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We hypothesized that understanding how these susceptibility factors synergize would uncover key pathomechanisms in the activation, function, and persistence of hyperactivated CD8\u00a0T cells. In IL-18 transgenic (Il18tg) mice, IL-18 effects on CD8\u00a0T cells drove MAS after a viral (lymphocytic choriomeningitis virus), but not innate (toll like receptor 9), trigger. In\u00a0vitro, CD8\u00a0T cells also required T-cell receptor (TCR) stimulation to fully respond to IL-18. IL-18 induced but perforin deficiency impaired immunoregulatory restimulation-induced cell death (RICD). Paralleling hyperinflammation, DS mice displayed massive postthymic oligoclonal CD8 T-cell hyperactivation in their spleens, livers, and bone marrow as early as 3\u00a0weeks. These cells increased proliferation and interferon gamma production, which contrasted with increased expression of receptors and transcription factors associated with exhaustion. Broad-spectrum antibiotics and antiretrovirals failed to ameliorate the disease. Attempting to genetically \u201cfix\u201d TCR antigen-specificity instead demonstrated the persistence of spontaneous HLH and hyperactivation, chiefly on T cells that had evaded TCR fixation. Thus, drivers of HLH may preferentially act on CD8\u00a0T cells: IL-18 amplifies activation and demand for RICD, whereas perforin supplies critical immunoregulation. Together, these factors promote a terminal CD8 T-cell activation state, combining features of exhaustion and effector function. Therefore, susceptibility to hyperinflammation may converge on a unique, unrelenting, and antigen-dependent state of CD8 T-cell hyperactivation.<\/jats:p>","DOI":"10.1182\/bloodadvances.2023010502","type":"journal-article","created":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T16:45:23Z","timestamp":1695401123000},"page":"6949-6963","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":17,"title":["Complementary HLH susceptibility factors converge on CD8 T-cell hyperactivation"],"prefix":"10.1182","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7635-7781","authenticated-orcid":false,"given":"Emily","family":"Landy","sequence":"first","affiliation":[{"name":"1Department of Immunology, University of Pittsburgh, Pittsburgh, PA"},{"name":"2Graduate Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jemy","family":"Varghese","sequence":"additional","affiliation":[{"name":"3Rheumatology & Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5396-2532","authenticated-orcid":false,"given":"Vinh","family":"Dang","sequence":"additional","affiliation":[{"name":"3Rheumatology & Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Szymczak-Workman","sequence":"additional","affiliation":[{"name":"1Department of Immunology, University of Pittsburgh, Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5198-516X","authenticated-orcid":false,"given":"Lawrence P.","family":"Kane","sequence":"additional","affiliation":[{"name":"1Department of Immunology, University of Pittsburgh, Pittsburgh, PA"}],"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":"3Rheumatology & Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"},{"name":"4Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2023,11,17]]},"reference":[{"issue":"1","key":"2023112812511798000_bib1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene Expression Omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res"},{"issue":"136","key":"2023112812511798000_bib2","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1136\/adc.27.136.519","article-title":"Familial haemophagocytic reticulosis","volume":"27","author":"Farquhar","year":"1952","journal-title":"Arch Dis Child"},{"issue":"3","key":"2023112812511798000_bib3","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.jaip.2018.11.050","article-title":"Hemophagocytic lymphohistiocytosis: clinical presentations and diagnosis","volume":"7","author":"Risma","year":"2019","journal-title":"J\u00a0Allergy Clin Immunol Pract"},{"issue":"2","key":"2023112812511798000_bib4","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1002\/pbc.21039","article-title":"HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis","volume":"48","author":"Henter","year":"2007","journal-title":"Pediatr Blood Cancer"},{"issue":"5","key":"2023112812511798000_bib5","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.jaci.2020.09.016","article-title":"Highways to hell: mechanism-based management of cytokine storm syndromes","volume":"146","author":"Canna","year":"2020","journal-title":"J\u00a0Allergy Clin Immunol"},{"issue":"3","key":"2023112812511798000_bib6","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/(SICI)1096-911X(199709)29:3<157::AID-MPO1>3.0.CO;2-C","article-title":"Contemporary classification of histiocytic disorders. 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