bims-maitce 2026-03-01 papers

Issue of 2026–03–01
six papers selected by
Andy E. Hogan, Maynooth University

J Immunol. 2026 Feb 09. pii: vkaf346. [Epub ahead of print]215(2):

Ellagic acid metabolism as a source of dietary MR1 ligands.

David O'Sullivan, Carl J H Wang, Jeffry S Tang, Ruth Stephens, Sophie Faulkner, Katie Gell, Yanyan Li, Alissa Cait, Mitchell McInerney, Anthony W Purcell, Jamie Rossjohn, Jérôme Le Nours, Olivier Gasser.

MR1 is an major histocompatibility complex class I-like molecule that presents small molecule metabolites to MR1-restricted T cells that include a major population of highly conserved T cells known as mucosal-associated invariant T (MAIT) cells. MAIT cells recognize bacterial riboflavin pathway-derived neoantigens and are being attributed an increasing number of immune and homeostatic functions. However, the chemical breadth and diversity of MR1-restricted ligands remain to be fully elucidated. Due to the largely (poly)cyclic structure of known MR1 ligands, we aimed to identify MR1 ligands from a library of dietary phenolic metabolites. Competitive MAIT cell inhibition assays using both cell lines and primary cells isolated from human blood identified gut microbial metabolites of ellagitannins that include ellagic acid (EA), urolithin D (UroD), and UroM5 as potential MR1 ligands. Fluorescence polarization binding assays demonstrated that EA, UroM5, UroC, and UroB bound to MR1, and we provide a structural basis for EA presentation by MR1. Overall, our findings indicate that EA metabolism provides dietary MR1 ligands that inhibit T cell receptor-dependent MAIT cell activation.

Keywords: MAIT cells; MR1; MR1-restricted T cells; dietary MR1 ligands

DOI: https://doi.org/10.1093/jimmun/vkaf346

Immunol Cell Biol. 2026 Feb 23.

The NF-κB transcription factor RelA directs mucosal-associated invariant T-cell development.

Thomas S Fulford, Hui-Fern Koay, Raelene Grumont, Darryl N Johnson, Sebastian Scheer, Hendrik J Nel, Ranjeny Thomas, Jeffrey Yw Mak, David P Fairlie, Charis E Teh, Daniel Hd Gray, Vanessa L Bryant, Colby Zaph, Lorraine A O'Reilly, Steven Gerondakis, Dale I Godfrey.

Mucosal-associated invariant T (MAIT) cells are characterized by rapid responses to nonpeptide antigens via invariant T-cell receptors (TCR), and expression of an "effector-like" T-cell phenotype. The transcription factor promyelocytic leukemia zinc finger (PLZF) is crucial for defining the function of MAIT cells and other unconventional T cells; however, the transcriptional programs that direct MAIT cell development are not fully elucidated. Here, we show that the canonical NF-κB transcription factor RelA is critical for MAIT cell thymic development, but not responsiveness to antigen, whereas NF-κB1 and c-Rel make more limited contributions. MAIT cell development is also impaired in the absence of the linear ubiquitin signaling complex (LUBAC), an upstream regulator of NF-κB signaling, implicating this pathway in establishing the MAIT cell pool. Collectively, these data suggest LUBAC and NF-κB signals as elements of the transcriptional network controlling MAIT cell development.

Keywords: LUBAC; MAIT cells; NF‐κB; RelA; development

DOI: https://doi.org/10.1111/imcb.70096

bioRxiv. 2026 Feb 19. pii: 2026.02.18.706493. [Epub ahead of print]

Opposing roles for SNAP23 and SNAP25 in mediating MR1 trafficking and antigen presentation.

Se-Jin Kim, Corinna A Kulicke, David M Lewinsohn, Elham Karamooz.

MHC class I-related protein 1 (MR1) is a highly conserved antigen presenting molecule that presents small molecule metabolites derived from diverse microbial pathogens to mucosal-associated invariant T (MAIT) cells. We have shown previously that MR1 traffics through endosomal compartments via soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, including Syntaxin 4 and vesicle-associated membrane protein (VAMP) 4. Here, we investigate the role of synaptosome-associated proteins (SNAPs), which pair with Syntaxins and VAMPs to form functional SNARE complexes, in MR1-mediated antigen presentation. Among SNAP homologs, we identify that SNAP23 contributes to the presentation of Mycobacterium tuberculosis (Mtb)-derived antigens and loss of SNAP23 reduces the number of MR1-containing vesicles during infection. In contrast, SNAP25 suppresses MR1 presentation for both intracellular pathogens Mtb and Mycobacterium avium , as well as extracellular pathogen Candida albicans . This study demonstrates opposing roles for SNAP23 and SNAP25 in MR1 antigen presentation to MAIT cells, and extends our understanding of how SNAP family proteins regulate MR1 trafficking.

DOI: https://doi.org/10.64898/2026.02.18.706493

J Biol Chem. 2026 Feb 25. pii: S0021-9258(26)00187-0. [Epub ahead of print] 111317

Mutations outside the MR1 antigen binding groove differentially inhibit presentation of exogenous antigens.

Corinna A Kulicke, Chance Lemon, Jason R Krawic, Luisa Maria Nieto Ramirez, Se-Jin Kim, Gitanjali Narayanan, Fikadu G Tafesse, William H Hildebrand, Karen M Dobos, David M Lewinsohn.

The antigen presenting molecule MHC class I-related protein 1 (MR1) binds small molecule metabolites derived from the microbial riboflavin biosynthetic pathway and presents them at the cell surface for surveillance by MR1-restricted mucosal-associated invariant T cells (MAIT cells). MR1 ligands can originate in the extracellular space or in endosomal compartments that contain microbial pathogens. Distinct, complementary antigen processing and presentation pathways enable MR1 to survey diverse intracellular locations and present both exogenous and intracellular antigens. Here, we generated a panel of BEAS-2B MR1 KO cells reconstituted with MR1 proteins mutated at amino acids 9 - 16. The over-expressed mutated MR1 molecules differentially translocated to the cell surface in response to 6-formylpterin and differed in their ability to present mycobacterial antigens to MAIT cell clones. While they barely presented Mycobacterium smegmatis supernatant and other exogenous MAIT cell antigens, their ability to present antigens derived from mycobacterial infection and a 5-A-RU prodrug that requires endosomal processing remained largely intact. Protein co-immunoprecipitation and mass spectrometry-based proteomic analysis showed that mutated MR1 differentially associated with calnexin and β2-microglobulin (B2M). Knock-down of B2M in cells over-expressing wildtype MR1 phenocopied the loss of exogenous antigen presentation but did not impact presentation of intracellular antigens. Thus, the MR1-mediated presentation of exogenous antigen appears to be limited by binding to B2M whereas a lower sensitivity to B2M deficiency suggests that MAIT cell activation via the endosomal antigen presentation pathway may be limited by the availability of MR1 itself.

Keywords: MAIT cells; MR1-restricted T cells; T-cell; antigen presentation; cellular immune response; mucosal immunology

DOI: https://doi.org/10.1016/j.jbc.2026.111317

Vaccines (Basel). 2026 Jan 26. pii: 117. [Epub ahead of print]14(2):

Targeting the MR1-MAIT Cell Axis for Vaccination Against Infectious Disease.

Mattie S M Timmer, Lisa M Connor, Bridget L Stocker.

Mucosal-associated invariant T (MAIT) cells exist in high numbers in the body and have a unique and highly conserved T cell receptor (TCR). They can be activated in a TCR-dependent manner by ligands presented on the monomorphic protein MHC class I-related protein 1 (MR1) which is found on many cell types, including professional antigen presenting cells (APCs) and epithelial cells. This has sparked interest in the potential to exploit the MR1-MAIT cell axis for the development of vaccines against infectious disease. Within this context an MR1 ligand, typically 5-(2-oxopropylideneamino)-d-ribitylaminouracil (5-OP-RU), is administered with or without a Toll-like receptor (TLR) ligand or cytokine in a pan vaccination approach that would prime the immune response to provide protection against a variety of bacterial and viral pathogens. This strategy has led to enhanced protection in murine models of Legionella longbeachae, Francisella tularensis, Klebsiella pneumoniae, Streptococcus pneumoniae and influenza infection. However, studies against Mycobacterium tuberculosis infection have proven less successful. The second vaccination approach involves pairing the MR1 ligand with more conventional antigens that could activate CD4+ and/or CD8+ T cells. This approach has been successful in murine models of cholera, influenza, and SARS-CoV-2, including in the context of subunit vaccines. However, there are several challenges when using MR1-MAIT cell-mediated vaccine adjuvants. These include the inherent instability of 5-OP-RU and the need for more advanced studies to better understand how the use of MR1 ligands would translate to applications in humans. This review will discuss these aspects and highlight the mechanistic studies that have been undertaken to understand how MAIT cells might elicit their effects within the context of MAIT cell-mediated vaccines for infectious disease.

Keywords: 5-OP-RU; MAIT cell; MR1; adjuvant; immune cell; infectious disease; ligand; vaccine

DOI: https://doi.org/10.3390/vaccines14020117

Int J Mol Sci. 2026 Feb 20. pii: 2017. [Epub ahead of print]27(4):

The Fibro-Immune Landscape Across Organs: A Single-Cell Comparative Study of Human Fibrotic Diseases.

Guofei Deng, Yusheng Luo, Xiaorong Lin, Yuzhi Zhang, Yuqing Lin, Yuxi Pan, Yueheng Ruan, Xiaocong Mo, Shuo Fang.

Fibrosis is a hallmark of the tumor microenvironment in many solid cancers, driving tumor progression, immune evasion, and treatment resistance; however, the molecular and cellular mechanisms underlying fibrogenesis-particularly stromal-immune crosstalk across organs-remain incompletely understood, compounded by organ-specific heterogeneity and a lack of reliable immune-related biomarkers. To address this, we performed an integrative single-cell RNA sequencing (scRNA-seq) analysis of fibrotic tissues from four major organs-liver, lung, heart, and kidney-alongside non-fibrotic controls, applying unsupervised clustering, trajectory inference, cell-cell communication modeling, and gene set variation analysis (GSVA) to map the fibro-immune landscape. Our analysis revealed both conserved and organ-specific features: fibroblasts were the dominant extracellular matrix (ECM)-producing cells in liver and lung, whereas endothelial-derived stromal populations prevailed in heart and kidney. Immune profiling uncovered distinct infiltration patterns-macrophages displayed organ-specific polarization states; T cells were enriched for tissue-resident subsets in lung and mucosal-associated invariant T (MAIT) cells in liver; and B cells exhibited marked heterogeneity, including a pathogenic interferon-responsive subset prominent in pulmonary fibrosis. GSVA further identified divergent signaling programs across organs and lineages, including TGF-β/TNF-α in the heart, NOTCH/mTOR in the kidney, glycolysis/ROS in the lung, and KRAS/interferon pathways in the liver. Cell-cell communication analysis highlighted robust crosstalk between macrophages, T/B cells, and stromal cells mediated by collagen, laminin, and CXCL signaling axes. Together, this cross-organ atlas delineates a highly heterogeneous fibro-immune ecosystem in human fibrotic diseases, revealing shared mechanisms alongside organ-specific regulatory networks, with immediate translational implications for precision anti-fibrotic therapy, immunomodulatory drug repurposing, and the development of context-specific biomarkers for clinical stratification and therapeutic monitoring.

Keywords: anti-fibrotic therapies; fibrosis; organ specificity; single-cell RNA sequencing; stromal–immune crosstalk

DOI: https://doi.org/10.3390/ijms27042017