bims-maitce 2025-08-03 papers

Issue of 2025–08–03
two papers selected by
Andy E. Hogan, Maynooth University

J Immunol. 2025 Jul 26. pii: vkaf143. [Epub ahead of print]

The MAIT cell response to controlled oral enterotoxigenic E. coli challenge.

Kerri G Lal, Dohoon Kim, Matthew Creegan, Adam T Waickman, Jeffrey R Currier, Dominic Paquin-Proulx, Milton Maciel, Michael A Eller, Johan K Sandberg.

Mucosal-associated invariant T (MAIT) cells recognize conserved microbial antigens presented by the non-polymorphic MR1 molecules and play important roles in barrier immunity. Enterotoxigenic E. coli (ETEC) is a major cause of diarrheal disease in children in lower-income countries and among travelers. Here we investigate the potential role of MAIT cells in ETEC infection using blood samples from a controlled human challenge model with two ETEC strains, H10407 and B7A. On day 7 following challenge, MAIT cells exhibited an elevated activated phenotype accompanied by increased functionality and proliferation in peripheral blood, with the most pronounced pattern observed in individuals who developed moderate-to-severe diarrhea (MSD). This response was evident at both the protein and transcriptional levels. The MSD-positive group demonstrated elevated expression of CCR9 and α4β7 on MAIT cells, indicating increased homing potential to the gut mucosa. Additionally, this group experienced an expansion of the peripheral MAIT cell pool 28 d after the challenge. Interestingly, the initial expansion of the MAIT cell pool on day 7 post-challenge correlated with disease severity score. These findings indicate that MAIT cells can respond systemically with activation and expansion to ETEC infection, and that this response is associated with the development of symptomatic disease.

Keywords: ETEC; MAIT cells; MR1; enterotoxigenic E. coli; human

DOI: https://doi.org/10.1093/jimmun/vkaf143

Front Immunol. 2025 ;16 1618393

Unconventional T cells in anti-cancer immunity.

Ariel Laub, Nathalia Rodrigues de Almeida, Shouxiong Huang.

Unlike conventional T cells that detect peptide antigens loaded to major histocompatibility complex (MHC) molecules, unconventional T cells respond to non-peptidic metabolite antigens presented by MHC class I-like proteins, such as CD1 and MHC-related protein 1 (MR1). Semi-invariant mucosal-associated invariant T (MAIT) cells, γδ T cells, and invariant natural killer T (iNKT) cells, together with other CD1- or MR1-restricted T cell subsets expressing diverse T cell receptors (TCR), elicit an innate-like response independent of diverse MHC genetics. In contrast to an overall enhanced response to bacterial-derived riboflavin precursor metabolites in infections, MAIT cells often exhibit an immunosuppressive or exhausted phenotype in glioblastoma, lung cancer, colorectal cancer, and various hematological malignancies. Whereas some tumor cells can activate MAIT cells, the structures and functions of tumor-derived MR1 ligands remain largely unknown. Novel discoveries of mammalian-derived agonists and antagonists binding to MR1 protein are our knowledge of MR1 ligand structures and functions from MAIT cell activation in healthy conditions to anti-cancer immunity. Recent findings reveal that nucleoside and nucleobase analogs, as self-metabolites to activate MR1-restricted T cells, are regulated in the tumor microenvironment. Likewise, iNKT cells exhibit a dynamic role in cancer, capable of both protumor and antitumor immunity. Similarly, γδ T cells have also demonstrated both protective and tumor-promoting roles, via recognizing stress-induced protein and metabolite ligands. This review further depicts the distinct kinetics of responses, highlighting a rapid activation of unconventional T cells in solid versus hematological cancers. Emerging therapeutic strategies, including antigen-loaded MR1 and CD1, adoptive T cell transfer, chimeric antigen receptor-T (CAR-T) cells, T cell receptor-T (TCR-T) cells, and combination treatments with immune checkpoint inhibitors, yet remain challenging, hold promise in overcoming tumor-induced immunosuppression and genetic restriction of conventional T cell therapies. By addressing critical gaps, such as novel structures and functions of cancer metabolite antigens, unconventional T cells offer unique advantages in anti-cancer immunotherapy.

Keywords: CD1; MHC class I-related protein 1 (MR1); cancer; immunotherapy; lipids; polar metabolites; unconventional T cells

DOI: https://doi.org/10.3389/fimmu.2025.1618393