bims-maitce 2025-08-10 papers

Issue of 2025–08–10
four papers selected by
Andy E. Hogan, Maynooth University

Exp Mol Med. 2025 Aug 08.

Human MAIT cells undergo clonal selection and expansion during thymic maturation and aging.

Myeong-Seok Lee, Suyeong Park, Jung-Hwan Choi, Seon Yong Bae, Han Suk Ryu, Min-Sung Kim, Jae Gun Kwak, You Jeong Lee.

Mucosal-associated invariant T (MAIT) cells harbor conserved T cell receptors (TCRs) recognizing riboflavin metabolites, yet exhibit substantial diversity similar to conventional memory T cells. However, the mechanisms shaping this diversity related to their thymic ontogeny remain unclear. Here we analyze 37 samples of human thymic MAIT cells across ages and compare them with other unconventional T cells, such as iNKT and γδ T cells. We find that CD27 and CD161 serve as common markers distinguishing the maturation stages of unconventional T cells such as MAIT, iNKT and Vγ9+Vδ2+ γδ T cells. Notably, CD161+ mature MAIT cells clonally expand proportionally to aging with the upregulation of genes associated with tissue residency. MAIT cell diversity is initially determined by diverse CDR3β sequences, which become reduced upon maturation. Furthermore, 25% of MAIT cells express polyclonal dual TCRα transcripts, suggesting they arise from double-positive thymocytes with random TCRα rearrangement. Collectively, these findings show that thymic MAIT cells undergo dynamic regulation of repertoire selection, similar to conventional T cells.

DOI: https://doi.org/10.1038/s12276-025-01509-x

Cell Rep Methods. 2025 Jul 29. pii: S2667-2375(25)00156-0. [Epub ahead of print] 101120

MR1-ligand cross-linking identifies vitamin B6 metabolites as TCR-reactive antigens.

Thierry Schmidlin, Enas Behiry, Hannah Thomas, Garry Dolton, Fabio Marino, Samiul Hasan, Magdalena von Essen, Rose M Gathungu, Barbara A Steigenberger, Hayden Selvadurai, Joseph Dukes, Paul E Brennan, Owen B Spiller, Jonathan D Silk, Andrew K Sewell, Nicola Ternette.

Major histocompatibility complex class I-related protein 1 (MR1) plays a central role in the immune recognition of infected cells and can mediate T cell detection of cancer. Knowledge of the nature of the ligands presented by MR1 is still sparse and has been limited by a lack of efficient approaches for MR1 ligand discovery. Here, we present a cross-linking strategy to investigate Schiff base-bound MR1 ligands. Our methodology employs reductive amination to stabilize the labile Schiff base bond between MR1 and its ligand, allowing for the detection of ligands as covalent MR1 adducts by mass spectrometry-based proteomics. We apply our approach to identifying vitamin B6 vitamers pyridoxal and pyridoxal 5'-phosphate (PLP) as MR1 ligands and show that both compounds are recognized by T cells expressing either A-F7, a mucosal-associated invariant T (MAIT) cell T cell receptor (TCR), or MC.7.G5, an MR1-restricted TCR reported to recognize cancer cells, highlighting them as immunogenic MR1 ligands.

Keywords: CP: Immunology; MAIT; MR1; T cell; TCR; antigen presentation; cross-linking; mass spectrometry; metabolite antigens; pyridoxal; vitamin B6

DOI: https://doi.org/10.1016/j.crmeth.2025.101120

Front Immunol. 2025 ;16 1576861

High-dimensional single-cell phenotyping unveils persistent differences in immune cell profiles between severe and moderate seasonal influenza.

Johanna Bodin, Gro Tunheim, Anja B Kristoffersen, Tove K Herstad, Eleonora Vianello, Mariëlle C Haks, Suzanne van Veen, Torgun Wæhre, Anne-Marte B Kran, Sarah L Lartey, Fan Zhou, Rebecca J Cox, Tom H M Ottenhoff, Anne M Dyrhol-Riise, Unni C Nygaard, Fredrik Oftung, Siri Mjaaland.

Background: Influenza viruses with pandemic potential and possible burden of post-viral sequelae are a global concern. To prepare for future pandemics and the development of improved vaccines, it is vital to identify the immunological changes underlying influenza disease severity.
Methods: We combined unsupervised high-dimensional single-cell mass cytometry with gene expression analyses, plasma CXCL13 measurements, and antigen-specific immune cell assays to characterize the immune profiles of hospitalized patients with severe and moderate seasonal influenza disease during active infection and at 6-month follow-up. We used age-matched healthy donors as controls.
Results: Severe disease was associated with a distinct immune profile, including lower frequencies of ICOS+ mucosal-associated invariant T (MAIT) cells, and CXCR5+ memory B and CD4+CXCR5+CD95+ICOS+ and CD8+CXCR3+CD95+PD-1+TIGIT+ memory T cells, as well as lower CD4 gene expression. Higher frequencies of CD16+CD161+ NK cells, CD169+ monocytes, CD123+/- dendritic cells, and CD38high plasma cells and high CXCL13 plasma levels were also associated with severe disease. Alterations in immune cell subpopulations persisted at convalescence for the severely ill patients only.
Conclusions: Our results indicated a reduction in regulatory MAIT cells and memory T and B cells and an increase in the inhibitory subpopulations of monocytes and NK cells in severe influenza that persisted at convalescence. These immune cell alterations were associated with higher age and the presence of several underlying conditions that may contribute to frailty. This study illustrates the power and sensitivity of high-dimensional single-cell analyses in identifying potential cellular biomarkers for disease severity after influenza infection.

Keywords: biomarkers; disease severity; hospitalization; immune profiling; influenza; mass cytometry

DOI: https://doi.org/10.3389/fimmu.2025.1576861

PLoS Pathog. 2025 Aug;21(8): e1013342

Two-pore channels in MR1-dependent presentation of Mycobacterium tuberculosis infection.

Elham Karamooz, Se-Jin Kim, Jessie C Peterson, Allison E Tammen, Shogo Soma, Aviva C R Soll, Erin W Meermeier, Sharon Khuzwayo, David M Lewinsohn.

MR1 is a ubiquitously expressed MHC-Ib molecule that presents microbial metabolites to MR1-restricted T cells, but there are differences in the antigen presentation pathway of an intracellular microbe compared to exogenously delivered antigen. We have shown the importance of endosomal trafficking proteins in MR1-dependent presentation of Mycobacterium tuberculosis (Mtb) infection. Two pore channels (TPCs) are endosomal calcium channels that regulate endosomal trafficking. Due to their location on endosomes, we hypothesized that TPCs could be required for MR1-dependent presentation of antigens derived from the intracellular microbe Mtb. We found that TPC1 is critical for the presentation of Mtb infection by MR1; inhibition of TPCs had no effect on MR1 presentation of exogenously delivered antigens, HLA-B presentation, or HLA-II presentation. Finally, we found that the calcium-sensitive trafficking protein Synaptotagmin 7 was also key in the presentation of Mtb infection by MR1. TPC1 and Synaptotagmin 7 may be part of an endosomal pathway by which MR1 can sample intracellular mycobacterial infections.

DOI: https://doi.org/10.1371/journal.ppat.1013342