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


Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, 1462 Clifton Rd. N.E, Atlanta, GA, 30322, USA. [Email]


Caspase-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-/- and Casp8-/-Ripk3K51A/K51A mice mount robust antiviral T cell responses to control MCMV infection. Studies in Casp8-/-Ripk3-/- mice show that CASP8 restrains expansion of MCMV-specific natural killer (NK) and CD8 T cells without compromising contraction or immune memory. Infected Casp8-/-Ripk3-/- or Casp8-/-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 in Casp8-/-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 secondary challenge. Interferon (IFN)γ is recognized as a key cytokine for adaptive immune control of MCMV. Ifngr-/-Casp8-/-Ripk3-/- mice exhibit increased lifelong persistence in salivary glands as well as lungs compared to Ifngr-/- and Casp8-/-Ripk3-/- mice. Thus, mice deficient in CASP8 and RIPK3 are more dependent on IFNγ mechanisms for sustained T cell immune control of MCMV. Overall, appropriate NK- and T cell immunity to MCMV is dependent on host CASP8 function independent of RIPK3-regulated pathways.


Apoptosis,Cell death,Herpesvirus,Necroptosis,Proliferation,Ripoptosome,