Multimodal induction of fulminant HLH by IL-18 includes virus-specific NK immunodeficiency

Macrophage Activation Syndrome (MAS) is a cytokine storm syndrome associated with Stills Disease, XIAP deficiency, and elevation of both total and free IL-18. Modeling excess IL-18 using Il18tg mice, we found mild NK-cytopenia and cytotoxic T lymphocyte (CTL) activation in resting mice reminiscent of Stills patients. Infection with Lymphocytic Choriomeningitis Virus (LCMV) triggered MAS via and IFN{gamma}, despite normal viral clearance. Il18tg NK cell transcriptomes showed replicative activity, but few changes in canonical NK function or maturation pathways. LCMV clearance is NK-independent, so we challenged Il18tg mice with mousepox in which NK cells are critical early orchestrators of clearance. Il18tg mices NK cells failed to activate or expand, but mousepox further activated their CTL and early viral control was normal. Il18tg mice soon developed "MAS" including hepatosplenic necrosis, but (contrasting with LCMV) they showed poor virus-specific CTL expansion and viral clearance. Though more normal at rest, Il18bpKO mices NK cells were similarly inert upon mousepox infection, and the mice succumbed to viremic MAS like Il18tg. Rescue of Il18tg mice, and mousepox-specific CTL responses, by NK cell transfer required in vitro NK pre-activation. Thus, IL-18 can induce both hyperinflammation (CTL hyperactivation) and immunodeficiency (NK cell hypoactivation) depending on the nature of the infectious trigger.