Excess IL-18 profoundly protects from CNS autoimmunity via continuous effects on CD8 T-cells 4546

Abstract Description IL-18 is an inflammasome-activated cytokine known for driving IFNγ production and “Type 1” immunity. Dramatically elevated IL-18 is observed in an autoinflammatory form of cytokine storm, but paradoxically patients may be protected from autoimmunity. We speculated that excess IL-18 may antagonize autoimmunity development. To understand this, we tested the effects of excess IL-18 (in Il18bp-/- or Il18tg mice, or IL-18 agonist administration) in MOG35-55 induced Experimental Autoimmune Encephalomyelitis (EAE). Regardless of delivery mechanism, mice were strongly protected from EAE onset and progression. Protection was associated with decreased MOG-specific CD4 T-cell activation and spinal cord abundance. Protection required signaling through the IL-18R, and was lost when signaling was disrupted even 12 days after EAE induction. By genetically restricting Il18r1 expression, we found that protection in Il18tg mice required signaling by T-cells, but not FoxP3+ CD4 Tregs. Partial, temporal deletion of Il18r1 in CD8T-cells, however, was sufficient to eliminate protection. IL-18 pretreatment enhanced EAE suppression by adoptively transferred CD8 T-cells. Protection by IL-18 required IFNg, but not perforin. These data demonstrate that IL-18 signaling on CD8 T-cells suppresses autoreactive CD4 T-cells, and EAE, in a manner dependent on IFNγ but not granule-mediated cytotoxicity. This novel protective mechanism may inform cytokine strategies or cellular therapeutics in autoimmunity. Funding Sources NIH/NICHD R01HD098428 Rheumatology Research Foundation Children’s Hospital of Philadelphia Research Institute Topic Categories Therapeutic Approaches to Autoimmunity (THER)