bims-maitce 2024-05-05 papers

Issue of 2024–05–05
five papers selected by
Andy E. Hogan, Maynooth University

PLoS One. 2024 ;19(5): e0294695

Evaluation of mucosal-associated invariant T-cells as a potential biomarker to predict infection risk in liver cirrhosis.

Bonnie Bengtsson, Christopher Maucourant, Johan K Sandberg, Niklas K Björkström, Hannes Hagström.

BACKGROUND AND AIMS: Infection is a serious complication in patients with cirrhosis. Mucosal-associated invariant T (MAIT) cells are involved in the immune defense against infections and known to be impaired in several chronic conditions, including cirrhosis. Here, we evaluated if MAIT cell levels in peripheral blood are associated with risk of bacterial infections in patients with cirrhosis.
METHODS: Patients with cirrhosis seen at the Karolinska University Hospital, Stockholm, Sweden, between 2016 and 2019 were included. Levels of MAIT cells in peripheral blood were determined using flow cytometry. Baseline and follow-up data after at least two years of follow-up were collected by chart review for the primary outcome (bacterial infection) and secondary outcomes (decompensation and death). Competing risk and Cox regression were performed.
RESULTS: We included 106 patients with cirrhosis. The median MAIT cells fraction in the circulation was 0.8% in cirrhosis compared to 6.1% in healthy controls. In contrast to our hypothesis, we found an association in the adjusted analysis between relatively preserved MAIT cell levels, and a slightly higher risk to develop bacterial infections (adjusted subdistribution hazard ratio (aSHR) 1.15 (95%CI = 1.01-1.31). However, MAIT cell levels were not associated with the risk of hepatic decompensation (aSHR 1.19 (95%CI = 0.91-1.56)) nor with death (adjusted hazard ratio 1.10 (95%CI = 0.97-1.22)).
CONCLUSIONS: Relatively preserved MAIT cell levels in blood of patients with cirrhosis were associated with a somewhat higher risk of bacterial infections. The clinical relevance of this might not be strong. MAIT cells might however be an interesting biomarker to explore in future studies.

DOI: https://doi.org/10.1371/journal.pone.0294695

EBioMedicine. 2024 Apr 27. pii: S2352-3964(24)00173-7. [Epub ahead of print]103 105138

Mucosal-associated invariant T cells promote ductular reaction through amphiregulin in biliary atresia.

Man-Huan Xiao, Sihan Wu, Peishi Liang, Dong Ma, Jiang Zhang, Huadong Chen, Zhihai Zhong, Juncheng Liu, Hong Jiang, Xuyang Feng, Zhenhua Luo.

BACKGROUND: Biliary atresia (BA) is a neonatal fibro-inflammatory cholangiopathy with ductular reaction as a key pathogenic feature predicting poor survival. Mucosal-associated invariant T (MAIT) cells are enriched in human liver and display multiple roles in liver diseases. We aimed to investigate the function of MAIT cells in BA.
METHODS: First, we analyzed correlations between liver MAIT cell and clinical parameters (survival, alanine transaminase, bilirubin, histological inflammation and fibrosis) in two public cohorts of patients with BA (US and China). Kaplan-Meier survival analysis and spearman correlation analysis were employed for survival data and other clinical parameters, respectively. Next, we obtained liver samples or peripheral blood from BA and control patients for bulk RNA sequencing, flow cytometry analysis, immunostaning and functional experiments of MAIT cells. Finally, we established two in vitro co-culture systems, one is the rhesus rotavirus (RRV) infected co-culture system to model immune dysfunction of human BA which was validated by single cell RNA sequencing and the other is a multicellular system composed of biliary organoids, LX-2 and MAIT cells to evaluate the role of MAIT cells on ductular reaction.
FINDINGS: Liver MAIT cells in BA were positively associated with low survival and ductular reaction. Moreover, liver MAIT cells were activated, exhibited a wound healing signature and highly expressed growth factor Amphiregulin (AREG) in a T cell receptor (TCR)-dependent manner. Antagonism of AREG abrogated the proliferative effect of BA MAIT cells on both cholangiocytes and biliary organoids. A RRV infected co-culture system, recapitulated immune dysfunction of human BA, disclosed that RRV-primed MAIT cells promoted cholangiocyte proliferation via AREG, and further induced inflammation and fibrosis in the multicellular system.
INTERPRETATION: MAIT cells exhibit a wound healing signature depending on TCR signaling and promote ductular reaction via AREG, which is associated with advanced fibrosis and predictive of low survival in BA.
FUNDING: This work was funded by National Natural Science Foundation of China grant (82001589 and 92168108), National Key R&D Program of China (2023YFA1801600) and by Basic and Applied Basic Research Foundation of Guangdong (2020A1515110921).

Keywords: AREG; Biliary atresia; Ductular reaction; MAIT cells; TCR-dependent

DOI: https://doi.org/10.1016/j.ebiom.2024.105138

J Exp Clin Cancer Res. 2024 May 03. 43(1): 134

CXCR6-positive circulating mucosal-associated invariant T cells can identify patients with non-small cell lung cancer responding to anti-PD-1 immunotherapy.

Jingjing Qu, Binggen Wu, Lijun Chen, Zuoshi Wen, Liangjie Fang, Jing Zheng, Qian Shen, Jianfu Heng, Jianya Zhou, Jianying Zhou.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells have been reported to regulate tumor immunity. However, the immune characteristics of MAIT cells in non-small cell lung cancer (NSCLC) and their correlation with the treatment efficacy of immune checkpoint inhibitors (ICIs) remain unclear.
PATIENTS AND METHODS: In this study, we performed single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence assays to determine the proportion and characteristics of CD8+MAIT cells in patients with metastatic NSCLC who did and did not respond to anti-PD-1 therapy. Survival analyses were employed to determine the effects of MAIT proportion and C-X-C chemokine receptor 6 (CXCR6) expression on the prognosis of patients with advanced NSCLC.
RESULTS: The proportion of activated and proliferating CD8+MAIT cells were significantly higher in responders-derived peripheral blood mononuclear cells (PBMCs) and lung tissues before anti-PD-1 therapy, with enhanced expression of cytotoxicity-related genes including CCL4, KLRG1, PRF1, NCR3, NKG7, GZMB, and KLRK1. The responders' peripheral and tumor-infiltrating CD8+MAIT cells showed an upregulated CXCR6 expression. Similarly, CXCR6+CD8+MAIT cells from responders showed higher expression of cytotoxicity-related genes, such as CST7, GNLY, KLRG1, NKG7, and PRF1. Patients with ≥15.1% CD8+MAIT cells to CD8+T cells ratio and ≥35.9% CXCR6+CD8+MAIT cells to CD8+MAIT cells ratio in peripheral blood showed better progression-free survival (PFS) after immunotherapy. The role of CD8+MAIT cells in lung cancer immunotherapy was potentially mediated by classical/non-classical monocytes through the CXCL16-CXCR6 axis.
CONCLUSION: CD8+MAIT cells are a potential predictive biomarker for patients with NSCLC responding to anti-PD-1 therapy. The correlation between CD8+MAIT cells and immunotherapy sensitivity may be ascribed to high CXCR6 expression.

Keywords: CXCR6; Circulating mucosal-associated invariant T cells; Immunotherapy; Non-small cell lung cancer; Single-cell RNA-sequencing

DOI: https://doi.org/10.1186/s13046-024-03046-3

Angew Chem Int Ed Engl. 2024 Apr 28. e202400632

Potent Immunomodulators Developed from an Unstable Bacterial Metabolite of Vitamin B2 Biosynthesis.

Jeffrey Y W Mak, Ryan J D Rivero, Huy N Hoang, Xin Yi Lim, Jieru Deng, Hamish E G McWilliam, Jose A Villadangos, James McCluskey, Alexandra J Corbett, David P Fairlie.

Bacterial synthesis of vitamin B2 generates a by-product, 5-(2-oxopropylideneamino)-d-ribityl-aminouracil (5-OP-RU), with potent immunological properties in mammals, but rapid inactivation in water limits practical uses. This natural product covalently bonds to immunological protein MR1 in antigen presenting cells (APCs), enabling MR1 to traffic to the cell surface, where it interacts with T cell receptors (TCRs) on mucosal associated invariant T lymphocytes (MAIT cells), activating their immunological and antimicrobial properties. Here, we develop several new series of water-stable compounds tailored for powerful and distinctive immunological functions. We report their water stability, capacity to bind MR1 and traffic it to the cell surface (EC50 17 nM), potent activation (EC50 56 pM) or inhibition (IC50 80 nM) of interacting MAIT cells, and develop compounds with diazirine-alkyne, biotin, or fluorophore labels for studying cellular MR1. Computer modelling casts new light on the molecular mechanism of activation, revealing that activators are first captured in MR1 via pi-interactions and H-bonds, before tighter covalent bonding to Lys43 in MR1. This chemical study advances our molecular understanding of how bacterial metabolites are captured by MR1, influence cell surface expression of MR1, interact and modify human T cells; offering new clues for developing novel vaccine adjuvants, immunotherapeutics, and cancer drugs.

Keywords: Biological activity; Chemical tools; Covalent ligands; Immunology; Natural Products

DOI: https://doi.org/10.1002/anie.202400632

Immunol Cell Biol. 2024 May 01.

Highlight of 2023: Unconventional T cells: recent insights on development, trafficking and target cell recognition.

Sarah Pasquin.

In this article for the Highlights of 2023 Series, we discuss recent research on unconventional T cells with a focus on gamma delta T cell development and cancer cell targeting, as well as the contributions of MAIT cells to wound repair.

Keywords: Activation; MAIT cells; development; function; unconventional T cells; γδ T cells

DOI: https://doi.org/10.1111/imcb.12767