{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:15:59Z","timestamp":1791605759279,"version":"4.3.4"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"51","license":[{"start":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T00:00:00Z","timestamp":1574726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2014-6722"],"award-info":[{"award-number":["2014-6722"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2018-02475"],"award-info":[{"award-number":["2018-02475"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2016-03052"],"award-info":[{"award-number":["2016-03052"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["2017\/777"],"award-info":[{"award-number":["2017\/777"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,12,17]]},"abstract":"<jats:p>Streptococcal toxic shock syndrome (STSS) is a rapidly progressing, life-threatening, systemic reaction to invasive infection caused by group A streptococci (GAS). GAS superantigens are key mediators of STSS through their potent activation of T cells leading to a cytokine storm and consequently vascular leakage, shock, and multiorgan failure. Mucosal-associated invariant T (MAIT) cells recognize MR1-presented antigens derived from microbial riboflavin biosynthesis and mount protective innate-like immune responses against the microbes producing such metabolites. GAS lack de novo riboflavin synthesis, and the role of MAIT cells in STSS has therefore so far been overlooked. Here we have conducted a comprehensive analysis of human MAIT cell responses to GAS, aiming to understand the contribution of MAIT cells to the pathogenesis of STSS. We show that MAIT cells are strongly activated and represent the major T cell source of IFN\u03b3 and TNF in the early stages of response to GAS. MAIT cell activation is biphasic with a rapid TCR V\u03b22-specific, TNF-dominated response to superantigens and a later IL-12- and IL-18-dependent, IFN\u03b3-dominated response to both bacterial cells and secreted factors. Depletion of MAIT cells from PBMC resulted in decreased total production of IFN\u03b3, IL-1\u03b2, IL-2, and TNF\u03b2. Peripheral blood MAIT cells in patients with STSS expressed elevated levels of the activation markers CD69, CD25, CD38, and HLA-DR during the acute compared with the convalescent phase. Our data demonstrate that MAIT cells are major contributors to the early cytokine response to GAS, and are therefore likely to contribute to the pathological cytokine storm underlying STSS.<\/jats:p>","DOI":"10.1073\/pnas.1910883116","type":"journal-article","created":{"date-parts":[[2019,11,26]],"date-time":"2019-11-26T17:26:10Z","timestamp":1574789170000},"page":"25923-25931","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":65,"title":["MAIT Cells Are Major Contributors to the Cytokine Response in Group A Streptococcal Toxic Shock Syndrome"],"prefix":"10.1073","volume":"116","author":[{"given":"Johanna","family":"Emg\u00e5rd","sequence":"first","affiliation":[{"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 141 52 Huddinge, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Bergsten","sequence":"additional","affiliation":[{"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 141 52 Huddinge, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3742-7289","authenticated-orcid":false,"given":"John K.","family":"McCormick","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Western University, London, ON N6A 5C1, Canada;"},{"name":"Lawson Health Research Institute, London, ON N6C 2R5, Canada;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israel","family":"Barrantes","sequence":"additional","affiliation":[{"name":"Microbial Interactions and Processes Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;"},{"name":"Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center, 18057 Rostock, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steinar","family":"Skrede","sequence":"additional","affiliation":[{"name":"Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway;"},{"name":"Department of Clinical Science, University of Bergen, N-5020 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6275-0750","authenticated-orcid":false,"given":"Johan K.","family":"Sandberg","sequence":"additional","affiliation":[{"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 141 52 Huddinge, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9372-1795","authenticated-orcid":false,"given":"Anna","family":"Norrby-Teglund","sequence":"additional","affiliation":[{"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 141 52 Huddinge, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,11,26]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1128\/CMR.00101-13","article-title":"Disease manifestations and pathogenic mechanisms of Group A Streptococcus","volume":"27","author":"Walker M. 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