Mechanisms of necroptosis in T cells

Author:

Ch’en Irene L.1,Tsau Jennifer S.1,Molkentin Jeffery D.2,Komatsu Masaaki3,Hedrick Stephen M.1

Affiliation:

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

2. Department of Pediatrics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229

3. PRESTO (Precursory Research for Embryonic Science and Technology), Japan Science and Technology Corporation, Kawaguchi and Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan

Abstract

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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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