bims-maitce 2026-07-12 papers

Issue of 2026–07–12
four papers selected by
Andy E. Hogan, Maynooth University

bioRxiv. 2026 Jul 01. pii: 2026.06.28.735088. [Epub ahead of print]

Mucosal-associated invariant T cells support IL-15-dependent Treg response in skin injury and promote resolution of skin inflammation.

Grace E Crossland, Andre Armero, Vianey Chavez, Zachary T Peters, Lennard Ostendorf, Shriya Kannan, Lindsay K Mendyka, Olivia F Brooker, Kaitlyn Dowling, Himanshu B Goswami, Dorothea Barton, Sonia Leach, Fred W Kolling, Pamela C Rosato, Mark S Sundrud, Theresa T Lu, Deepak A Rao, Michael G Constantinides, Sladjana Skopelja-Gardner.

Mucosal-associated invariant T (MAIT) cells are enriched at barrier sites, but their role in autoimmune skin inflammation remains unknown. Using cutaneous lupus as a model, we identify MAIT cells as protective regulators of skin inflammation and as critical upstream modulators of regulatory T cells (Treg). Topical MAIT cell activation with 5-OP-RU induced durable resolution of spontaneous skin lesions in MRL/lpr mice and suppressed TLR7-driven skin inflammation. MAIT cell activation selectively expanded and activated Treg populations in both healthy and lupus-like skin, while suppressing effector T cell cytokine production and cytotoxic programs. This MAIT-Treg axis was also activated in UV light-driven barrier injury in healthy murine and human skin, where MAIT cells were required for UV-elicited Treg expansion and function. In lupus-like skin, local MAIT cell activation restored the defective UVB-induced Treg response and limited CD8+ T cell expansion. Mechanistically, CCR2+ monocyte-derived antigen-presenting cells and IL-15 signaling were required for MAIT cell-driven Treg accumulation and therapeutic benefits of MAIT cells in inflamed skin. These studies identify a MAIT-IL-15-Treg axis that links barrier injury sensing to immune regulation, which is disrupted in cutaneous lupus, and nominate therapeutic MAIT cell activation as an unappreciated strategy for restoring immune homeostasis in inflamed skin.

DOI: https://doi.org/10.64898/2026.06.28.735088

Front Immunol. 2026 ;17 1797918

Mucosal-associated invariant T cells recognize a tumor-derived metabolite in the DNA synthesis pathway.

Mucosal-associated invariant T (MAIT) cells recognize metabolite-derived ligands, but the identity of such ligands in the context of cancer remains poorly defined. Herein, we demonstrate that the tumor-derived metabolite 5-formyl tetrahydrofolate (5-formyl THF), which is an intermediate of the folate metabolism pathway, induces T cell receptor (TCR)-dependent activation of mouse mucosal-associated invariant T (MAIT) cells. The activity was weaker than that of a potent MAIT cell agonist 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU). Amino methyltransferase (Amt), an enzyme that is necessary for the generation of 5-formyl THF from tumor cells, was essential for the activation of mouse MAIT cells. Genetic deletion of Amt in the tumor resulted in impaired activation of mouse MAIT cells. In contrast, Amt overexpression in the tumor led to an enhancement in the agonistic activity of the MAIT cells. The introduction of mouse MAIT TCRs to primary T cells from MAIT cell-deficient mice also conferred reactivity to 5-formyl THF. Using single-cell TCR sequencing analysis, a 5-formyl THF-reactive MAIT cell clonotype was identified in humans. These results demonstrate that 5-formyl THF is the first tumor-derived ligand recognized by MAIT cells in both humans and mice. However, the functional relevance of this pathway in vivo remains to be determined.

Keywords: DNA synthesis; T cells; cancer; ligand; metabolite

DOI: https://doi.org/10.3389/fimmu.2026.1797918

Front Immunol. 2026 ;17 1852383

Synergistic TCR-independent action of IL-33 and IL-12 drive a potent IFNγ secretory program in human circulating MAIT cells with immunomodulatory properties.

Carlota García-Escribano, Maria Gallardo-Jiménez, Ana García-Cadarso, Paloma Fernández Martínez, Ricardo Arroyo-Solera, Luis Senador Zaldívar-Martínez, Kelin Lin, Jeffrey Aubé, Patricia Barral, Tomás Chivato, Domingo Barber, Maria M Escribese, Elena Izquierdo, Juan Carlos López-Rodríguez.

Introduction: Mucosal-Associated Invariant T (MAIT) cells are a subset of unconventional T cells that rapidly respond to early signs of inflammation, infection, and tissue damage. While MAIT cells have been typically associated with microbial infections, given their ability to respond to both microbial-derived riboflavin metabolites and proinflammatory cytokines such as IL-12, IL-15, or IL-18, their role in other inflammatory conditions remains mostly unknown. Alarmins, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), are crucial effectors for early inflammatory responses, being released upon epithelial damage and strongly promoting the polarization of a wide variety of immune cells, including leukocytes like neutrophils, monocytes, macrophages, dendritic cells (DCs), NK cells, ILCs and T cells. However, how alarmins-induced environments influence MAIT cells' activity and function is yet to be explored.
Methods: In this study, we investigate the roles of alarmins in controlling MAIT cell activation and function.
Results: We found that IL-33, but not IL-25 or TSLP, combined with the TCR-independent stimuli IL-12p70 (but not 5-OP-RU), induces a potent IFNγ secretory/cytotoxic program on MAIT cells. This response was strongly dependent on p38 MAPK signaling and glycolytic metabolism. Beyond IFNγ, IL-33/IL-12p70-activated MAIT cells secrete a diverse panel of immune mediators, including TNF, VEGF, OSM, CXCL11, and CCL3. Notably, conditioned media from purified Vα7.2+ T cells (enriched on MAIT cells) were able to polarize CD14+ monocytes towards a M1-like inflammatory phenotype, increasing both the expression of proinflammatory genes and phagocytic capacity.
Discussion: These findings reveal a broader immunomodulatory potential for MAIT cells to influence diverse immune compartments during inflammatory response.

Keywords: Glycolysis; IFNγ; IL-12p70; IL-33; MAIT cells; P38-MAPK; monocytes; secretome

DOI: https://doi.org/10.3389/fimmu.2026.1852383

Adv Pharmacol. 2026 ;pii: S1054-3589(26)00035-9. [Epub ahead of print]106 65-99

T Cell subsets for therapy-unconventional CD1d-restricted natural killer T cells.

Monika Holubová, Valentina Sofia Caputo Galarce, Miroslava Čedíková.

Unconventional T cells, including gamma delta (γδ) T cells, mucosal-associated invariant T (MAIT) cells, and CD1d-restricted natural killer T (NKT) cells, comprise a unique component of the immune system. These cells play critical roles in host defense, immune regulation, and disease pathogenesis. In particular, invariant NKT (iNKT) cells have emerged as key immunological orchestrators that bridge innate and adaptive immunity by rapidly recognizing lipid antigens presented by CD1d molecules. This chapter provides a comprehensive overview of iNKT cell biology, including their development, phenotypic and functional heterogeneity, and activation mechanisms. It discusses the role of iNKT cells in pathological conditions in detail. Their ability to directly kill tumor cells, as well as their potential to orchestrate the immune response, opens up new possibilities for anti-cancer therapy. Their contribution to immune response regulation and tolerance highlights their critical role in infectious diseases and transplantation. The chapter summarizes current clinical approaches aimed at harnessing iNKT cells, including in vivo activation strategies, adoptive transfer of ex vivo-expanded cells, and developing chimeric antigen receptor (CAR)-engineered iNKT cells. These emerging therapies have advantages over conventional CAR-T approaches, such as reduced toxicity and the potential for allogeneic use. Finally, the chapter discusses the role of type II NKT cells and their cross-regulatory interactions with iNKT cells. Overall, CD1d-restricted NKT cells are a promising target for next-generation immunotherapies. However, further mechanistic and clinical studies are needed to realize their full therapeutic potential.

Keywords: Adoptive cell therapy; CAR-iNKT therapy; CD1d; Immunomodulation; Invariant natural killer T cells (iNKT); Lipid antigens; Tumor microenvironment; Type II NKT cells; Unconventional T cells

DOI: https://doi.org/10.1016/bs.apha.2026.05.006