Excess IL-18 drives fatal mousepox cytokine storm via NK cell immunodeficiency and nonspecific T-cell hyperactivation

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

doi:10.1172/jci.insight.199201

Excess IL-18 drives fatal mousepox cytokine storm via NK cell immunodeficiency and nonspecific T-cell hyperactivation

Jemy A. Varghese,¹ Leonardo Huang,² Stephen D. Carro,³ Emily E. Landy,⁴ Anastasia Frank-Kamenetskii,² Hannah Klinghoffer,² Jeremy A. Morrissette,² Vinh Dang,² Laurence C. Eisenlohr,³ and Scott W. Canna¹

Published October 20, 2026 - More info

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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 (Il18^tg), 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 Il18^tg mice causes HLH/MAS without affecting viral control, but is not a significant NK challenge. Early after infection with NK-dependent mousepox, Il18^tg NKs failed to activate appropriately, but CTLs quickly hyperactivated and mousepox control remained intact. Mousepox-infected Il18^tg mice then developed signs of HLH/MAS including hepatosplenic necrosis. Their viral control was impaired, possibly because they failed to expand mousepox-specific CTLs. Il18bp^KO mice, despite more normal resting lymphocytes, succumbed similarly to viremic HLH/MAS. Transfer of pre-activated NKs into Il18^tg 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.

Excess IL-18 drives fatal mousepox cytokine storm via NK cell immunodeficiency and nonspecific T-cell hyperactivation

Jemy A. Varghese,¹ Leonardo Huang,² Stephen D. Carro,³ Emily E. Landy,⁴ Anastasia Frank-Kamenetskii,² Hannah Klinghoffer,² Jeremy A. Morrissette,² Vinh Dang,² Laurence C. Eisenlohr,³ and Scott W. Canna¹

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Excess IL-18 drives fatal mousepox cytokine storm via NK cell immunodeficiency and nonspecific T-cell hyperactivation

Jemy A. Varghese,1 Leonardo Huang,2 Stephen D. Carro,3 Emily E. Landy,4 Anastasia Frank-Kamenetskii,2 Hannah Klinghoffer,2 Jeremy A. Morrissette,2 Vinh Dang,2 Laurence C. Eisenlohr,3 and Scott W. Canna1

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Jemy A. Varghese,¹ Leonardo Huang,² Stephen D. Carro,³ Emily E. Landy,⁴ Anastasia Frank-Kamenetskii,² Hannah Klinghoffer,² Jeremy A. Morrissette,² Vinh Dang,² Laurence C. Eisenlohr,³ and Scott W. Canna¹