Impaired apoptosis in immune effector cells such as macrophages has been implicated in the development of autoimmune disease by promoting the breakdown of self-tolerance and the sustained production of cytotoxic molecules. Macrophages from nonobese diabetic (NOD) mouse, an animal model of human autoimmune diabetes, exhibit several defects that are causally linked to the onset and progression of the disease. In this context, we investigated whether NOD macrophages have a defect in a cell death pathway, and if that is the case, the mechanism underlying such dysregulation of cell death. We found that NOD macrophages were resistant to treatment with a broad spectrum of cell death stimuli, triggering both apoptotic and non-apoptotic death. Through analysis of intracellular signaling pathways along with the expression of apoptosis-related proteins, we found that atypical resistance to cell death was associated with an elevated expression of anti-apoptotic Bcl-X-L but not the NF-kappa B signaling pathway in NOD macrophages. Further, ABT-737, which can inhibit Bcl-X-L function, sensitized NOD macrophages to apoptosis induced by diverse apoptotic stimuli, thus restoring sensitivity to cell death. Taken together, our results suggest a macrophage-intrinsic defect in cell death as a potential mechanism that promotes an immune attack towards pancreatic beta-cells and the development of autoimmune diabetes in NOD mice. (C) 2012 Elsevier Inc. All rights reserved.