Genetic deletion of granzyme B does not confer resistance to the development of spontaneous diabetes in non‐obese diabetic mice

Summary Granzyme B ( GzmB ) and perforin are proteins, secreted mainly by natural killer cells and cytotoxic T lymphocytes that are largely responsible for the induction of apoptosis in target cells. Because type 1 diabetes results from the selective destruction of β cells and perforin deficiency effectively reduces diabetes in non‐obese diabetic ( NOD ) mice, it can be deduced that β cell apoptosis involves the GzmB /perforin pathway. However, the relevance of GzmB remains totally unknown in non‐obese diabetic ( NOD) mice. In this study we have focused on GzmB and examined the consequence of GzmB deficiency in NOD mice. We found that NOD . GzmB –/– mice developed diabetes spontaneously with kinetics similar to those of wild‐type NOD ( wt‐ NOD ) mice. Adoptive transfer study with regulatory T cell ( T reg )‐depleted splenocytes ( SPC s) into NOD ‐ SCID mice or in‐vivo T reg depletion by anti‐ CD 25 antibody at 4 weeks of age comparably induced the rapid progression of diabetes in the NOD . GzmB –/– mice and wt‐ NOD mice. Expression of GzmA and F as was enhanced in the islets from pre‐diabetic NOD . GzmB –/– mice. In contrast to spontaneous diabetes, GzmB deficiency suppressed the development of cyclophosphamide‐promoted diabetes in male NOD mice. Cyclophosphamide treatment led to a significantly lower percentage of apoptotic CD 4 + , CD 8 + and CD 4 + CD 25 + T cells in SPC s from NOD . GzmB –/– mice than those from wt‐ NOD mice. In conclusion, GzmB , in contrast to perforin, is not essentially involved in the effector mechanisms for β cell destruction in NOD mice.