Programmed cell death can be mediated by different mechanisms, including apoptosis, autophagy and programmed necrosis (also termed necroptosis). Although caspase 8 initiates T cell apoptosis following death receptor ligation, caspase 8-deficient T cells display decreased survival after stimulation compared with wild-type T cells. A recent study solved this paradox by demonstrating that caspase 8 is an inhibitor of a necroptosis pathway in T cells that is mediated by receptor-interacting serine/threonine protein kinase 3 (RIPK3).

Ch'en et al. investigated which mechanism of cell death is responsible for the decreased viability of activated caspase 8-deficient T cells. Cyclophilin D (also known as PPID) is an essential component of the mitochondrial permeability transition pore, which has been suggested to mediate necroptosis. However, T cells deficient for both caspase 8 and cyclophilin D still exhibited decreased survival in vitro and impaired population expansion in response to viral infection in vivo. This suggests that cell death induced in activated caspase 8-deficient T cells does not rely on cyclophilin D-mediated necroptosis.

caspase 8 is an inhibitor of a necroptosis pathway in T cells that is mediated by RIPK3

So, is autophagy responsible for the decreased viability of activated caspase 8-deficient T cells? Inhibition of autophagy in activated T cells resulted in enhanced apoptosis, presumably owing to an increase in mitochondrial numbers. Moreover, the survival of activated T cells lacking both caspase 8 and autophagy-related protein 7 (ATG7) was even more impaired than the survival of caspase 8-deficient T cells. Although addition of the necroptosis inhibitor necrostatin 1 promoted expansion of caspase 8-deficient T cell populations following activation, it had only a partial effect on T cells deficient for both caspase 8 and ATG7. These results indicate that the decreased survival of caspase 8-deficient T cells is mediated by a necroptosis mechanism that is independent of autophagy-induced cell death.

Necroptosis was previously suggested to be initiated by a complex of RIPK1 and RIPK3. Indeed, deletion of Ripk3 led to increased survival of activated caspase 8-deficient T cells. Moreover, following viral infection, T cells deficient for both caspase 8 and RIPK3 showed population expansion that was comparable to that of control T cells. These results demonstrate that caspase 8 inhibits RIPK3-mediated necroptosis. Interestingly, mice with T cells that lack both caspase 8 and RIPK3 develop a lymphoproliferative disorder over time, suggesting that both caspase 8-mediated apoptosis and RIPK3-mediated necroptosis are crucial for the control of T cell homeostasis.

These findings are in accordance with three recently published Nature papers, which demonstrated suppression of RIPK-mediated necroptosis by caspase 8, as well as by FAS-associated death domain protein (FADD) and the long splice variant of FLICE-like inhibitory protein (FLIPL), during embryonic development and T cell proliferation.