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However, their role in immune defense against\n                      <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                      and the impact of bacterial immune evasion mechanisms are incompletely understood. Here, we have investigated MAIT cell responses to\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      and the impact of its broadly expressed leukocidin toxin HlgAB on MAIT cell responses in different human tissue sites. MAIT cells respond to\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      with a complex polyfunctional profile spanning proinflammatory IL-17, TNF, and IFN\u03b3, anti-inflammatory IL-10, plus granzymes A, B, and K, perforin, and granulysin. The quality of responses was influenced by the microbial dose and time of exposure and was dependent on both MR1-presented antigen and cytokine co-activation. CD56\n                      <jats:sup>+<\/jats:sup>\n                      MAIT cells displayed stronger effector responses and higher HlgAB sensitivity compared to CD56\u207b cells. MAIT cells were partially resistant to HlgAB-toxicity compared to monocytes; blood-derived MAIT cells remained susceptible, whereas tonsillar MAIT cells showed minimal sensitivity. Notably, activation reduced the MAIT cell susceptibility to HlgAB, and such activation also afforded indirect protection to monocytes in co-cultures. The reduced susceptibility of tonsillar MAIT cells correlated with lower CCR2 and CXCR1 expression, a pattern shared with barrier tissues such as the lung and intestines. In conclusion, these findings indicate that MAIT cells exhibit tissue- and context-dependent responses to\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      and sensitivity to HlgAB-mediated immune evasion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Mucosa-associated invariant T (MAIT) cells are an evolutionarily conserved unconventional T cell subset that responds to riboflavin pathway-derived antigens from a range of microbes. Here, we found that the human MAIT cell response to the pathogen\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      is robust with the polyfunctional complexity influenced by bacterial concentration and response kinetics. The ubiquitously expressed\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      immune-evasive toxin HlgAB attacks MAIT cells via CCR2. However, the sensitivity of MAIT cells to HlgAB varies depending on tissue localization, where in particular tissue-resident MAIT cells in tonsils are resistant. Antigen-specific activation of MAIT cells reduces HlgAB sensitivity, with protection also afforded to monocytes in the vicinity. These findings uncover the complex and dynamic interaction between an evolutionarily conserved arm of immunity and immune evasion mechanisms of the important pathogen\n                      <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00663-26","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T13:03:17Z","timestamp":1789650197000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["MAIT cell responses to\n                    <i>Staphylococcus aureus<\/i>\n                    and sensitivity to HlgAB toxin are modulated by activation and tissue-dependent virulence effects"],"prefix":"10.1128","volume":"17","author":[{"given":"Elisa J. M.","family":"Raineri","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Boulouis","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elli","family":"Mouchtaridi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Nils\u00e9n","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet","place":["Stockholm, Sweden"]},{"id":[{"id":"https:\/\/ror.org\/00m8d6786","id-type":"ROR","asserted-by":"publisher"}],"name":"ME Transplantation, Karolinska University Hospital Huddinge","place":["Stockholm, Sweden"]},{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Science, Intervention and Technology, Karolinska Institutet","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis","family":"Cai","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Infectious Medicine, 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and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Bassett","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Stamper","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey Y. W.","family":"Mak","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00rqy9422","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Chemistry and Drug Discovery, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, The University of Queensland","place":["Brisbane, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David P.","family":"Fairlie","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00rqy9422","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Chemistry and Drug Discovery, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, The University of Queensland","place":["Brisbane, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Tibbitt","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9372-1795","authenticated-orcid":true,"given":"Anna","family":"Norrby-Teglund","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Marquardt","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny","family":"Mj\u00f6sberg","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Infectious Medicine, Department of Medicine, Karolinska Institutet","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Jorns","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00m8d6786","id-type":"ROR","asserted-by":"publisher"}],"name":"ME Transplantation, Karolinska University Hospital Huddinge","place":["Stockholm, Sweden"]},{"id":[{"id":"https:\/\/ror.org\/056d84691","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical Science, Intervention and Technology, Karolinska Institutet","place":["Stockholm, 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