MAIT cell responses to Staphylococcus aureus and sensitivity to HlgAB toxin are modulated by activation and tissue-dependent virulence effects

@article{raineri2026mait,
  title = {{MAIT cell responses to Staphylococcus aureus and sensitivity to HlgAB toxin are modulated by activation and tissue-dependent virulence effects}},
  author = {Elisa J. M. Raineri and Caroline Boulouis and Elli Mouchtaridi and Vera Nilsén and Curtis Cai and Tobias Kammann and Juliette Tabusse and Takuya Sekine and Nicole Wild and Christian Constantz and Eoghann White and Thomas R. Müller and Anne Marchalot and Sabrina Ferreira and Jyotsana Kaushal and Akhirunnesa Mily and Miriam Franklin and Elena Bonaiti and Mary-Lyn Eichhorn and John Bassett and Chris Stamper and Jeffrey Y. W. Mak and David P. Fairlie and Chris Tibbitt and Anna Norrby-Teglund and Nicole Marquardt and Jenny Mjösberg and Carl Jorns and Jenny Driving and Edwin Leeansyah and Marcus Buggert and Johan K. Sandberg},
  journal = {mBio},
  year = {2026},
  month = sep,
  doi = {10.1128/mbio.00663-26},
  url = {https://doi.org/10.1128/mbio.00663-26},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - MAIT cell responses to Staphylococcus aureus and sensitivity to HlgAB toxin are modulated by activation and tissue-dependent virulence effects
AU  - Elisa J. M. Raineri
AU  - Caroline Boulouis
AU  - Elli Mouchtaridi
AU  - Vera Nilsén
AU  - Curtis Cai
AU  - Tobias Kammann
AU  - Juliette Tabusse
AU  - Takuya Sekine
AU  - Nicole Wild
AU  - Christian Constantz
AU  - Eoghann White
AU  - Thomas R. Müller
AU  - Anne Marchalot
AU  - Sabrina Ferreira
AU  - Jyotsana Kaushal
AU  - Akhirunnesa Mily
AU  - Miriam Franklin
AU  - Elena Bonaiti
AU  - Mary-Lyn Eichhorn
AU  - John Bassett
AU  - Chris Stamper
AU  - Jeffrey Y. W. Mak
AU  - David P. Fairlie
AU  - Chris Tibbitt
AU  - Anna Norrby-Teglund
AU  - Nicole Marquardt
AU  - Jenny Mjösberg
AU  - Carl Jorns
AU  - Jenny Driving
AU  - Edwin Leeansyah
AU  - Marcus Buggert
AU  - Johan K. Sandberg
PY  - 2026
DA  - 2026/09/17
JO  - mBio
DO  - 10.1128/mbio.00663-26
UR  - https://doi.org/10.1128/mbio.00663-26
AB  - Mucosa-associated invariant T (MAIT) cells are unconventional T cells with innate-like rapid antimicrobial effector functions and serve as resident sentinels at mucosal and non-mucosal barriers. However, their role in immune defense against Staphylococcus aureus and the impact of bacterial immune evasion mechanisms are incompletely understood. Here, we have investigated MAIT cell responses to S. aureus and the impact of its broadly expressed leukocidin toxin HlgAB on MAIT cell responses in different human tissue sites. MAIT cells respond to S. aureus with a complex polyfunctional profile spanning proinflammatory IL-17, TNF, and IFNγ, 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+ MAIT cells displayed stronger effector responses and higher HlgAB sensitivity compared to CD56⁻ 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 S. aureus and sensitivity to HlgAB-mediated immune evasion.  IMPORTANCE: 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 S. aureus is robust with the polyfunctional complexity influenced by bacterial concentration and response kinetics. The ubiquitously expressed S. aureus 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 S. aureus.
SN  - 2150-7511
ER  -