{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:21:58Z","timestamp":1785424918866,"version":"3.56.0"},"posted":{"date-parts":[[2026,1,28]]},"group-title":"Immunology","reference-count":103,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01HD098428"],"award-info":[{"award-number":["R01HD098428"]}],"id":[{"id":"https:\/\/ror.org\/04byxyr05","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006260","name":"Rheumatology Research Foundation","doi-asserted-by":"crossref","award":["1269102"],"award-info":[{"award-number":["1269102"]}],"id":[{"id":"10.13039\/100006260","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  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 (CD4T\n                  <jats:sub>auto<\/jats:sub>\n                  ). We hypothesized that IL-18 would exacerbate immunopathology in EAE. Instead, excess IL-18 was profoundly protective. IL-18 did not impair CD4T\n                  <jats:sub>auto<\/jats:sub>\n                  priming or early expansion. Rather, it selectively restricted later accumulation of highly activated, splenic CD4T\n                  <jats:sub>auto<\/jats:sub>\n                  bearing CNS-homing integrins. Despite high IL-18 receptor expression on CD4T\n                  <jats:sub>auto<\/jats:sub>\n                  and Foxp3\n                  <jats:sup>+<\/jats:sup>\n                  CD4T\n                  <jats:sub>reg<\/jats:sub>\n                  , excess IL-18 acted specifically through mature CD8 T-cells to promote a highly activated CD8T\n                  <jats:sub>effector<\/jats:sub>\n                  phenotype and IFN\u03b3-dependent protection from EAE. Therapeutic administration of a \u201cdecoy-resistant\u201d IL-18 agonist (DR-18) to wild-type mice, even after CD4T\n                  <jats:sub>auto<\/jats:sub>\n                  expansion, nevertheless engaged CD8 T-cells to diminish CD4T\n                  <jats:sub>auto<\/jats:sub>\n                  abundance, prevent CNS infiltration, and block immunopathology. Together, these findings demonstrate IL-18\u2019s unexpected, dominant ability to mobilize protective CD8 T-cells against highly activated CD4T\n                  <jats:sub>auto<\/jats:sub>\n                  and protect from CNS autoimmune pathology; illustrating a potential therapeutically relevant mechanism by which autoinflammation actively opposes autoimmunity.\n                <\/jats:p>","DOI":"10.64898\/2026.01.26.701759","type":"posted-content","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T23:35:15Z","timestamp":1769643315000},"source":"Crossref","is-referenced-by-count":0,"title":["The innate cytokine IL-18 inhibits CNS autoimmunity through preferential activation of protective CD8 T-cells"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4507-8634","authenticated-orcid":false,"given":"Jeremy A.","family":"Morrissette","sequence":"first","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States"},{"name":"Immunology Graduate Program & Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5396-2532","authenticated-orcid":false,"given":"Vinh","family":"Dang","sequence":"additional","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Huang","sequence":"additional","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jemy","family":"Varghese","sequence":"additional","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States"},{"name":"Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7229-0973","authenticated-orcid":false,"given":"Zachary R.","family":"Lanzar","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0470-7444","authenticated-orcid":false,"given":"Anastasia","family":"Frank-Kamenetskii","sequence":"additional","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3837-5337","authenticated-orcid":false,"given":"Scott W.","family":"Canna","sequence":"additional","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States"},{"name":"Immunology Graduate Program & Institute for Immunology and Immune Health, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020510502429000_2026.01.26.701759v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-030121-041528"},{"key":"2026020510502429000_2026.01.26.701759v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-023-01053-w"},{"key":"2026020510502429000_2026.01.26.701759v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2015.06.005"},{"key":"2026020510502429000_2026.01.26.701759v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/378088a0"},{"key":"2026020510502429000_2026.01.26.701759v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2015.13"},{"key":"2026020510502429000_2026.01.26.701759v1.6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI61029"},{"key":"2026020510502429000_2026.01.26.701759v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0201-4"},{"key":"2026020510502429000_2026.01.26.701759v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.mucimm.2023.05.004"},{"key":"2026020510502429000_2026.01.26.701759v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/77811"},{"key":"2026020510502429000_2026.01.26.701759v1.10","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190669"},{"key":"2026020510502429000_2026.01.26.701759v1.11","doi-asserted-by":"crossref","unstructured":"Elaziz DA , Baran A , Lulecioglu AA , Gervais A , Zhang C , Beziat V , et al. 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