bims-maitce Biomed News
on MAIT cells
Issue of 2026–05–03
seven papers selected by
Andy E. Hogan, Maynooth University
  1. Lactate conditioning reprograms mucosal-associated invariant T cell metabolism boosting effector function.
  2. Mucosal-associated invariant T cells drive bile duct inflammation.
  3. Ketogenic diet synergistic reprogramming of both host and microbiome promotes tissue regeneration.
  4. A miniaturized MR1 metabolite display system with native-like protein features.
  5. Protective role of mucosa-associated invariant T cells in sepsis-related liver injury.
  6. Mucosal-Associated Invariant T (MAIT) cells in the Tumor Microenvironment: Opportunities and Challenges.
  7. Tissue-specific adaptation of human T cells is preserved during tissue inflammation.
  1. J Immunol. 2026 Apr 15. pii: vkag073. [Epub ahead of print]215(4):
    Lactate conditioning reprograms mucosal-associated invariant T cell metabolism boosting effector function.
    Ardena Berisha, Benjamin J Jenkins, Nidhi Kedia-Mehta, Eimear K Ryan, Shauna Mayock, Odhran Ryan, Cian Davis, Helen Heneghan, Donal O'Shea, Nicholas Jones, Andrew E Hogan.
      Mucosal-associated invariant T (MAIT) cells are unconventional T cells, which upon activation can display potent cytotoxic and cytokine-producing capabilities. Together, these features make MAIT cells promising candidates for cancer immunotherapy. In this study, we show that MAIT cells can be efficiently amplified in vitro, and these amplified MAIT cells are armed with potent anticancer functions, including the ability to produce significant amounts of effector molecules such as IFNγ and granzyme B. Excitingly, we demonstrate that MAIT cells can be redirected to potently kill cancerous cells using a clinically relevant bispecific monoclonal antibody. Furthermore, in an attempt to metabolically condition MAIT cells to improve function, we demonstrate that MAIT cells possess the molecular machinery to transport and metabolize lactate, an abundant metabolite within the solid tumor microenvironment. Activating MAIT cells in the presence of exogenous sodium lactate remodels their cellular metabolism, with a significant increase in mitochondrial metabolism. Functionally, this supports elevated production of effector molecules (IFNγ, granzymes A and B), leading to boosted engager mediated MAIT cell cytotoxicity. These data collectively show that MAIT cells can be pharmacologically directed to target cancer cells and in vitro conditioning using sodium lactate can enhance their anticancer capabilities through reprogrammed cellular metabolism. Our findings represent a novel strategy for a potential new adoptive cancer immunotherapy.
    Keywords:  BiTEs; immunotherapy; lactate; mucosal associated invariant T cells
    DOI:  https://doi.org/10.1093/jimmun/vkag073
  2. Cell Mol Gastroenterol Hepatol. 2026 Apr 28. pii: S2352-345X(26)00072-X. [Epub ahead of print] 101794
    Mucosal-associated invariant T cells drive bile duct inflammation.
    Kathrine S Nordhus, Fei Zheng, Natalie L Berntsen, Oda Helgesen Ramberg, Laura Valestrand, Jonas Øgaard, Brian K Chung, Xiaojun Jiang, Espen Melum.
       BACKGROUND & AIMS: Mucosal-associated invariant T (MAIT) cells recognize microbial-derived vitamin B metabolites presented by MR1. Since bile from patients with chronic biliary inflammation contain MAIT antigens, we investigated whether intrabiliary MAIT antigen exposure activates MAIT cells and induce pathogenic biliary inflammation.
    METHODS: E.coli, PBS or the known MAIT ligand 5-OP-RU were injected into bile ducts of mice with increased MAIT cell frequencies (Mr1+ B6- MAITCAST and iVα19 Cα-/- Tg). Mice were monitored clinically and liver tissue analyzed after 1-14 days. Portal inflammation was assessed histologically. The immunophenotype of lymphocytes was determined by flow cytometry, and serum liver enzymes were measured. Hepatic MAIT cell transcriptional profiles were analyzed by single-nucleus RNA sequencing (snRNA-seq) RESULTS: Intrabiliary injection of E.coli in iVα19 Cα-/- Tg mice caused cholangitis at day 2, elevated ALT, increased histologic grade of cholangitis and portal accumulation of T-lymphocytes and macrophages. This coincided with marked hepatic MAIT cells activation. Similar signs of experimental cholangitis were observed in mice containing 2% MAIT cells (Mr1+ B6- MAITCAST). Selective activation with 5-OP-RU in iVα19 Cα-/- Tg mice confirmed the MAIT specificity of the inflammatory response. In Mr1+ B6-MAITCAST mice, the MAIT cell frequency was too low to induce biliary inflammation. snRNA-seq of MAIT cells from 5-OP-RU injected iVα19 Cα-/- Tg mice demonstrated antigen-driven transcriptional reprogramming toward a MAIT17-skewed phenotype with enrichment of TCR signaling pathways.
    CONCLUSIONS: MAIT cells can drive pathogenic bile duct inflammation in vivo when locally exposed to antigens. These findings suggest that modulation of MAIT driven immune pathways may represent a therapeutic approach in inflammatory cholangiopathies.
    Keywords:  Bile duct injection; E.coli; MAIT cells; Mr1(+) B6-MAIT(CAST) mice; PSC and 5-OP-RU; cholangitis; iVα19 Cα(−/−) Tg mice
    DOI:  https://doi.org/10.1016/j.jcmgh.2026.101794
  3. bioRxiv. 2026 Apr 13. pii: 2026.04.11.717958. [Epub ahead of print]
    Ketogenic diet synergistic reprogramming of both host and microbiome promotes tissue regeneration.
    Motoyoshi Nagai, Victor Band, Liang Chi, Margery Smelkinson, Benjamin Schwarz, Nathan T Brandes, Andrew Burns, Paula Juliana Perez-Chaparro, Kathryn E McCauley, Dan Corral, Nicolas Bouladoux, Verena M Link, Lixin Zheng, Michael G Constantinides, Michael Otto, Niki M Moutsopoulos, Yasmine Belkaid.
      Nutrition influences host physiological processes, yet how diets reshape host physiology, microbial functions, or host-microbe interactions to promote regeneration remains poorly explored. Here, we show that a ketogenic diet (KD), enriched in fats and low in carbohydrates, reprograms both skin microbial and immune functions to promote tissue repair. KD enhances IL-17A activity in γδ T cells and mucosal-associated invariant T (MAIT) cells, accelerating tissue repair, while KD-induced skin lipidomic alterations enhance both the abundance and metabolic output of Staphylococcus epidermidis . Metatranscriptomic and lipidomic analyses revealed increased riboflavin biosynthesis and sphingomyelinase (Sph)-dependent ceramide production in S. epidermidis under KD conditions. Genetic depletion of microbial ribD, a key enzyme for riboflavin biosynthesis, or of sph compromised the ability of the bacteria to promote tissue repair. Thus, host nutritional status drives tissue regeneration by synergistically rewiring host and microbial functions, providing new insights into how diet can be harnessed to regulate host physiology.
    DOI:  https://doi.org/10.64898/2026.04.11.717958
  4. bioRxiv. 2026 Apr 15. pii: 2026.04.13.718121. [Epub ahead of print]
    A miniaturized MR1 metabolite display system with native-like protein features.
    Photis Rotsides, Omkar Shinde, Julia N Danon, Nikolaos G Sgourakis.
      Major histocompatibility complex class I-related protein 1 (MR1) presents metabolite-derived antigens to mucosal-associated invariant T (MAIT) cells and other MR1-restricted T cells, playing a critical role in immune surveillance during infection and disease. Biochemical and structural studies of MR1 have been limited by the intrinsic instability of the molecule, which requires both ligand binding and association with beta-2-microglobulin (β 2 m) for proper folding and stability. Here, we adapt MR1 to the SMART protein platform to generate a minimalistic system for studying MR1 ligand presentation and T cell receptor (TCR) recognition. SMART-MR1 consists of the MR1 α 1 /α 2 ligand-binding platform fused to a helical stabilizing domain that functionally replaces the α 3 and β 2 m domains, resulting in a truncated protein that preserves the architecture of the antigen-binding groove. We show that SMART-MR1 can be efficiently produced recombinantly and retains the ability to bind chemically diverse classes of MR1 ligands. The reduced size of SMART-MR1 enables amide-based solution NMR experiments, and its simplified structure allows for ligand screening using fluorescence polarization. Importantly, SMART-MR1 maintains binding to the MAIT-derived A-F7 TCR, as confirmed by isothermal titration calorimetry. Finally, cryo-EM structural analysis of SMART-MR1/5-OP-RU bound to A-F7 revealed that ligand presentation and TCR recognition are nearly identical to those observed in native MR1. Together, these results establish SMART-MR1 as a minimal yet native-like system, expanding the experimental toolkit available for studying MR1 interactions and facilitating future efforts aimed at targeting MR1 pathways.
    Significance Statement: MR1 is a highly conserved antigen-presenting molecule that enables T cells to detect metabolite signals from microbial infections and host metabolism. Despite its importance in immunity, mechanistic studies of MR1 have been limited by the instability of the native protein. We developed a simplified and stabilized version of MR1 that preserves the ligand-binding platform while eliminating structural elements that complicate biochemical analysis. This minimal system retains native-like antigen presentation and T cell receptor (TCR) recognition, while enabling experimental approaches that are difficult with full-length MR1. By lowering technical barriers to studying MR1-ligand and MR1-TCR interactions, this platform provides a versatile tool for exploring how antigens shape immune responses and for accelerating discovery of therapeutic strategies targeting MR1.
    DOI:  https://doi.org/10.64898/2026.04.13.718121
  5. Front Immunol. 2026 ;17 1779656
    Protective role of mucosa-associated invariant T cells in sepsis-related liver injury.
    Wei Bu, Qiang Ji, Yuhang Yao, Yuping Liang, Xuexue Pu, Nian Liu, Min Shao.
       Background and objective: Sepsis is a life-threatening condition characterized by increasing global incidence, fundamentally driven by immune dysregulation. The liver, crucial for pathogen clearance and inflammatory modulation during sepsis, frequently exhibits functional impairment. Mucosal-associated invariant T (MAIT) cells bridge innate and adaptive immunity and are integral to antimicrobial defense. Their specific role in sepsis-related liver injury (SRLI) remains unclear. This study aims to elucidate MAIT cell alterations and function in SRLI using clinical cohorts and murine models.
    Methods: The cohort comprised 47 SRLI patients, 37 with non-septic acute liver injury (NSLI), 34 patients with non-associated liver injury in sepsis (NLIS), and 115 healthy controls (HC). Peripheral blood MAIT cells were characterized by flow cytometry for frequency, phenotype, and cytokine production. In vitro experiments assessed effects of bilirubin and cytokines on MAIT cells. A murine SRLI model was established via intraperitoneal lipopolysaccharide (LPS) injection. Liver injury severity, inflammatory cytokines, and histopathology were compared between wild-type and MAIT cell-deficient mice.
    Results: In the SRLI group, the proportion of peripheral blood MAIT cells was significantly decreased compared to the HC group. Regarding activation (CD69+, CD25+) and exhaustion (PD-1+, Tim-3+) phenotypes, the expression levels of CD69 and PD-1 were markedly upregulated relative to all other groups, while the expression of CD25 and Tim-3 was increased compared to the HC and NSLI groups. In vitro assays indicated that upon stimulation, these MAIT cells preferentially produced IL-17A, TNF-α, and granzyme B, suggesting a bias toward Th17-like differentiation. Elevated concentrations of bilirubin exacerbated both the activation and exhaustion of MAIT cells through a TCR-dependent mechanism. In the septic murine model, MAIT cells deficiency led to more severe liver injury, and higher serum levels of transaminases, bilirubin, and pro-inflammatory cytokines compared to wild-type.
    Conclusion: In the context of SRLI, peripheral blood MAIT cells exhibit a diminished frequency, functional impairment, and a phenotypic shift toward a Th17-like profile. Among these, bilirubin plays a key role. Ultimately, MAIT cells exert a protective role in sepsis-induced liver injury by suppressing excessive inflammatory responses.
    Keywords:  cytokine; flow cytometry; inflammations; mucosal associated invariant T (MAIT) cells; sepsis-related liver injury (SRLI)
    DOI:  https://doi.org/10.3389/fimmu.2026.1779656
  6. Crit Rev Oncol Hematol. 2026 Apr 28. pii: S1040-8428(26)00227-1. [Epub ahead of print] 105340
    Mucosal-Associated Invariant T (MAIT) cells in the Tumor Microenvironment: Opportunities and Challenges.
    Kai Wang, Kaizhou Jin, Qinglin Fei, Tianjiao Li, Shuai Wang, Xianjun Yu, Weiding Wu, Longyun Ye.
      Mucosal associated constant T (MAIT) cells are a unique subset of innate T lymphocytes that play a critical role in the host's defense against bacterial and viral pathogens. However, its function in the tumor microenvironment (TME) remains controversial. This review systematically explores the dual role of MAIT cells in tumor immunity by integrating existing literature evidence, and proposes a three-level causal hierarchy that determines the functional fate of MAIT cells. In order to solve the prognostic paradox across cancer types, we introduced the barrier and systemic tumor classification criteria. Based on the above mechanisms, we explored clinical translation pathways such as MR1 targeted intervention, iPSC derived reMAIT cells, and CAR-MAIT engineering. Future research should utilize spatial omics and dynamic tracking techniques to achieve a shift from descriptive observations to precise predictive healthcare driven by biomarkers.
    Keywords:  CAR-MAIT; MAIT cells; MR1; cytokine; iPSC; immunotherapy; microbiome; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105340
  7. bioRxiv. 2026 Apr 16. pii: 2026.04.09.717255. [Epub ahead of print]
    Tissue-specific adaptation of human T cells is preserved during tissue inflammation.
    Nicole B Potchen, Hugh R MacMillan, Eva Domenjo-Vila, Andrew J Konecny, Alexis K Taber, Caitlin S DeJong, Geervani Daggupati, Swati Shree, Stephen A McCartney, Shelton W Wright, Evan W Newell, Douglas R Dixon, Martin Prlic.
      T cells play an essential role in protecting tissues against pathogens and regulating tissue homeostasis. Previous studies highlight that T cells display tissue-specific phenotypic and functional properties, suggesting that T cells adapt to their local environment. Whether inflammation disrupts tissue-specific T cell adaptation remains poorly understood. To address this open question, we examined the T cell compartment - including conventional CD4 and CD8 T cells, regulatory T cells, γδ T cells, and MAIT cells - from healthy and inflamed human mucosal tissues. Using high-parameter spectral flow cytometry, we examined phenotype ex vivo and the functional capacity following stimulation, utilizing conventional gating and unsupervised clustering analysis approaches. Overall, we analyzed 65 tissue samples including mild, moderate, and severely inflamed oral gingiva, healthy and inflamed lung, along with healthy and inflamed tissue from the decidual-placental interface. Across these mucosal barrier tissues, we find that tissue location plays a dominant role in shaping the composition, phenotype, and functional capacity of the T cell compartment. Importantly, these tissue-specific adaptations were largely maintained during states of tissue inflammation. This included the ability to exert tissue repair functions, which was preserved across T cell subsets, even in severely inflamed tissues.
    DOI:  https://doi.org/10.64898/2026.04.09.717255
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒11 at 8:09.