We have studied the role of Fas in the induction of autoimmune diabetes in NOD mice and found that although Fas is required for the development of diabetes, early overexpression of this molecule on pancreatic β cells delays diabetes onset and reduces diabetes incidence in NOD mice. Moreover, Fas overexpression on β cells is not sufficient to restore the diabetic phenotype in Fas-deficient NOD mice. On the other hand we show that induction of β cell death by CD4 T cells is dependent on the expression of Fas on β cells. IL-1β and IFNγ are key cytokines involved in Fas up-regulation on mouse β cells. However, here we demonstrate that IL-1β is not required for either spontaneous t or adoptively transferred diabetes. Interestingly we have also observed that FasL overexpression on β cells seems to confer immune-privilege to islet cells against diabetogenic CD4 T cells.

We hypothesize that early, immune-independent, Fas expression on β cells protects from diabetes by promoting immune tolerance to islet antigens, while late, cytokine-mediated induction of Fas has the opposite effect by promoting massive β cell death and diabetes. There is redundancy regarding the cytokines involved in Fas up-regulation on β cells in vivo.