Complementary HLH susceptibility factors converge on CD8 T-cell hyperactivation

Area of Science:

• Immunology
• Molecular Biology
• Pathology

Background:

• Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are severe hyperinflammatory conditions.
• Familial HLH stems from impaired cytotoxicity (e.g., perforin deficiency), while MAS involves excess interleukin-18 (IL-18).
• Mice with combined susceptibility to these factors develop lethal spontaneous hyperinflammation.

Purpose of the Study:

• To investigate the synergistic mechanisms underlying HLH and MAS in dual-susceptible mice.
• To elucidate the role of CD8 T cells in the pathogenesis of these hyperinflammatory syndromes.
• To identify key molecular pathways driving T-cell hyperactivation and disease progression.

Main Methods:

• Utilized genetically modified mice (Prf1⁻/⁻Il18tg) exhibiting dual susceptibility to HLH and MAS.
• Administered viral (lymphocytic choriomeningitis virus) and innate (Toll-like receptor 9) triggers.
• Performed in vitro studies involving T-cell receptor (TCR) stimulation and IL-18 treatment.
• Analyzed T-cell populations, proliferation, cytokine production, and gene expression.

Main Results:

• IL-18 signaling in CD8 T cells promoted MAS following viral, but not innate, triggers.
• Perforin deficiency impaired IL-18-induced restimulation-induced cell death (RICD) in CD8 T cells.
• Dual-susceptible mice exhibited massive oligoclonal CD8 T-cell hyperactivation with increased proliferation and interferon-gamma production.
• T cells displayed markers of both exhaustion and effector function, indicating a unique activation state.

Conclusions:

• Synergy between IL-18 and perforin deficiency drives a terminal CD8 T-cell hyperactivation state.
• This state combines features of exhaustion and effector function, leading to lethal hyperinflammation.
• Understanding these pathomechanisms offers insights into HLH and MAS pathogenesis and potential therapeutic targets.