bims-maitce Biomed News
on MAIT cells
Issue of 2025–06–29
two papers selected by
Andy E. Hogan, Maynooth University
  1. A molecular basis underpinning TRBV28+ T cell receptor recognition of MR1-antigen.
  2. Polyunsaturated fatty acid-induced metabolic exhaustion and ferroptosis impair the anti-tumour function of MAIT cells in MASLD.
  1. J Biol Chem. 2025 Jun 24. pii: S0021-9258(25)02266-5. [Epub ahead of print] 110416
    A molecular basis underpinning TRBV28+ T cell receptor recognition of MR1-antigen.
    Wael Awad, Nicholas A Gherardin, Lisa Ciacchi, Andrew N Keller, Ligong Liu, David P Fairlie, James McCluskey, Dale I Godfrey, Jamie Rossjohn.
      Mucosal-associated invariant T (MAIT) cells express a TRAV1-2+ T cell receptor (TCR) that recognises microbial vitamin B2-derivatives presented by the MHC class I-related molecule, MR1. Most MAIT TCRs incorporate a biased TCR-β repertoire, predominantly TRBV20-1 and TRBV6, but some utilise other TRBV genes, including TRBV28. A second conserved, albeit less frequent TRAV36+ TRBV28+ T cell population exhibits MAIT-like phenotypic features but use a markedly distinct mode of MR1-antigen-recognition compared to MAIT TCR-MR1 binding. Nevertheless, our understanding of how differing TCR gene usage results in altered MR1 binding modes remains incomplete. Here, binding studies demonstrated differential affinities and antigen-specificities between TRBV6+ and TRBV28+ MR1-restricted TCRs. Alanine-scanning mutagenesis on the TRAV36-TRBV28 TCR, revealed a strong dependence on germline-encoded residues within the highly selected CDR3α loop, similar to TRAV1-2- TRBV6 TCRs, and further alanine-scanning mutagenesis experiments demonstrate differential energetic footprints by these TCRs atop MR1. We determined the crystal structure of a MAIT TRAV1-2-TRBV28+ TCR-MR1-5-OP-RU ternary complex. This structure revealed a docking mode conserved amongst other TRAV1-2+ MAIT TCRs, with the TRBV28-encoded TCR-β chain adopting highly distinct docking modes between the TRAV1-2+ and TRAV36+ TCRs. This indicates that the TCR-α chain dictates the positioning and role of the TCR-β chain. Taken together, these findings provide new molecular insights into MR1-Ag driven selection of paired TCR-α and TCR-β chains.
    Keywords:  Antigen presentation; MAIT; MHC-related molecule 1 (MR1); TCR; protein structure
    DOI:  https://doi.org/10.1016/j.jbc.2025.110416
  2. J Hepatol. 2025 Jun 19. pii: S0168-8278(25)02273-1. [Epub ahead of print]
    Polyunsaturated fatty acid-induced metabolic exhaustion and ferroptosis impair the anti-tumour function of MAIT cells in MASLD.
    Sebastian Deschler, Junika Pohl-Topcu, Lukas Ramsauer, Philippa Meiser, Sophia Erlacher, Robin P Schenk, H Carlo Maurer, Peng Shen, Juliane Kager, Joseph Zink, Karyna Pistrenko, Enric Redondo Monte, Julius Weber, Lena Wasmaier, Melanie Laschinger, Norbert Hüser, Fabian Geisler, Douglas Thorburn, Hanno Nieß, Gabriela M Wiedemann, Hans Zischka, Mathias Heikenwälder, Karin Kleigrewe, Carolin Mogler, Jan P Böttcher, Percy A Knolle, Roland M Schmid, Katrin Böttcher.
       BACKGROUND & AIMS: Mucosal-associated invariant T (MAIT) cells constitute a highly abundant innate-like T cell population in the human liver that is critical for immune surveillance of hepatic cancers but often dysfunctional in human hepatocellular carcinoma (HCC) for unclear reasons. Here, we sought to determine mechanisms that drive MAIT cells dysfunction in metabolic dysfunction-associated steatotic liver disease (MASLD), a chronic liver disease predisposing patients for HCC development.
    METHODS: We studied MAIT cell functionality, metabolism and anti-cancer activity directly ex vivo in patients with MASLD, as well as in co-culture models mimicking MASLD. (Single-cell) RNA sequencing was used for translation into clinical cohorts of patients with MASLD and MASLD-associated HCC.
    RESULTS: We show that MAIT cells have lost their effector functions in patients with MASLD. We uncover that MAIT cell dysfunction is caused by MASLD-associated polyunsaturated fatty acids (PUFAs), which selectively accumulate in MAIT cells but not conventional CD8+ T cells or NK cells. Mechanistically, PUFAs drive MAIT cell dysfunction through intracellular formation of lipid peroxides that promote a state of 'metabolic exhaustion' characterised by compromised mitochondrial respiration and glycolysis in MAIT cells. Excessive signalling through this MASLD-PUFA-lipid peroxide axis results in MAIT cell death by ferroptosis. Interference with PUFA-induced lipid peroxide formation in MAIT cells reversed their metabolic exhaustion and prevented ferroptotic MAIT cell death, thereby restoring MAIT cell effector function and anti-cancer activity. In patients with HCC, high enrichment of the MAIT cell-PUFA gene signature linked to MAIT cell dysfunction was associated with poor survival.
    CONCLUSIONS: Our findings uncover a novel immunometabolic axis that serves as a functional barrier for MAIT cell-mediated anti-cancer immunity and could be exploited for enhancement of immunotherapy. IMPACT AND IMPLICATIONS: ; This study identifies a novel immunometabolic axis by which polyunsaturated fatty acids (PUFAs) accumulating in MASLD liver tissue drive MAIT cell dysfunction through lipid peroxide-induced metabolic exhaustion and ferroptosis, thereby impairing their anti-tumour activity. These findings reveal how MASLD creates an immune-permissive environment that may facilitate HCC development and -progression. Targeting the PUFA-lipid peroxide axis could restore MAIT cell function and enhance current immunotherapeutic anti-cancer strategies.
    Keywords:  HCC; MAIT cells; MASLD; ferroptosis; immunometabolism; lipid peroxidation
    DOI:  https://doi.org/10.1016/j.jhep.2025.06.006
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