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J Exp Med. 2011 Apr 11;208(4):633-41. doi: 10.1084/jem.20110251. Epub 2011 Mar 14.

Mechanisms of necroptosis in T cells.

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Division of Biological Sciences, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.


Cell populations are regulated in size by at least two forms of apoptosis. More recently, necroptosis, a parallel, nonapoptotic pathway of cell death, has been described, and this pathway is invoked in the absence of caspase 8. In caspase 8-deficient T cells, necroptosis occurs as the result of antigen receptor-mediated activation. Here, through a genetic analysis, we show that necroptosis in caspase 8-deficient T cells is related neither to the programmed necrosis as defined by the requirement for mitochondrial cyclophilin D nor to autophagy as defined by the requirement for autophagy-related protein 7. Rather, survival of caspase 8-defective T cells can be completely rescued by loss of receptor-interacting serine-threonine kinase (Ripk) 3. Additionally, complementation of a T cell-specific caspase 8 deficiency with a loss of Ripk3 gives rise to lymphoproliferative disease reminiscent of lpr or gld mice. In conjunction with previous work, we conclude that necroptosis in antigen-stimulated caspase 8-deficient T cells is the result of a novel Ripk1- and Ripk3-mediated pathway of cell death.

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