{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:52:42Z","timestamp":1790628762733,"version":"4.1.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":13,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Ka 502\/19-3"],"award-info":[{"award-number":["Ka 502\/19-3"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ImCheck Therapeutics"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The activation of human V\u03b42 \u03b3\u03b4 T cells by phosphoantigens (pAg) strictly depends on transmembrane butyrophilin (BTN) molecules, specifically BTN3A isoforms and BTN2A1. Several bacteria, including M. tuberculosis, produce potent pAg and thus trigger a strong activation of V\u03b42 T cells. The antigen-specific activation of CD4 and regulatory (Treg) T cells can be monitored by the rapid upregulation of CD154 and CD137, respectively. We have previously established that CD137 is also rapidly upregulated on V\u03b42 T cells upon stimulation with pAg. In the present study, we have used antagonistic anti-BTN3A\/2A1 antibodies to dissect the pAg-dependent and pAg-independent activation of V\u03b42 T cells by various microbes. While the activation of V\u03b42 T cells by pAg and aminobisphosphonate zoledronate was completely blocked by anti-BTN3A\/2A1 antibodies, only partial inhibition was observed for activation with M. tuberculosis and other bacteria as analyzed by CD137\/CD154 upregulation and intracellular interferon-\u03b3 expression. Similarly, anti-TCR antibody 7A5 and Lck inhibitor emodin had only a minimal inhibitory effect on activation by bacteria but strongly reduced pAg activation of V\u03b42 T cells. Further studies revealed a crucial role of IL-18 in the BTN\/TCR-independent early activation of V\u03b42 T cells by bacteria. Neutralizing anti-IL-18 antibodies and inflammasome inhibition did not affect pAg activation of V\u03b42 T cells but strongly reduced their activation by bacteria. Our results identify a BTN\/TCR-independent but IL-18 and inflammasome-dependent activation pathway of V\u03b42 T cells, which might be relevant for the role of V\u03b42 T cells during bacterial infections.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgaf358","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T08:10:42Z","timestamp":1763021442000},"source":"Crossref","is-referenced-by-count":4,"title":["Butyrophilin 3A\/2A1-independent activation of human V\u03b39V\u03b42 \u03b3\u03b4 T cells by bacteria"],"prefix":"10.1093","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0815-6582","authenticated-orcid":false,"given":"Daniel","family":"Gombert","sequence":"first","affiliation":[{"name":"Institute of Immunology, Christian-Albrechts-University and University Hospital Schleswig-Holstein Campus Kiel , Kiel 24105 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9033-6394","authenticated-orcid":false,"given":"Jara","family":"Simeonov","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Christian-Albrechts-University and University Hospital Schleswig-Holstein Campus Kiel , Kiel 24105 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9450-5987","authenticated-orcid":false,"given":"Katharina","family":"Klein","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Christian-Albrechts-University and University Hospital Schleswig-Holstein Campus Kiel , Kiel 24105 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6642-2810","authenticated-orcid":false,"given":"Sophie","family":"Agaugu\u00e9","sequence":"additional","affiliation":[{"name":"ImCheck Therapeutics , Marseille 13009 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0626-343X","authenticated-orcid":false,"given":"Alexander","family":"Scheffold","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Christian-Albrechts-University and University Hospital Schleswig-Holstein Campus Kiel , Kiel 24105 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4160-7103","authenticated-orcid":false,"given":"Dieter","family":"Kabelitz","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Christian-Albrechts-University and University Hospital Schleswig-Holstein Campus Kiel , Kiel 24105 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