{"id":{"repo_id":"penn","oai_identifier":"oai:repository.upenn.edu:20.500.14332/62891"},"canonical_url":"https://search.dev.ndltd.org/etd/penn/oai:repository.upenn.edu:20.500.14332/62891","repository":{"repo_id":"penn","name":"University of Pennsylvania","base_url":"https://repository.upenn.edu/server/oai/request"},"display":{"title":"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 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.","abstract_html":"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.","abstract_has_math":false,"creators":["Morrissette, Jeremy"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Canna, Scott, W"],"committee_chairs":[],"committee_members":[],"year":2026,"date_issued":"2026","date_published":"2026","updated_at":"2026-07-24T03:46:32Z","subjects":["Immunology and Infectious Disease"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://repository.upenn.edu/handle/20.500.14332/62891","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Canna, Scott, W"]},{"key":"dc:creator","label":"Author","values":["Morrissette, Jeremy"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-06-05T16:20:11Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2026-06-05T16:20:11Z"]},{"key":"dc:date.issued","label":"Date","values":["2026"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation/Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Immunology and Infectious Disease"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://repository.upenn.edu/handle/20.500.14332/62891"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["2026"]},{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["PhD"]},{"key":"dc:title","label":"Title","values":["THE INNATE CYTOKINE IL-18 INHIBITS CNS AUTOIMMUNITY THROUGH PREFERENTIAL ACTIVATION OF PROTECTIVE CD8 T-CELLS"]}]}],"canonical_facts":{"dc:contributor.advisor":["Canna, Scott, W"],"dc:creator":["Morrissette, Jeremy"],"dc:date.accessioned":["2026-06-05T16:20:11Z"],"dc:date.available":["2026-06-05T16:20:11Z"],"dc:date.issued":["2026"],"dc:description":["2026"],"dc:description.abstract":["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."],"dc:description.degree":["PhD"],"dc:identifier.uri":["https://repository.upenn.edu/handle/20.500.14332/62891"],"dc:language.iso":["en"],"dc:subject":["Immunology and Infectious Disease"],"dc:title":["THE INNATE CYTOKINE IL-18 INHIBITS CNS AUTOIMMUNITY THROUGH PREFERENTIAL ACTIVATION OF PROTECTIVE CD8 T-CELLS"],"dc:type":["Dissertation/Thesis"]},"updated_at":"2026-07-24T03:46:32Z"}