Caspase-8 expression in CD8⁺ T cells promotes pathogen restriction in the brain during Toxoplasma gondii infection

Cell death is an integral restriction mechanism against intracellular pathogens. We have previously reported extensive cell death in the brain during infection with the intracellular parasite, Toxoplasma gondii. Here, we focus on the role of caspase-8, a regulator of extrinsic apoptosis, during T. gondii infection. We find that Casp8^-/-Ripk3^-/- mice have increased brain parasite burden in comparison to controls and succumb to infection despite the generation of robust immune responses. We observed that neurons, astrocytes, and CD8⁺ T cells had high rates of parasite interactions in Casp8^-/-Ripk3^-/- mice compared to wild-type mice. While Casp8 deficiency in neurons and astrocytes did not affect control of infection, deletion of Casp8 in CD8⁺ T cells led to impaired survival, increased parasite burden, and direct infection of CD8⁺ T cells in the brain. We conclude that in addition to well-characterized effector functions, CD8⁺ T cells use caspase-8 to control T. gondii in the brain.