bims-maitce 2025-07-06 papers

bims-maitce

Biomed News

on MAIT cells

Issue of 2025–07–06
six papers selected by
Andy E. Hogan, Maynooth University

Mast cells boost anti-tumor potency of MAIT cells via inflammasome-dependent secretion of IL-18.
The emerging relationship between mucosal-associated invariant T cell populations and the onset and progression of type 1 diabetes.
Disruption of riboflavin biosynthesis in mycobacteria establishes riboflavin pathway intermediates as key precursors of MAIT cell agonists.
Distinct T Cell Receptor Clonotypes in the Sardinian Population Highlight the Role of Mucosal-Associated Invariant T Cells and Invariant Natural Killer T Cells in Multiple Sclerosis.
Circulating mucosa-associated invariant T cells are decreased and have impaired function in patients with diffuse large B-cell lymphoma.
Selective inhibition of MR1-restricted T cell activation by a novel MR1-targeting nanobody.

Nat Commun. 2025 Jul 02. 16(1): 6074

Mast cells boost anti-tumor potency of MAIT cells via inflammasome-dependent secretion of IL-18.

Fanfan Fan, Jun Wang, Kun Liu, Shiyue Zhang, Jian Gao, Xiongfei Li, Jiaqiang Ma, Yue Zhao, Teng Li, Han Su, Xinfeng Yang, Han Han, Qingyuan Huang, Yiliang Zhang, Yunjian Pan, Ting Ye, Hong Hu, Yihua Sun, Fei Li, Zhiwei Cao, Yang Zhang, Xiaoming Zhang, Haiquan Chen.

Mast cells (MC) serve as pivotal sentinels in the regulation of immune responses and inflammation, yet their function in lung adenocarcinoma (LUAD) remains largely neglected. To decode their heterogeneity, we perform single-cell transcriptomic analysis of LUAD-infiltrating MCs. Our study uncovers the complexity in MC composition and identifies 9 distinct states, including proinflammation, chemotaxis, and antigen presentation. The proinflammatory MC subset, characterized by high IL-18 expression, is associated with improved outcomes for LUAD patients. This pro-inflammatory property is regulated by the activation of NLRP3 inflammasome within MCs, resulting in the formation of GSDMD pores and successive pyroptosis. Moreover, these MCs enhance the innate-like anti-tumor activity of MAIT cells by upregulating NKG2D and IFN-γ through the cytokine-activation mechanism. Our results uncover an unappreciated state of MCs and describe an inflammasome-dependent, MC-mediated regulation of MAIT cells in LUAD. These findings diversify our understanding of the functional repertoire and mechanistic equipment of MCs and MAIT cells, and suggest a potential therapeutic target for cancer treatment.

DOI: https://doi.org/10.1038/s41467-025-61324-w
Front Immunol. 2025 ;16 1602934

The emerging relationship between mucosal-associated invariant T cell populations and the onset and progression of type 1 diabetes.

Devin R Fraser, Andrew W Stadnyk.

  Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by autoreactive CD8+ T cells that destroy insulin-producing pancreatic β-cells. CD8+ T cells are unlikely to be the only cells involved in diabetes. Relatively recently described and still enigmatic, Mucosal-associated invariant T (MAIT) cells, innate-like T cells that recognize microbial-derived peptides, exist in the blood and tissues and are implicated in early immune responses. Immunological differences, some of which implicate MAIT cells, exist between individuals at different stages of T1D progression. This review explores the emerging relationship between gastrointestinal and pancreatic MAIT cell populations and the onset and progression of T1D. Early microbial colonization is critical for immune maturation, homeostasis, and MAIT cell development, and disruptions such as Caesarean delivery or antibiotic-induced dysbiosis correlate with increased T1D incidence. Diabetes progression in the diabetes-prone NOD mice is associated with reduced gut mucosal integrity, impairing the protective IL-17 and IL-22 responses of gut-resident MAIT cells and exacerbating systemic inflammation. MAIT cells recruited to the inflamed pancreas during T1D onset likely contribute to β-cell destruction through IFN-γ and granzyme B production. This hypothesis is supported by altered MAIT cell frequencies and phenotypes in individuals with T1D; MAIT cells are reduced in the blood of children recently diagnosed with T1D, potentially corresponding to pancreatic migration, while adults with long-term T1D have persistent, circulating MAIT cells with exhaustion markers. MAIT cells appear to have dual protective and pathogenic roles impacted by microbiome interactions. Understanding these relationships may inform non-invasive biomarkers for the disease.

Keywords:  MAIT cell; inflammation; interleukin; microbiome; type 1 diabetes

DOI:  https://doi.org/10.3389/fimmu.2025.1602934
PLoS Pathog. 2025 Jul 01. 21(7): e1012632

Disruption of riboflavin biosynthesis in mycobacteria establishes riboflavin pathway intermediates as key precursors of MAIT cell agonists.

Melissa D Chengalroyen, Nurudeen Oketade, Aneta Worley, Megan Lucas, Luisa Maria Nieto Ramirez, Mabule L Raphela, Gwendolyn M Swarbrick, Paul S Soma, Mandisa Zuma, Digby F Warner, Deborah A Lewinsohn, Carolina Mehaffy, Erin J Adams, William Hildebrand, Karen M Dobos, Valerie Mizrahi, David M Lewinsohn.

Mucosal-associated invariant T (MAIT) cells exhibit an intrinsic ability to recognize and respond to microbial infections. The semi-invariant antigen recognition receptor of MAIT cells specifically detects the non-polymorphic antigen-presenting molecule, major histocompatibility complex class I-related protein 1 (MR1), which primarily binds riboflavin-derived metabolites of microbial origin. To further interrogate the dependence of these antigens on riboflavin biosynthesis in mycobacteria, we deleted individual genes in the riboflavin biosynthesis pathways in Mycobacterium smegmatis (Msm) and Mycobacterium tuberculosis (Mtb) and evaluated the impact thereof on MAIT cell activation. Blocking the early steps of the pathway by deletion of RibA2 or RibG profoundly reduced, but did not completely ablate, MAIT cell activation by Msm or Mtb, whereas deletion of RibC, which catalyzes the last step in the pathway, had no significant effect. Interestingly, deletion of the lumazine synthase (RibH) specifically enhanced MAIT cell recognition of Mtb whereas loss of lumazine synthase activity had no impact on MAIT cell activation by Msm. MAIT cell activation by Msm was likewise unaffected by blocking the production of the MAIT cell antagonist, Fo (by inhibiting its conversion from the riboflavin pathway intermediate, 5-amino-6-D-ribitylaminouracil (5-A-RU), through the deletion of fbiC). Together, these results confirm a central role for 5-A-RU in generating mycobacterial MR1 ligands and reveal similarities and differences between Msm and Mtb in terms of the impact of riboflavin pathway disruption on MAIT cell activation.

DOI: https://doi.org/10.1371/journal.ppat.1012632
Immunology. 2025 Jun 29.

Distinct T Cell Receptor Clonotypes in the Sardinian Population Highlight the Role of Mucosal-Associated Invariant T Cells and Invariant Natural Killer T Cells in Multiple Sclerosis.

Jiaxin Shen, Elena Rita Simula, Yisu Liu, Gustavo Sganzerla Martinez, Xiaofen Wen, David J Kelvin, Leonardo A Sechi.

  Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory disease of the central nervous system, driven by T-cell mediated immune responses. Studying T-cell receptor (TCR) clonotypes specific to MS in distinct populations can provide insights into disease mechanisms. The Sardinian population, with its unique genetic background resulting from geographical isolation, presents a high-risk cohort for MS research, offering a valuable context for understanding the disease's pathogenesis. We analysed the frequency of unique TCR clonotypes in peripheral blood samples from Sardinian MS patients and healthy controls, focusing on TCRα and TCRβ CDR3 sequences. Clonotypes were functionally annotated for antigen-specific interactions, and hierarchical analysis was performed to identify shared TCR clonotypes between MS patients and healthy controls. A total of 119 TCRβ and 521 TCRα CDR3 clonotypes were significantly more frequent in MS patients compared to healthy controls (p < 0.05). Several TCR-α clonotypes, such as CAVLDSNYQLIW (a MAIT cell clonotype targeting the BST2 antigen) and CAVNTGNQFYF (cross-reactive to multiple antigens, including CMV p65 and BST2), were identified as specific to MS. Shared clonotype analysis revealed the involvement of mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells in MS pathogenesis. Notably, HCV-specific TCR-α clonotypes (NS3-HCV) were significantly increased in MS patients, suggesting a link between infectious disease-related and autoimmune-related clonotypes. No significant differences were observed for other antigens, such as VP22, p65 and BST2. This study identifies distinct TCR clonotypes associated with MS in the Sardinian population, highlighting the role of MAIT and iNKT cells in the disease's pathogenesis. The findings suggest that HCV-specific TCR repertoires may contribute to the development of MS. These results improve our understanding of T-cell mediated immune mechanisms in MS and offer potential targets for therapeutic intervention, particularly within the Sardinian cohort.

Keywords:  MAIT and iNKT cells; Sardinian population; T cell receptor (TCR) clonotypes; multiple sclerosis (MS)

DOI:  https://doi.org/10.1111/imm.70013
Transl Oncol. 2025 Jun 27. pii: S1936-5233(25)00192-5. [Epub ahead of print]59 102461

Circulating mucosa-associated invariant T cells are decreased and have impaired function in patients with diffuse large B-cell lymphoma.

Jingru Liu, Jiadi Chen, Shucheng Chen, Yanrong Huang, Kaiming Xu, Danni Cai, Xinai Liao, Ruolan You, Xiaolin Xu, Xiaoting Wang, Diyu Hou, Shuxia Zhang, Fuwen Yang, Huifang Huang.

  Mucosa-associated invariant T (MAIT) cells are associated with tumor immunity. However, their role in diffuse large B-cell lymphoma (DLBCL) remains unclear. Therefore, this study aimed to elucidate frequency and functional characteristics of circulating MAIT cells in DLBCL patients. The findings revealed a significant reduction in the frequency of circulating MAIT cells in DLBCL patients compared to age-matched healthy controls. Moreover, circulating MAIT cells from DLBCL patients exhibited proapoptotic and senescent phenotypes and demonstrated dysfunction, as evidenced by elevated expression of activation and exhaustion markers, including CD69, CD25, HLA-DR, PD-1, and Tim-3. MAIT cells derived from DLBCL produced lower levels of crucial anti-tumor cytokines, such as interferon-gamma, interleukin-17, tumor necrosis factor-α and granzyme B, suggesting impaired anti-tumor immunity. Additionally, MAIT cells from DLBCL patients showed diminished cytotoxicity against DLBCL cells compared to those from healthy donors. Notably, a lower frequency of circulating MAIT cells in patients with DLBCL was associated with poor prognosis. In summary, this study reveals reduced and impaired circulating MAIT cells in DLBCL patients, suggesting their importance in anti-lymphoma immunity.

Keywords:  Diffuse large B-cell lymphoma; Dysfunction; Mucosa-associated invariant T cells; Prognosis

DOI:  https://doi.org/10.1016/j.tranon.2025.102461
bioRxiv. 2025 Jun 17. pii: 2025.06.11.659204. [Epub ahead of print]

Selective inhibition of MR1-restricted T cell activation by a novel MR1-targeting nanobody.

Timothy Bates, Corinna Kulicke, Sintayehu Gurmessa, Se-Jin Kim, Sushant Suresh, Jules Reyes-Weinstein, Audrey Hinchliff, John Burke, David Lewinsohn, Fikadu G Tafesse.

MR1 is a non-polymorphic, ubiquitously expressed, MHC class I-like antigen-presenting molecule that presents small-molecule metabolites to T cells. Studies have shown that MR1 plays a role in microbial infection, inflammation, and tumor immunity. The antigens it presents include metabolites of microbial and self-origin as well as small-molecule drugs and form stable complexes with MR1 that are displayed on the cell surface to activate T cells. However, unlike classical MHC I and II molecules, the fundamental biology of MR1 remains poorly understood, particularly the mechanisms governing antigen loading and intracellular trafficking. This knowledge gap is largely due to the lack of molecular tools available to precisely manipulate MR1 function. In this study, we describe a high-affinity (1.6 nM K D ) anti-MR1 nanobody, MR1Nb1. We characterize the binding of this nanobody including affinity by ELISA and kinetics by BLI. Crucially, we map the binding epitope of MR1Nb1 on MR1 by HDX-MS, providing key insights into the mechanism through which it blocks MR1T cell activation. In functional assays MR1Nb1 effectively and specifically blocks MAIT cell activation by cells infected with M. tuberculosis or treated with M. smegmatis supernatant. This nanobody represents a unique and versatile tool for the field, as it can be produced inexpensively and expressed intracellularly within antigen-presenting cells. Hence, our study provides a powerful new molecular probe for dissecting the mechanistic underpinnings of MR1 biology and uncover its broader roles in immunity.

DOI: https://doi.org/10.1101/2025.06.11.659204