bims-maitce 2025-11-30 papers

Issue of 2025–11–30
five papers selected by
Andy E. Hogan, Maynooth University

J Exp Med. 2026 Feb 02. pii: e20250711. [Epub ahead of print]223(2):

The antigen-presenting molecule MR1 binds host-generated riboflavin catabolites.

Mohamed R Abdelaal, Jieru Deng, Mitchell P McInerney, Emi Ito, Anthony W Purcell, Sho Yamasaki, Jose A Villadangos, Hamish E G McWilliam, Nicholas A Gherardin, Jamie Rossjohn, Wael Awad.

MHC class I-related protein (MR1) presents vitamin B-based antigens (Ags) to mucosal-associated invariant T (MAIT) cells. While microbial riboflavin (RF) precursors are well-documented MR1 ligands, it is unclear whether host-generated RF catabolites influence MR1 immunity. Here, we report that RF catabolites, including 10-formylmethylflavin (FMF), lumichrome, lumiflavin, and alloxazine, bind to MR1 with moderate affinity, while RF itself binds weakly. In contrast to the MR1-upregulating microbial RF precursors, RF catabolites reduced the surface level of MR1 by inducing its retention in the endoplasmic reticulum and inhibiting exit. These RF catabolites weakly competed with vitamin B-based Ags for MR1 binding, thereby selectively inhibiting MAIT activation. The crystal structures of MR1 with RF, FMF, lumiflavin, and lumichrome show binding in the A'-pocket of MR1. Here, lumichrome formed a "flavin bond" covalent interaction with MR1-Lys43 differing from the typical Schiff base. Collectively, we identified three-ringed isoalloxazines that bind MR1 and reduce surface levels, suggesting a potential role in dampening MAIT cell immunity.

DOI: https://doi.org/10.1084/jem.20250711

bioRxiv. 2025 Oct 14. pii: 2025.10.13.682223. [Epub ahead of print]

MAIT cells induced by engineered Listeria exhibit antibacterial and antitumor activity.

Rafael Rivera-Lugo, Jesse Garcia Castillo, Mariya Lobanovska, Eugene Tang, Andrea Anaya-Sanchez, Scott Espich, Sarah A Stanley, Michel DuPage, Daniel A Portnoy.

Mucosal-associated invariant T (MAIT) cells are among the most conserved and abundant innate-like T cells in humans that recognize microbial-derived riboflavin precursors and elicit potent antimicrobial responses 1 . The foodborne pathogen Listeria monocytogenes is a broad host-range facultative intracellular pathogen 2 that lacks the riboflavin biosynthetic pathway 3 , leading us to hypothesize that this deficiency is pathoadaptive and allows the pathogen to evade MAIT cells. Here, we show that L. monocytogenes strains engineered to produce riboflavin ( L. monocytogenes-ribDEAHT ) are attenuated in wild-type mice but fully virulent in MAIT cell-deficient mice. Infection with L. monocytogenes-ribDEAHT prompted rapid and robust MAIT cell expansion in multiple tissues and required the cytolytic effector perforin to eliminate infected cells in vivo and in vitro . We also assessed the therapeutic potential of L. monocytogenes-ribDEAHT- stimulated MAIT cells in both infectious disease and cancer mouse models. Infection with L. monocytogenes-ribDEAHT provided protection against Francisella tularensis in the lungs and inhibited tumor growth even in the absence of CD8 + T cells. These findings highlighted the importance of MAIT cell evasion during L. monocytogenes infection and reveal the therapeutic potential of engineered L. monocytogenes to activate and harness MAIT cells for protection against infectious disease and cancer.

DOI: https://doi.org/10.1101/2025.10.13.682223

bioRxiv. 2025 Nov 01. pii: 2025.10.29.685375. [Epub ahead of print]

Acetoacetate suppresses colon cancer via an MR1-MAIT axis.

Slater L Clay, Geniver El Tekle, Edrees H Rashan, Diogo Fonseca-Pereira, Yern-Hyerk Shin, Natalia Andreeva, Geicho Nakatsu, Ayesha F Lobo, Sway P Chen, Sena Bae, Monia Michaud, Jonathan N Glickman, Jon Clardy, Matthew G Vander Heiden, Wendy S Garrett.

Colorectal cancer (CRC) is a leading cause of cancer mortality and additional preventative, and therapeutic strategies are urgently needed. Ketogenic diets have mixed effects on tumorigenesis and compliance is challenging. Exogenous ketones, β-hydroxybutyrate (βHB) or acetoacetate (AcAc), offer an alternative approach. While βHB has been investigated, the anti-cancer effects of AcAc are poorly defined. Here, we show that orally administering ethyl AcAc (EAA) suppresses tumor growth in several pre-clinical CRC models. Single-cell RNA sequencing, flow cytometry, and genetic and antibody-mediated depletion studies reveal that EAA selectively expands and activates cytotoxic mucosal-associated invariant T (MAIT) cells in an MHC class I-related protein 1 (MR1)-dependent manner. EAA increases MR1 expression by tumor monocytes, which is recapitulated in human cell cultures, where AcAc and 5-amino-6-D-ribitylaminouracil (5-A-RU) induce MAIT cell expansion and tumor killing. Mechanistically, AcAc converts to methylglyoxal, combining with microbially-derived 5-A-RU to generate 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a potent MR1 ligand. These findings identify an AcAc-MR1-MAIT cell axis as a potential immunotherapy approach for CRC therapy.

DOI: https://doi.org/10.1101/2025.10.29.685375

Sci Rep. 2025 Nov 27.

Molecular recognition of natural compounds by MR1 and their implication in MAIT cell activation elucidated through McMD-based dynamic docking simulations.

Gert-Jan Bekker, Mitsugu Araki, Kanji Oshima, Yasushi Okuno, Narutoshi Kamiya.

Keywords: Binding mechanism; MHC class I-related protein 1; Mucosal-associated invariant T cells; Multicanonical molecular dynamics simulation; Natural small molecule compounds

DOI: https://doi.org/10.1038/s41598-025-28682-3

J Med Virol. 2025 Dec;97(12): e70732

Subset Remodeling of MAIT and NK Cells Correlates With Immune Reconstitution in People Living With HIV Following Four Years of Antiretroviral Therapy.

Zhuoya Deng, Xin Zhang, Aiwei Zhu, Xiaodong Yang, Qiuyue Zhang, Hongxia Yan, Hao Wu, Tong Zhang, Christiane Moog, Bin Su.

Despite effective viral suppression, a subpopulation of people living with HIV (PLWH) receiving combination antiretroviral therapy (ART) experience a suboptimal immunological response, failing to restore CD4+ T-cell counts to levels deemed indicative of good immune recovery. Innate immune cell dysregulation, particularly in mucosal-associated invariant T (MAIT) and natural killer (NK) cells, is increasingly recognized as a key contributor to immune reconstitution. However, the dynamic changes, interactive crosstalk, and potential roles of these immune cells in immune reconstitution remain poorly understood. A total of 89 participants were enrolled, including 29 healthy controls and 60 HIV-infected individuals, who were classified as immune responders (IRs, CD4 ≥ 500 cells/µL; n = 34) and suboptimal immunological responders (SIRs, CD4 < 500 cells/µL; n = 26) on the basis of immune recovery status. Longitudinal flow cytometric analysis was performed to assess the phenotypic changes in MAIT and NK cell subsets in peripheral blood mononuclear cells (PBMCs) before treatment (T0) and after 4 years of ART (T4). Correlation analysis was conducted to explore their associations with CD4+ T-cell recovery. After 4 years of ART, both IRs and SIRs exhibited persistent depletion of total MAIT and invariant natural killer T (iNKT) cells, whereas pretreatment-diminished CD56bright and CD56dim NK cell subsets increased significantly. MAIT cells also underwent phenotypic remodeling in both groups, with decreased CD4-CD8+ and increased CD4-CD8- subsets. Notably, these cell subset proportions and quantitative changes correlated significantly with CD4+ T-cell counts in IRs but not SIRs. In IRs, CD4+ T-cell recovery positively correlated with baseline CD4-CD8- MAIT and CD56bright NK cell numbers, but negatively with baseline CD4-CD8+ MAIT cell numbers. Correlation networks revealed distinct MAIT-NK interactions across ART stages. LASSO models integrating MAIT and NK subsets achieved high predictive accuracy, highlighting the dynamic role of CD4-CD8+ MAIT cells in immune reconstitution. Our study highlights the dynamic correlations between and within MAIT and NK cell subset proportions in PLWH, revealing that phenotypic remodeling rather than absolute cell counts plays a key role in immune reconstitution. CD4-CD8+ MAIT cells show time-dependent predictive shifts, reflecting functional adaptation. These findings identify MAIT and NK subset dynamics as potential biomarkers and therapeutic targets for enhancing immune recovery of PLWH during ART.

Keywords: HIV; MAIT cells; NK cells; antiretroviral therapy; immunological responder; incomplete immune reconstitution; suboptimal immunological responder

DOI: https://doi.org/10.1002/jmv.70732