Caspase-3-Dependent β-Cell Apoptosis in the Initiation of Autoimmune Diabetes Mellitus

Abstract

β-Cell apoptosis is a key event contributing to the pathogenesis of type 1 diabetes mellitus. In addition to apoptosis being the main mechanism by which β cells are destroyed, β-cell apoptosis has been implicated in the initiation of type 1 diabetes mellitus through antigen cross-presentation mechanisms that lead to β-cell-specific T-cell activation. Caspase-3 is the major effector caspase involved in apoptotic pathways. Despite evidence supporting the importance of β-cell apoptosis in the pathogenesis of type 1 diabetes, the specific role of caspase-3 in this process is unknown. Here, we show that Caspase-3 knockout (Casp3^{− /−}) mice were protected from developing diabetes in a multiple-low-dose streptozotocin autoimmune diabetes model. Lymphocyte infiltration of the pancreatic islets was completely absent in Casp3^{− /−} mice. To determine the role of caspase-3-dependent apoptosis in disease initiation, a defined antigen-T-cell receptor transgenic system, RIP-GP/P14 double-transgenic mice with Casp3 null mutation, was examined. β-cell antigen-specific T-cell activation and proliferation were observed only in the pancreatic draining lymph node of RIP-GP/P14/Casp3^{+ /−} mice, but not in mice lacking caspase-3. Together, our findings demonstrate that caspase-3-mediated β-cell apoptosis is a requisite step for T-cell priming, a key initiating event in type 1 diabetes.

ACKNOWLEDGMENTS

This work was supported by the Canadian Institutes of Health Research, Banting and Best Diabetes Centre and Bickell's Foundation. N.L. is supported by the Canadian Institutes of Health Research/Canadian Diabetes Association and Banting and Best Diabetes Centre studentships. This work was also funded by the NCIC with funds from the Canadian Cancer Society to P.S.O. M.W. is a recipient of the CHIR New Investigator Award and a BBDC Denis Scholar.

We thank Kelvin So and Michelle Sleiman for their technical assistance. We also thank Laurent Sabbagh, Jacinth Abraham, Mark Cattral, Kinh Tung Nguyen, and Paul Doherty for critical review of the manuscript.