A role for c-FLIPL in the regulation of apoptosis, autophagy, and necroptosis in T lymphocytes

Abstract

Caspase 8 plays a dual role in the survival of T lymphocytes. Although active caspase 8 mediates apoptosis upon death receptor signaling, the loss of caspase 8 activity leads to receptor-interacting protein (RIP)-1/RIP-3-dependent necrotic cell death (necroptosis) upon TCR activation. The anti-apoptotic protein c-FLIP (cellular caspase 8 (FLICE)-like inhibitory protein) suppresses death receptor-induced caspase 8 activation. Moreover, recent findings suggest that c-FLIP is also involved in inhibiting necroptosis and autophagy. It remains unclear whether c-FLIP protects primary T lymphocytes from necroptosis or regulates the threshold at which autophagy occurs. Here, we used a c-FLIP isoform-specific conditional deletion model to show that c-FLIP L -deficient T cells underwent RIP-1-dependent necroptosis upon TCR stimulation. Interestingly, although previous studies have only described necroptosis in the absence of caspase 8 activity, we found that pro-apoptotic caspase 8 activity and apoptosis were also enhanced in c-FLIP L -deficient T lymphocytes. Furthermore, c-FLIP L -deficient T cells exhibited enhanced autophagy, which served a cytoprotective function. Together, these findings indicate that c-FLIP L plays an important antinecroptotic role and is a key regulator of apoptosis, autophagy, and necroptosis in T lymphocytes.

Acute organ failure following the loss of anti-apoptotic cellular FLICE-inhibitory protein involves activation of innate immune receptors

“…21 Other forms of cell death were unaffected. 22,23 Previous studies have observed an important contribution of programmed necrosis in Alfp-and Mx1-Cre transgenic models, which was not observed to the same extent herein and likely reflect differences in the different animal models used. 10 The onset of liver injury was preceded by increasing concentrations of inflammatory cytokines/chemokines including IL-6, IFN-γ, TNF and CCL2 in serum.…”

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

“…During rapid growth, such as that experienced by T cells after antigenic stimulation, T cells switch their energy metabolism from favoring oxidative phosphorylation (TCA cycle) to aerobic glycolysis (43), a process that can be enhanced by IL-15 signaling through CD122 (44). Cells that are stuck favoring the TCA cycle and unable to meet increased energy demands are more likely to die from necroptosis (45). Necroptosis is another form of programmed cell death often mediated by the protein kinases RIPK1 and RIPK3 (46,47) and enhanced by the presence of reactive oxygen species.…”

RIP kinases: key decision makers in cell death and innate immunity

“…66 Caspase 8 has also been shown to repress necrosis by processing CYLD. 67 Interestingly, caspase 8 appears to act in a proteolytically active complex with FADD and cFLIP to block RIP1-and RIP3-mediated necrosis, 65,68 with c-FLIP- 69 and FADD-70,71 deficient cells being highly sensitive to death by necrosis. This is consistent with the developmental lethality, due to cardiac failure, in FADDdeficient embryos, 72 with RIP1 deficiency rescuing the embryonic lethality associated with FADD deficiency.…”