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The role of T and NK-cells in protection\/immunopathogenesis remains unclear for dengue. We performed a longitudinal phenotypic, functional and transcriptional analyses of T and NK-cells in 124 dengue patients using flow cytometry and single-cell RNA-sequencing. We show that T\/NK-cell signatures early in infection discriminate patients who develop severe dengue (SD) from those who do not. These signatures are exacerbated in patients with overweight\/obesity compared to healthy weight patients, supporting their increased susceptibility to SD. In SD, CD4\n                    <jats:sup>+<\/jats:sup>\n                    \/CD8\n                    <jats:sup>+<\/jats:sup>\n                    T-cells and NK-cells display increased co-inhibitory receptor expression and decreased cytotoxic potential compared to non-SD. Using transcriptional and proteomics approaches we show decreased type-I Interferon responses in SD, suggesting defective innate immunity may underlie NK\/T-cell dysfunction. We propose that dysfunctional T and NK-cell signatures underpin dengue pathogenesis and may represent novel targets for immunomodulatory therapy in dengue.\n                  <\/jats:p>","DOI":"10.1038\/s41467-025-60941-9","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T07:26:16Z","timestamp":1751354776000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight"],"prefix":"10.1038","volume":"16","author":[{"given":"Michaela","family":"Gregorova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Santopaolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6461-252X","authenticated-orcid":false,"given":"Lucy C.","family":"Garner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1627-9187","authenticated-orcid":false,"given":"Rahma F.","family":"Hayati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Diamond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narayan","family":"Ramamurthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vi Thuy","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5960-7849","authenticated-orcid":false,"given":"Nguyet Minh","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5418-5392","authenticated-orcid":false,"given":"Kate J.","family":"Heesom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2684-3041","authenticated-orcid":false,"given":"Vuong Lam","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eben","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7668-3917","authenticated-orcid":false,"given":"Mike","family":"Nsubuga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0893-7311","authenticated-orcid":false,"given":"Curtis","family":"Luscombe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8694-5272","authenticated-orcid":false,"given":"Hoa Thi My","family":"Vo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanh Quang","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chau Thi Xuan","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam Thi Hoai","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duyen Thi Le","family":"Huynh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam Thi","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1136-4008","authenticated-orcid":false,"given":"Andrew D.","family":"Davidson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Klenerman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Yacoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6213-9794","authenticated-orcid":false,"given":"Laura","family":"Rivino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"60941_CR1","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1038\/nature12060","volume":"496","author":"S Bhatt","year":"2013","unstructured":"Bhatt, S. et al. 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