Caspase-8-dependent control of NK- and T cell responses during cytomegalovirus infection

AbstractCaspase-8 (CASP8) impacts antiviral immunity in expected as well as unexpected ways. Mice with combined deficiency in CASP8 and RIPK3 cannot support extrinsic apoptosis or RIPK3-dependent programmed necrosis, enabling studies of CASP8 function without complications of unleashed necroptosis. These extrinsic cell death pathways are naturally targeted by murine cytomegalovirus (MCMV)-encoded cell death suppressors, showing they are key to cell-autonomous host defense. Remarkably,Casp8–/–Ripk3–/–,Ripk1–/–Casp8–/–Ripk3–/– andCasp8–/–Ripk3K51A/K51A mice mount robust antiviral T cell responses to control MCMV infection. Studies inCasp8–/–Ripk3–/– mice show that CASP8 restrains expansion of MCMV-specific natural killer (NK) and CD8 T cells without compromising contraction or immune memory. InfectedCasp8–/–Ripk3–/– orCasp8–/–Ripk3K51A/K51A mice have higher levels of virus-specific NK cells and CD8 T cells compared to matched RIPK3-deficient littermates or WT mice. CASP8, likely acting downstream of Fas death receptor, dampens proliferation of CD8 T cells during expansion. Importantly, contraction proceeds unimpaired in the absence of extrinsic death pathways owing to intact Bim-dependent (intrinsic) apoptosis. CD8 T cell memory develops inCasp8–/–Ripk3–/– mice, but memory inflation characteristic of MCMV infection is not sustained in the absence of CASP8 function. Despite this,Casp8–/–Ripk3–/– mice are immune to secon...
Source: Medical Microbiology and Immunology - Category: Microbiology Source Type: research