THE INNATE CYTOKINE IL-18 INHIBITS CNS AUTOIMMUNITY THROUGH PREFERENTIAL ACTIVATION OF PROTECTIVE CD8 T-CELLS

Chronic innate immune activation is widely thought to challenge self-tolerance. IL-18 is an innate, inflammasome-activated cytokine and potent amplifier of T-cell activation. In excess, IL-18 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 CD4T-cells (CD4Tauto). Prior data suggested that IL-18 would exacerbate immunopathology in EAE. Instead, excess IL-18 was profoundly protective. Excess 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 CD8T-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, engaged CD8T-cells to diminish CD4Tauto abundance, prevent CNS infiltration, and block immunopathology. Together, these findings demonstrate the unexpected, dominant ability of IL-18 to mobilize protective CD8T-cells against highly activated CD4Tauto and protect from CNS autoimmune pathology; illustrating a potential therapeutically relevant mechanism by which autoinflammation actively opposes autoimmunity.

Author dc:creator

• Morrissette, Jeremy

Advisor dc:contributor.advisor

• Canna, Scott, W

• Immunology and Infectious Disease

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/62891

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/62891