{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:42:14Z","timestamp":1792514534055,"version":"4.5.0"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:00:00Z","timestamp":1792454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"US National Institutes of Health","award":["R01HD098428"],"award-info":[{"award-number":["R01HD098428"]}]},{"name":"UPMC Children's Hospital\/ RK Mellon Institute for Pediatric Research","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]},{"name":"CHOP Research Institute","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Hemophagocytic Lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with multiple contributors, often including an infectious trigger. The Macrophage Activation Syndrome (MAS) subtype is linked to marked IL-18 excess, cytotoxic T-lymphocyte (CTL) activation, and natural killer (NK) cell abnormalities. We asked how excess IL-18 shapes NK and CTL responses to viral challenge. Mice with chronic IL-18 overproduction (\n                    <jats:italic>\n                      Il18\n                      <jats:sup>tg<\/jats:sup>\n                    <\/jats:italic>\n                    ), showed baseline NK-cytopenia and CTL activation resembling MAS-susceptible patients. NK transcriptomes reflected IL-18\/IFNg-axis activation and cell cycle upregulation. LCMV infection of\n                    <jats:italic>\n                      Il18\n                      <jats:sup>tg<\/jats:sup>\n                    <\/jats:italic>\n                    mice causes HLH\/MAS without affecting viral control, but is not a significant NK challenge. Early after infection with NK-dependent mousepox,\n                    <jats:italic>\n                      Il18\n                      <jats:sup>tg<\/jats:sup>\n                    <\/jats:italic>\n                    NKs failed to activate appropriately, but CTLs quickly hyperactivated and mousepox control remained intact. Mousepox-infected\n                    <jats:italic>\n                      Il18\n                      <jats:sup>tg<\/jats:sup>\n                    <\/jats:italic>\n                    mice then developed signs of HLH\/MAS including hepatosplenic necrosis. Their viral control was impaired, possibly because they failed to expand mousepox-specific CTLs.\n                    <jats:italic>\n                      Il18bp\n                      <jats:sup>KO<\/jats:sup>\n                    <\/jats:italic>\n                    mice, despite more normal resting lymphocytes, succumbed similarly to viremic HLH\/MAS. Transfer of pre-activated NKs into\n                    <jats:italic>\n                      Il18\n                      <jats:sup>tg<\/jats:sup>\n                    <\/jats:italic>\n                    mice partially rescued virus-specific CTL responses, viral control, and survival. Thus, excess IL-18 contributes to HLH\/MAS via disparate effects on CTL and NK cells, demonstrating a novel, context-specific NK immunodeficiency and highlighting how subtle host-pathogen interactions can affect the mechanisms and treatment rationale of life-threatening HLH\/MAS.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.199201","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:00:48Z","timestamp":1792512048000},"source":"Crossref","is-referenced-by-count":0,"title":["Excess IL-18 drives fatal mousepox cytokine storm via NK cell immunodeficiency and nonspecific T-cell hyperactivation"],"prefix":"10.1172","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0073-8780","authenticated-orcid":true,"given":"Jemy A.","family":"Varghese","sequence":"first","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children's Hospital of Philadelphia, Philadelphia, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Huang","sequence":"additional","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Carro","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Philadelphia, Philadelphia, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily E.","family":"Landy","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Pittsburgh, Pittsburgh, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Frank-Kamenetskii","sequence":"additional","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Klinghoffer","sequence":"additional","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy A.","family":"Morrissette","sequence":"additional","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinh","family":"Dang","sequence":"additional","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence C.","family":"Eisenlohr","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Philadelphia, Philadelphia, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3837-5337","authenticated-orcid":true,"given":"Scott W.","family":"Canna","sequence":"additional","affiliation":[{"name":"Rheumatology and Immune Dysregulation, Children's Hospital of Philadelphia, Philadelphia, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,10,20]]},"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/insight.jci.org\/articles\/view\/199201\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:00:49Z","timestamp":1792512049000},"score":1,"resource":{"primary":{"URL":"http:\/\/insight.jci.org\/articles\/view\/199201"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,20]]},"references-count":0,"alternative-id":["10.1172\/jci.insight.199201"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.199201","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,20]]}}}