than the role of Fas in ␤-cell destruction per se (34). In keeping with this notion, NOD-lpr/lpr islets transplanted into normal female NOD mice did not give protection from diabetes development (1).…”