bims-maitce 2024-03-31 papers

bims-maitce

Biomed News

on MAIT cells

Issue of 2024–03–31
eight papers selected by
Andy E. Hogan, Maynooth University

Mouse mucosal-associated invariant T cell receptor recognition of MR1 presenting the vitamin B metabolite, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil.
Innate-like T cell subset commitment in the murine thymus is independent of TCR characteristics and occurs during proliferation.
Enrichment of liver MAIT cells in a mouse model of Alzheimer's disease.
Phenotype and function of MAIT cells in patients with alveolar echinococcosis.
Investigating Vα7.2+/CD161- T Cell and MAIT Cell Profiles Using Flow Cytometry in Healthy Subjects and Subjects with Atopic Dermatitis.
Chronic Viral Infection Compromises the Quality of Circulating Mucosal-Associated Invariant T Cells and Follicular T Helper Cells via Expression of Inhibitory Receptors.
Mucosal-associated invariant T cells in cancer: dual roles, complex interactions and therapeutic potential.
Signals that control MAIT cell function in healthy and inflamed human tissues.

J Biol Chem. 2024 Mar 25. pii: S0021-9258(24)01726-5. [Epub ahead of print] 107229

Mouse mucosal-associated invariant T cell receptor recognition of MR1 presenting the vitamin B metabolite, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil.

Lisa Ciacchi, Jeffrey Y W Mak, Jeremy P Le, David P Fairlie, James McCluskey, Alexandra J Corbett, Jamie Rossjohn, Wael Awad.

  Mucosal-associated invariant T (MAIT) cells can elicit immune responses against riboflavin-based antigens presented by the evolutionary conserved MHC Class I related-1 protein, MR1. While we have an understanding of the structural basis of human MAIT cell receptor (TCR) recognition of human MR1 presenting a variety of ligands, how the semi-invariant mouse MAIT TCR binds mouse MR1-ligand remains unknown. Here we determine the crystal structures of two mouse TRAV1-TRBV13-2+ MAIT TCR-MR1-5-OP-RU ternary complexes, whose TCRs differ only in the composition of their CDR3β loops. These mouse MAIT TCRs mediate high affinity interactions with mouse MR1-5-OP-RU and cross-recognise human MR1-5-OP-RU. Similarly, a human MAIT TCR could bind mouse MR1-5-OP-RU with high affinity. This cross-species recognition indicates the evolutionary conserved nature of this MAIT TCR-MR1 axis. Comparing crystal structures of the mouse versus human MAIT TCR-MR1-5-OP-RU complexes provides structural insight into the conserved nature of this MAIT TCR-MR1 interaction, and conserved specificity for the microbial antigens, whereby key germline-encoded interactions required for MAIT activation are maintained. This is an important consideration for the development of MAIT cell-based therapeutics that will rely on preclinical mouse models of disease.

Keywords:  5-OP-RU; Antigen presentation; MHC-related molecule (MR1); Mouse MAIT TCR; protein structure

DOI:  https://doi.org/10.1016/j.jbc.2024.107229
Proc Natl Acad Sci U S A. 2024 Apr 02. 121(14): e2311348121

Innate-like T cell subset commitment in the murine thymus is independent of TCR characteristics and occurs during proliferation.

Vadim K Karnaukhov, Anne-Laure Le Gac, Linda Bilonda Mutala, Aurélie Darbois, Laetitia Perrin, Francois Legoux, Aleksandra M Walczak, Thierry Mora, Olivier Lantz.

  How T-cell receptor (TCR) characteristics determine subset commitment during T-cell development is still unclear. Here, we addressed this question for innate-like T cells, mucosal-associated invariant T (MAIT) cells, and invariant natural killer T (iNKT) cells. MAIT and iNKT cells have similar developmental paths, leading in mice to two effector subsets, cytotoxic (MAIT1/iNKT1) and IL17-secreting (MAIT17/iNKT17). For iNKT1 vs iNKT17 fate choice, an instructive role for TCR affinity was proposed but recent data argue against this model. Herein, we examined TCR role in MAIT and iNKT subset commitment through scRNAseq and TCR repertoire analysis. In our dataset of thymic MAIT cells, we found pairs of T-cell clones with identical amino acid TCR sequences originating from distinct precursors, one of which committed to MAIT1 and the other to MAIT17 fates. Quantitative in silico simulations indicated that the number of such cases is best explained by lineage choice being independent of TCR characteristics. Comparison of TCR features of MAIT1 and MAIT17 clonotypes demonstrated that the subsets cannot be distinguished based on TCR sequence. To pinpoint the developmental stage associated with MAIT sublineage choice, we demonstrated that proliferation takes place both before and after MAIT fate commitment. Altogether, we propose a model of MAIT cell development in which noncommitted, intermediate-stage MAIT cells undergo a first round of proliferation, followed by TCR characteristics-independent commitment to MAIT1 or MAIT17 lineage, followed by an additional round of proliferation. Reanalyzing a published iNKT TCR dataset, we showed that this model is also relevant for iNKT cell development.

Keywords:  MAIT; TCR; development; subset; thymus

DOI:  https://doi.org/10.1073/pnas.2311348121
J Neuroimmunol. 2024 Mar 21. pii: S0165-5728(24)00050-X. [Epub ahead of print]390 578332

Enrichment of liver MAIT cells in a mouse model of Alzheimer's disease.

Season K Wyatt-Johnson, Holly N Kersey, Randy R Brutkiewicz.

  Emerging evidence has supported a role for the immune system and liver in Alzheimer's disease (AD). However, our understanding of how hepatic immune cells are altered in AD is limited. We previously found that brain mucosal-associated invariant T (MAIT) cell numbers are increased in AD. Furthermore, loss of MAIT cells and their antigen-presenting molecule, MR1, reduced amyloid-β accumulation in the brain. MAIT cells are also significantly present in the liver. Therefore, we sought to analyze MAIT and other immune cells in the AD liver. Increased frequency of activated MAIT cells (but not conventional T cells) were found in 8-month-old 5XFAD mouse livers. Therefore, these data raise the possibility that there is a role for peripheral MAIT cells in AD pathology.

Keywords:  5XFAD; Alzheimer's disease; B cells; Liver; MAIT cells; T cells

DOI:  https://doi.org/10.1016/j.jneuroim.2024.578332
Front Immunol. 2024 ;15 1343567

Phenotype and function of MAIT cells in patients with alveolar echinococcosis.

Jintian Li, Hanyue Zhao, Guodong Lv, Kalibixiati Aimulajiang, Liang Li, Renyong Lin, Tuerganaili Aji.

  Mucosal-associated invariant T (MAIT) cells are a subpopulation of unconventional T cells widely involved in chronic liver diseases. However, the potential role and regulating factors of MAIT cells in alveolar echinococcosis (AE), a zoonotic parasitic disease by Echinococcus multilocularis (E. multilocularis) larvae chronically parasitizing liver organs, has not yet been studied. Blood samples (n=29) and liver specimens (n=10) from AE patients were enrolled. The frequency, phenotype, and function of MAIT cells in peripheral blood and liver tissues of AE patients were detected by flow cytometry. The morphology and fibrosis of liver tissue were examined by histopathology and immunohistochemistry. The correlation between peripheral MAIT cell frequency and serologic markers was assessed by collecting clinicopathologic characteristics of AE patients. And the effect of in vitro stimulation with E. multilocularis antigen (Emp) on MAIT cells. In this study, MAIT cells are decreased in peripheral blood and increased in the close-to-lesion liver tissues, especially in areas of fibrosis. Circulating MAIT exhibited activation and exhaustion phenotypes, and intrahepatic MAIT cells showed increased activation phenotypes with increased IFN-γ and IL-17A, and high expression of CXCR5 chemokine receptor. Furthermore, the frequency of circulating MAIT cells was correlated with the size of the lesions and liver function in patients with AE. After excision of the lesion site, circulating MAIT cells returned to normal levels, and the serum cytokines IL-8, IL-12, and IL-18, associated with MAIT cell activation and apoptosis, were altered. Our results demonstrate the status of MAIT cell distribution, functional phenotype, and migration in peripheral blood and tissues of AE patients, highlighting their potential as biomarkers and therapeutic targets.

Keywords:  alveolar echinococcosis; mucosa-associated invariant T cells; parasitic lesion; pro-fibrogenic; serum cytokine

DOI:  https://doi.org/10.3389/fimmu.2024.1343567
Int J Mol Sci. 2024 Mar 20. pii: 3486. [Epub ahead of print]25(6):

Investigating Vα7.2+/CD161- T Cell and MAIT Cell Profiles Using Flow Cytometry in Healthy Subjects and Subjects with Atopic Dermatitis.

Parvind Singh, Krisztian Gaspar, Andrea Szegedi, Laszlo Sajtos, Sandor Barath, Zsuzsanna Hevessy.

  This study investigates the roles of mucosal-associated invariant T (MAIT) cells and Vα7.2+/CD161- T cells in skin diseases, focusing on atopic dermatitis. MAIT cells, crucial for bridging innate and adaptive immunity, were analyzed alongside Vα7.2+/CD161- T cells in peripheral blood samples from 14 atopic dermatitis patients and 10 healthy controls. Flow cytometry and machine learning algorithms were employed for a comprehensive analysis. The results indicate a significant decrease in MAIT cells and CD69 subsets in atopic dermatitis, coupled with elevated CD38 and polyfunctional MAIT cells producing TNFα and Granzyme B (TNFα+/GzB+). Vα7.2+/CD161- T cells in atopic dermatitis exhibited a decrease in CD8 and IFNγ-producing subsets but an increase in CD38 activated and IL-22-producing subsets. These results highlight the distinctive features of MAIT cells and Vα7.2+/CD161- T cells and their different roles in the pathogenesis of atopic dermatitis and provide insights into their potential roles in immune-mediated skin diseases.

Keywords:  MAIT cells; Vα7.2+/CD161− T cells; atopic dermatitis; dimensionality reduction; flow cytometry; unsupervised clustering

DOI:  https://doi.org/10.3390/ijms25063486
Front Biosci (Landmark Ed). 2024 Mar 22. 29(3): 128

Chronic Viral Infection Compromises the Quality of Circulating Mucosal-Associated Invariant T Cells and Follicular T Helper Cells via Expression of Inhibitory Receptors.

Jaisheela Vimali, Yean K Yong, Amudhan Murugesan, Hong Y Tan, Ying Zhang, Rajeev Ashwin, Sivadoss Raju, Pachamuthu Balakrishnan, Marie Larsson, Vijayakumar Velu, Esaki M Shankar.

   BACKGROUND: Chronic viral infection results in impaired immune responses rendering viral persistence. Here, we compared the quality of T-cell responses among chronic hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV)-infected individuals by examining the levels of expression of selected immune activation and exhaustion molecules on circulating MAIT cells and Tfh cells.
METHODS: Cytokines were measured using a commercial Bio-plex Pro Human Cytokine Grp I Panel 17-plex kit (BioRad, Hercules, CA, USA). Inflammation was assessed by measuring an array of plasma cytokines, and phenotypic alterations in CD4+ T cells including circulating Tfh cells, CD8+ T cells, and TCR iVα7.2+ MAIT cells in chronic HBV, HCV, and HIV-infected patients and healthy controls. The cells were characterized based on markers pertaining to immune activation (CD69, ICOS, and CD27) proliferation (Ki67), cytokine production (TNF-α, IFN-γ) and exhaustion (PD-1). The cytokine levels and T cell phenotypes together with cell markers were correlated with surrogate markers of disease progression.
RESULTS: The activation marker CD69 was significantly increased in CD4+hi T cells, while CD8+ MAIT cells producing IFN-γ were significantly increased in chronic HBV, HCV and HIV infections. Six cell phenotypes, viz., TNF-α+CD4+lo T cells, CD69+CD8+ T cells, CD69+CD4+ MAIT cells, PD-1+CD4+hi T cells, PD-1+CD8+ T cells, and Ki67+CD4+ MAIT cells, were independently associated with decelerating the plasma viral load (PVL). TNF-α levels showed a positive correlation with increase in cytokine levels and decrease in PVL.
CONCLUSION: Chronic viral infection negatively impacts the quality of peripheral MAIT cells and Tfh cells via differential expression of both activating and inhibitory receptors.

Keywords:  HBV; HIV; MAIT cells; PD-1; T cell exhaustion

DOI:  https://doi.org/10.31083/j.fbl2903128
Front Immunol. 2024 ;15 1369236

Mucosal-associated invariant T cells in cancer: dual roles, complex interactions and therapeutic potential.

Mesut Yigit, Omer Faruk Basoglu, Derya Unutmaz.

  Mucosal-associated invariant T (MAIT) cells play diverse roles in cancer, infectious diseases, and immunotherapy. This review explores their intricate involvement in cancer, from early detection to their dual functions in promoting inflammation and mediating anti-tumor responses. Within the solid tumor microenvironment (TME), MAIT cells can acquire an 'exhausted' state and secrete tumor-promoting cytokines. On the other hand, MAIT cells are highly cytotoxic, and there is evidence that they may have an anti-tumor immune response. The frequency of MAIT cells and their subsets has also been shown to have prognostic value in several cancer types. Recent innovative approaches, such as programming MAIT cells with chimeric antigen receptors (CARs), provide a novel and exciting approach to utilizing these cells in cell-based cancer immunotherapy. Because MAIT cells have a restricted T cell receptor (TCR) and recognize a common antigen, this also mitigates potential graft-versus-host disease (GVHD) and opens the possibility of using allogeneic MAIT cells as off-the-shelf cell therapies in cancer. Additionally, we outline the interactions of MAIT cells with the microbiome and their critical role in infectious diseases and how this may impact the tumor responses of these cells. Understanding these complex roles can lead to novel therapeutic strategies harnessing the targeting capabilities of MAIT cells.

Keywords:  CAR-MAIT; MAIT cell; cancer; immunotherapy; microbiome; peripheral blood mononuclear cells

DOI:  https://doi.org/10.3389/fimmu.2024.1369236
Immunol Rev. 2024 Mar 22.

Signals that control MAIT cell function in healthy and inflamed human tissues.

Andrew J Konecny, Yin Huang, Manu Setty, Martin Prlic.

  Mucosal-associated invariant T (MAIT) cells have a semi-invariant T-cell receptor that allows recognition of antigen in the context of the MHC class I-related (MR1) protein. Metabolic intermediates of the riboflavin synthesis pathway have been identified as MR1-restricted antigens with agonist properties. As riboflavin synthesis occurs in many bacterial species, but not human cells, it has been proposed that the main purpose of MAIT cells is antibacterial surveillance and protection. The majority of human MAIT cells secrete interferon-gamma (IFNg) upon activation, while some MAIT cells in tissues can also express IL-17. Given that MAIT cells are present in human barrier tissues colonized by a microbiome, MAIT cells must somehow be able to distinguish colonization from infection to ensure effector functions are only elicited when necessary. Importantly, MAIT cells have additional functional properties, including the potential to contribute to restoring tissue homeostasis by expression of CTLA-4 and secretion of the cytokine IL-22. A recent study provided compelling data indicating that the range of human MAIT cell functional properties is explained by plasticity rather than distinct lineages. This further underscores the necessity to better understand how different signals regulate MAIT cell function. In this review, we highlight what is known in regards to activating and inhibitory signals for MAIT cells with a specific focus on signals relevant to healthy and inflamed tissues. We consider the quantity, quality, and the temporal order of these signals on MAIT cell function and discuss the current limitations of computational tools to extrapolate which signals are received by MAIT cells in human tissues. Using lessons learned from conventional CD8 T cells, we also discuss how TCR signals may integrate with cytokine signals in MAIT cells to elicit distinct functional states.

Keywords:  MAIT; agonist; human; inflammation; mucosal‐associated invariant T cell; signal integration; signals; tissue

DOI:  https://doi.org/10.1111/imr.13325