Complementary roles of FADD and RIPK3 in T cell homeostasis and antiviral immunity (163.24)

Abstract T cells lacking caspase 8 develop a hyper-autophagic morphology, and succumb to a programmed necrosis-like death process termed necroptosis. RIP kinases RIPK1 and RIPK3 together facilitate necroptosis in response to TNF-α ligation and mitogenic stimulation. We have previously shown the defective proliferation of T cells lacking caspase 8 activity is rescued by crossing with RIPK3-/- mice, and caspase-mediated cleavage of RIPK1/3 necrosis inducing complexes (necrosomes) is sufficient to prevent necroptosis. Enhanced recovery of these double-mutant T cells following stimulation demonstrates that caspase 8 and RIPK3 are essential for clonal expansion, contraction, and anti-viral responses, though such rescue ultimately leads to lymphadenopathy. Enhanced death in wildtype T cells blocked by RIPK1 inihibitor Nec-1 suggests an important physiological role for necroptotic signaling in normal T cells. The NF-κβ pathway plays a key role in regulating T cell death as well, as blockade of NF-κβ signaling results in increased death that can be rescued with Nec-1. This result implicates the role of NF-κβ in regulating levels of sensitivity to necroptosis in CD4+ vs. CD8+ cells. The mechanism of inhibition by NF-κB signaling as well as the spatial and temporal regulation of necrosomes are critical in regulating downstream activating and inhibitory pathways induced during necroptosis.