Caspase-3-dependent beta-cell apoptosis in the initiation of autoimmune diabetes mellitus.
beta-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 beta cells are destroyed, beta-cell apoptosis has been implicated in the initiation of type 1 diabetes mellitus through antigen cross-presentation mechanisms that lead to beta-cell-specific T-cell activation. Caspase-3 is the major effector caspase involved in apoptotic pathways. Despite evidence supporting the importance of beta-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. beta-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 beta-cell apoptosis is a requisite step for T-cell priming, a key initiating event in type 1 diabetes.
Liadis
Nicole
N
Ontario Cancer Institute, Rm. 8-205, 610 University Avenue, 8-205 Toronto, Ontario, Canada M5G 2M9.
Murakami
Kiichi
K
Eweida
Mohamed
M
Elford
Alisha R
AR
Sheu
Laura
L
Gaisano
Herbert Y
HY
Hakem
Razqallah
R
Ohashi
Pamela S
PS
Woo
Minna
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005934:Glucagon / Q000032:analysis / Q000378:metabolism; D007328:Insulin / Q000032:analysis / Q000378:metabolism; D007515:Islets of Langerhans / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020799:Pancrelipase / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D007328:Insulin; D020799:Pancrelipase; D005934:Glucagon; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases