Mechanisms of Beta Cell Death in Diabetes: Minor Role for CD95

It has been speculated that beta cell death results from CD95 ligand (CD95L)-induced apoptosis that results from binding of the CD95 ligand to the infiltrating T cells.

Also, studies with perforin-deficient NOD mice indicated that cytotoxic, CD8+ T cell attack is crucial in the final progression to diabetes.

Normal pancreatic islet cells do not express CD95 receptor in humans or mice.  Islet cells can synthesize the receptor in vitro, after incubation with interleukin 1b, or in vivo, after leukocyte infiltration.  Two groups used a CD95-deficient variant (lpr) of the NOD mouse and showed that diabetogenic NOD spleen cells or a NOD-derived CD8+ T cell clone specific for beta cells did not cause diabetes when transferred into NODlpr recipients. They also concluded that induction of CD95 expression on beta cells, and its engagement by CD95L on infiltrating T cells, represented the main pathogenic mechanism in autoimmune diabetes.

The findings of the research in the present study indicate that CD95 has a minor role in the effector phase of the autoimmune response but give no clue as to its involvement in initiation of disease. CD8+ T cells are essential to initiate infiltration in the NOD mouse pancreas, and the studies with perforin-deficient NOD animals have shown that perforin was not required for this to happen. CD95 may be a candidate, but because the immune system of lpr mice is so distorted, it is difficult to conclude anything from these animals, even though they do not develop insulitis.

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