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The classic example is toxic shock syndrome, a life-threatening complication of <jats:italic>Staphylococcus aureus<\/jats:italic> or <jats:italic>Streptococcus pyogenes<\/jats:italic> infection, which is driven by potent toxins known as superantigens (SAgs). SAgs are thought to promote immune evasion via the promiscuous activation of T cells, which subsequently become hyporesponsive, and act by cross-linking major histocompatibility complex class II molecules on antigen-presenting cells to particular \u03b2-chain variable (TRBV) regions of \u03b1\u03b2 T cell receptors (TCRs). Although some of these interactions have been defined previously, our knowledge of SAg-responsive TRBV regions is incomplete. In this study, we found that CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells expressing TRBV12-3\/12-4<jats:sup>+<\/jats:sup> TCRs were highly responsive to streptococcal pyrogenic exotoxin C (SpeC) and toxic shock syndrome toxin-1 (TSST-1). In particular, SpeC and TSST-1 specifically induced effector cytokine production and the upregulation of multiple coinhibitory receptors among TRBV12-3\/12-4<jats:sup>+<\/jats:sup> CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> memory T cells, and importantly, these biological responses were dependent on human leukocyte antigen (HLA)-DR. Collectively, these data provided evidence of functionally determinative and therapeutically relevant interactions between SpeC and TSST-1 and\u00a0CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> memory T cells expressing TRBV12-3\/12-4<jats:sup>+<\/jats:sup> TCRs, mediated via HLA-DR.<\/jats:p>","DOI":"10.1038\/s42003-023-04420-1","type":"journal-article","created":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T00:46:24Z","timestamp":1674261984000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The superantigens SpeC and TSST-1 specifically activate TRBV12-3\/12-4+ memory T cells"],"prefix":"10.1038","volume":"6","author":[{"given":"Freya R.","family":"Shepherd","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9807-1231","authenticated-orcid":false,"given":"Kate","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly L.","family":"Miners","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sian","family":"Llewellyn-Lacey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Kollnberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5492-2869","authenticated-orcid":false,"given":"James E.","family":"Redman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa M.","family":"Grant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9856-2938","authenticated-orcid":false,"given":"Kristin","family":"Ladell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9416-2737","authenticated-orcid":false,"given":"David A.","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7021-5934","authenticated-orcid":false,"given":"James E.","family":"McLaren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,20]]},"reference":[{"key":"4420_CR1","doi-asserted-by":"publisher","first-page":"629193","DOI":"10.3389\/fimmu.2021.629193","volume":"12","author":"M Olbei","year":"2021","unstructured":"Olbei, M. et al. 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