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Molecular and Cellular Biology, May 2005, p. 3620-3629, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3620-3629.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Nicole Liadis,1 Kiichi Murakami,1,4 Mohamed Eweida,1 Alisha R. Elford,1,4 Laura Sheu,2 Herbert Y. Gaisano,2 Razqallah Hakem,1,3 Pamela S. Ohashi,1,4 and Minna Woo1,2,5,6*

Department of Medical Biophysics,1 The Campbell Family Institute for Breast Cancer Research,4 Ontario Cancer Institute, Departments of Medicine and PhysiologyUniversity of Toronto,2 The Advanced Medical Discovery Institute (AMDI),3 St. Michael's Hospital,5 McLaughlin Centre for Molecular Medicine, Toronto, Ontario, Canada6

Received 16 August 2004/ Returned for modification 1 November 2004/ Accepted 7 January 2005

ß-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 ß cells are destroyed, ß-cell apoptosis has been implicated in the initiation of type 1 diabetes mellitus through antigen cross-presentation mechanisms that lead to ß-cell-specific T-cell activation. Caspase-3 is the major effector caspase involved in apoptotic pathways. Despite evidence supporting the importance of ß-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. ß-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 ß-cell apoptosis is a requisite step for T-cell priming, a key initiating event in type 1 diabetes.

* Corresponding author. Mailing address: Ontario Cancer Institute, Rm. 8-205, 610 University Ave., 8-205 Toronto, Ontario, Canada M5G 2M9. Phone: (416) 946-4501, ext. 3971. Fax: (416) 946-2086. E-mail: mwoo{at}uhnres.utoronto.ca.

Molecular and Cellular Biology, May 2005, p. 3620-3629, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3620-3629.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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