Abstract
Hemophagocytic Lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with multiple contributors, often including an infectious trigger. The Macrophage Activation Syndrome (MAS) subtype is linked to marked IL-18 excess, cytotoxic T-lymphocyte (CTL) activation, and natural killer (NK) cell abnormalities. We asked how excess IL-18 shapes NK and CTL responses to viral challenge. Mice with chronic IL-18 overproduction (Il18tg), showed baseline NK-cytopenia and CTL activation resembling MAS-susceptible patients. NK transcriptomes reflected IL-18/IFNg-axis activation and cell cycle upregulation. LCMV infection of Il18tg mice causes HLH/MAS without affecting viral control, but is not a significant NK challenge. Early after infection with NK-dependent mousepox, Il18tg NKs failed to activate appropriately, but CTLs quickly hyperactivated and mousepox control remained intact. Mousepox-infected Il18tg mice then developed signs of HLH/MAS including hepatosplenic necrosis. Their viral control was impaired, possibly because they failed to expand mousepox-specific CTLs. Il18bpKO mice, despite more normal resting lymphocytes, succumbed similarly to viremic HLH/MAS. Transfer of pre-activated NKs into Il18tg mice partially rescued virus-specific CTL responses, viral control, and 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.
Authors
Jemy A. Varghese, Leonardo Huang, Stephen D. Carro, Emily E. Landy, Anastasia Frank-Kamenetskii, Hannah Klinghoffer, Jeremy A. Morrissette, Vinh Dang, Laurence C. Eisenlohr, Scott W. Canna
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