Multimodal induction of hyperinflammation by IL-18 includes virus-specific NK immunodeficiency [NKstim_RNAseq]

Early after NK-dependent mousepox infection, Il18tg NKs failed to appropriately activate but their CTLs became hyperactivated, and mousepox control remained intact. However, mousepox-infected Il18tg mice then developed hepatosplenic necrosis and other signs of HLH/MAS; and their poor viral control paralleled their failed expansion of mousepox-specific CTLs. Il18bpKO mice, despite more normal resting lymphocytes, succumbed similarly to viremic HLH/MAS.

Transfer of pre-activated NKs into Il18tg mice restored their virus-specific CTL response and rescued survival. Thus, excess IL-18 contributes to HLH/MAS via disparate effects on CTL and NK cells, demonstrating a novel, context-specific NK immunodeficiency and highlighting how subtle host-pathogen interactions can affect the mechanisms and treatment rationale of life-threatening HLH/MAS.