{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T09:36:55Z","timestamp":1792575415152,"version":"4.5.0"},"reference-count":76,"publisher":"American Society of Hematology","issue":"5","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,7,31]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome arising in many contexts. Its underlying mechanisms are often unclear, but defective granule-mediated cytotoxicity (familial HLH) and excess interleukin-18 (IL-18; macrophage activation syndrome) provide clues. Mounting evidence suggests the causes of HLH converge on cytotoxic T lymphocyte (CTL) hyperactivation and interferon gamma (IFN-\u03b3) overproduction. We refined an in vitro system to simultaneously quantify multiple parameters of the murine CTL immune synapse (IS). Even in haploinsufficiency, perforin deficiency prolonged IS duration and increased IFN-\u03b3\/tumor necrosis factor production. Similarly, both target cell immortalization and inhibition of apoptotic caspases impaired IS termination and increased cytokine production. Strong CTL activation, through T-cell receptor or IL-18 signaling, also increased IFN-\u03b3 secretion but accelerated target cell death. Impaired IS termination synergized with strong CTL activation in driving IFN-\u03b3 production. Visually, both typical and Prf1\u2013\/\u2013 CTL-IS terminated with apoptotic contraction. Serendipitously, we observed many IL-18\u2013exposed CTL-IS terminated by target cell ballooning. Both IL-18\u2013activated CTL and IFN-\u03b3 pretreatment caused up to half of target cells to die by receptor-interacting protein kinase 1 (RIPK1)\u2013dependent necroptosis. In vivo, RIPK1 inhibition ameliorated virus-triggered HLH in Il18tg more than Prf1\u2013\/\u2013 mice. By quantifying CTL-IS duration, cytokine production, and mode of cell death, we modeled multiple HLH contributors and their interactions and identified 3 HLH mechanistic categories: impaired IS termination, intense CTL cytokine production, and inflammatory target cell death. Integrating the inputs and outcomes of a hyperinflammatory CTL-IS may provide a useful framework for understanding, predicting, or treating HLH in its many forms.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024027179","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T16:07:02Z","timestamp":1747152422000},"page":"558-570","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":10,"title":["Modeling the HLH immune synapse uncovers critical roles for IS termination, cytokine intensity, and target cell death"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0470-7444","authenticated-orcid":false,"given":"Anastasia","family":"Frank-Kamenetskii","sequence":"first","affiliation":[{"name":"1Division of Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"},{"name":"2Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Klinghoffer","sequence":"additional","affiliation":[{"name":"1Division of Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"},{"name":"2Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jemy","family":"Varghese","sequence":"additional","affiliation":[{"name":"1Division of Rheumatology and 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":"1Division of Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4507-8634","authenticated-orcid":false,"given":"Jeremy","family":"Morrissette","sequence":"additional","affiliation":[{"name":"1Division of Rheumatology and Immune Dysregulation, Children\u2019s Hospital of Philadelphia, Philadelphia, PA"},{"name":"2Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7900-8993","authenticated-orcid":false,"given":"Joseph A.","family":"Fraietta","sequence":"additional","affiliation":[{"name":"3Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"},{"name":"4Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"},{"name":"5Parker Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8005-3836","authenticated-orcid":false,"given":"Caroline","family":"Diorio","sequence":"additional","affiliation":[{"name":"6Division of Pediatric Oncology, Children\u2019s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8176-1375","authenticated-orcid":false,"given":"Janis K.","family":"Burkhardt","sequence":"additional","affiliation":[{"name":"7Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3837-5337","authenticated-orcid":false,"given":"Scott 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