The innate cytokine IL-18 inhibits CNS autoimmunity through preferential activation of protective CD8 T-cells

Abstract Chronic innate immune activation is widely thought to challenge self-tolerance. IL-18 is an inflammasome-activated cytokine and potent amplifier of T-cell activation whose excess is associated with certain autoinflammatory, but not autoimmune, diseases. We tested how excess IL-18 affected susceptibility to experimental autoimmune encephalomyelitis (EAE), a model of CNS autoimmunity driven by IL-18 responsive, myelin-autoreactive CD4 T-cells (CD4Tauto). We hypothesized that IL-18 would exacerbate immunopathology in EAE. Instead, excess IL-18 was profoundly protective. IL-18 did not impair CD4Tauto priming or early expansion. Rather, it selectively restricted later accumulation of highly activated, splenic CD4Tauto bearing CNS-homing integrins. Despite high IL-18 receptor expression on CD4Tauto and Foxp3+ CD4Treg, excess IL-18 acted specifically through mature CD8 T-cells to promote a highly activated CD8Teffector phenotype and IFNγ-dependent protection from EAE. Therapeutic administration of a “decoy-resistant” IL-18 agonist (DR-18) to wild-type mice, even after CD4Tauto expansion, nevertheless engaged CD8 T-cells to diminish CD4Tauto abundance, prevent CNS infiltration, and block immunopathology. Together, these findings demonstrate IL-18’s unexpected, dominant ability to mobilize protective CD8 T-cells against highly activated CD4Tauto and protect from CNS autoimmune pathology; illustrating a potential therapeutically relevant mechanism by which autoinflammation actively opposes autoimmunity. Competing Interest Statement SC has received in-kind support (reagent) from Simcha Therapeutics, been site PI for a Novartis-sponsored trial, received support for speaking by Sobi & BMS, and been an ad hoc consultant for Apollo therapeutics, BMS, Johnson & Johnson, Novartis, and Sobi. SC, VD, and JAM are named in provisional patent PCT/US24/37468 'Methods for modulating activity of IL-18 for treatment of CD4+ T cell mediated autoimmunity and immunopathology.'