OBJECTIVE: Oral lichen planus (OLP) is a chronic inflammatory disease characterized by a dense T-cell infiltration and the degeneration of basal keratinocytes. The potential functions of mucosal associated invariant T (MAIT) cells in OLP have been analyzed in our previous study. Keratinocytes under proinflammatory conditions have been demonstrated to activate T cells. This study was aimed to investigate how keratinocytes stimulate MAIT cells in OLP, and to explore the role of activated MAIT cells on keratinocytes.
RESULTS: Increased MAIT cells and higher activation marker CD69 were detected in OLP lesions by flow cytometry. The enhanced expression of MHC class I-like molecule (MR1) required for MAIT cell activation in the epithelial layer of OLP lesions was determined by immunohistochemistry. Keratinocytes treated by 5-A-RU prodrug and lipopolysaccharide, respectively, exhibited higher expression of MR1 and secretion of IL-18. In direct coculture systems consisting of keratinocytes and peripheral blood mononuclear cells, both 5-A-RU prodrug-pretreated keratinocytes and lipopolysaccharide-pretreated keratinocytes activated MAIT cells to secrete granzyme B, contributing to elevated keratinocyte apoptosis.
CONCLUSIONS: Keratinocytes were capable to activate MAIT cells via MR1 and cytokines in OLP, and granzyme B produced by activated MAIT cells intensified keratinocyte apoptosis, engaging in the pathogenesis of OLP.

The immune system classically consists of 2 lines of defense, innate and adaptive, both of which interact with one another effectively to protect us against any pathogenic threats. Importantly, there is a diverse subset of cells known as innate-like T cells that act as a bridge between the innate and adaptive immune systems and are pivotal players in eliciting inflammatory immune responses. A growing body of evidence has demonstrated the regulatory impact of these innate-like T cells in central nervous system (CNS) diseases and that such immune cells can traffic into the brain in multiple pathological conditions, which can be typically attributed to the breakdown of the blood-brain barrier. However, until now, it has been poorly understood whether innate-like T cells have direct protective or causative properties, particularly in CNS diseases. Therefore, in this review, our attention is focused on discussing the critical roles of 3 unique subsets of unconventional T cells, namely, natural killer T cells, γδ T cells, and mucosal-associated invariant T cells, in the context of CNS diseases, disorders, and injuries and how the interplay of these immune cells modulates CNS pathology, in an attempt to gain a better understanding of their complex functions.

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The major histocompatibility complex (MHC) class I-related molecule, MR1, is a key component of the immune system, presenting antigens to T-cell receptors (TCRs) and modulating the immune response against various antigens. MR1 possesses a compact ligand-binding pocket despite its ability to interact with ligands that can have either agonistic or antagonistic effects on the immune system. Agonistic ligands can stimulate the immune response, while antagonistic ligands do not elicit an immune response. In most cases, ligand binding to MR1 is mediated through a covalent bond with Lys43. However, recent studies have suggested that a variety of small molecules can interact with the MR1-binding site. In this study, we have used several approaches to improve the binding pose prediction of covalent ligands to MR1, including docking in mutated receptors, and imposing simple pharmacophore constraints and structural water molecules. The careful assignment of pharmacophore constraints and inclusion of structural water molecules in the challenging docking process of covalent docking improved the binding pose prediction and virtual screening performance. In a retrospective virtual screening, the proposed approach exhibited EF1% and EF2% values of 7.4 and 5.5, respectively. Conversely, when using the mutated receptor, both EF1% and EF2% were recorded as 0 for the conventional docking method. The performance of the pharmacophore constraints was also evaluated on other covalent docking cases, and compared to previously reported results for common covalent docking methods. The proposed approach achieved an average RMSD of 2.55, while AutoDock4, CovDock, FITTED, GOLD, ICM-Pro, and MOE exhibited average RMSD values of 3.0, 2.93, 3.04, 4.93, 2.44, and 3.36, respectively. Our results demonstrate that the inclusion of simple pharmacophore constraints and structural waters can improve the prediction of binding poses of covalent ligands to MR1, which can aid in the discovery of novel immunotherapeutic agents.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s13205-023-03694-w.

Metabolite-based T-cell immunity is emerging as a major player in antimicrobial immunity, autoimmunity, and cancer. Here, small-molecule metabolites were identified to be captured and presented by the major histocompatibility complex class-I-related molecule (MR1) to T cells, namely mucosal-associated invariant T cells (MAIT) and diverse MR1-restricted T cells. Both MR1 and MAIT are evolutionarily conserved in many mammals, suggesting important roles in host immunity. Rational chemical modifications of these naturally occurring metabolites, termed altered metabolite ligands (AMLs), have advanced our understanding of the molecular correlates of MAIT T cell receptor (TCR)-MR1 recognition. This review provides a generalized framework for metabolite recognition and modulation of MAIT cells.

Non-classical HLA restricted T cell subsets such as γδ T and NK-T cells are showing promises for immune-based therapy of hematological malignancies. Mucosal-Associated Invariant T cells (MAIT) belong to this family of innate-like T cell subsets and are the focus of many studies on infectious diseases, owing to their unusual recognition of bacterial/fungal metabolites. Their ability to produce type 1 cytokines (IFNγ, TNFα) as well as cytotoxic effector molecules endows them with potential anti-tumor functions. However, their contribution to tumor surveillance in solid cancers is unclear, and only few studies have specifically focused on MAIT cells in blood cancers. In this review, we wish to recapitulate our current knowledge on MAIT cells biology in hematological neoplasms, at diagnosis and/or during treatment, as well as tentative approaches to target them as therapeutic tools. We also wish to take this opportunity to briefly elaborate on what we think are important question to address in this field, as well as potential limitations to overcome in order to make MAIT cells the basis of future, novel therapies for hematological cancers.

The antigen presentation molecule MHC class I related protein-1 (MR1) is best characterized by its ability to present bacterially derived metabolites of vitamin B2 biosynthesis to mucosal-associated invariant T-cells (MAIT cells).
Through in vitro human cytomegalovirus (HCMV) infection in the presence of MR1 ligand we investigate the modulation of MR1 expression. Using coimmunoprecipitation, mass spectrometry, expression by recombinant adenovirus and HCMV deletion mutants we investigate HCMV gpUS9 and its family members as potential regulators of MR1 expression. The functional consequences of MR1 modulation by HCMV infection are explored in coculture activation assays with either Jurkat cells engineered to express the MAIT cell TCR or primary MAIT cells. MR1 dependence in these activation assays is established by addition of MR1 neutralizing antibody and CRISPR/Cas-9 mediated MR1 knockout.
Here we demonstrate that HCMV infection efficiently suppresses MR1 surface expression and reduces total MR1 protein levels. Expression of the viral glycoprotein gpUS9 in isolation could reduce both cell surface and total MR1 levels, with analysis of a specific US9 HCMV deletion mutant suggesting that the virus can target MR1 using multiple mechanisms. Functional assays with primary MAIT cells demonstrated the ability of HCMV infection to inhibit bacterially driven, MR1-dependent activation using both neutralizing antibodies and engineered MR1 knockout cells.
This study identifies a strategy encoded by HCMV to disrupt the MR1:MAIT cell axis. This immune axis is less well characterized in the context of viral infection. HCMV encodes hundreds of proteins, some of which regulate the expression of antigen presentation molecules. However the ability of this virus to regulate the MR1:MAIT TCR axis has not been studied in detail.

Mucosal-associated invariant T (MAIT) cells are a subset of innate T lymphocytes that express the semi-invariant T cell receptor and recognize riboflavin metabolites via the major histocompatibility complex class I-related protein. Given the abundance of MAIT cells in the human body, their role in human diseases has been increasingly studied in recent years. MAIT cells may serve as targets for clinical therapy. Specifically, this review discusses how MAIT cells are altered in gastric, esophageal, intestinal, and hepatobiliary diseases and describes their protective or pathogenic roles. A greater understanding of MAIT cells will provide a more favorable therapeutic approach for digestive diseases in the clinical field.

Strategies to modify the gut microbiome in cancer patients using fecal microbiota transplantation (FMT) have gained momentum as a therapeutic intervention. However, how FMT impacts innate-like, antimicrobial T lymphocytes is unclear. In this study, we assessed peripheral blood (PB) mucosa-associated invariant T (MAIT) cell frequencies and functions in patients with metastatic renal cell carcinoma (mRCC) before and seven days after they received FMT as part of a clinical trial. We found comparable MAIT cell frequencies in healthy controls and mRCC patients. In contrast, γδ T cells exhibited a numerical decline in mRCC, which was partially reversed by FMT. We also found a significant increase in the PB CD4+ MAIT cell compartment of mRCC patients with or without FMT. Paired sample analyses revealed CD69 upregulation on MAIT cells accompanied by decreased PD-1 levels post-FMT. These changes were unique to MAIT cells as non-MAIT T lymphocytes showed either no trend or a trend in the opposite direction. Importantly, FMT did not render MAIT cells exhausted as also judged by their stable expression of TIM-3, LAG-3, BTLA, CTLA-4, TIGIT and VISTA. These findings were corroborated in functional assays in which MAIT cells were stimulated with MR1 ligands or with a combination of IL-12 and IL-18 to produce inflammatory cytokines and granzyme B. Indeed, when stimulated ex vivo with IL-12 and IL-18, MAIT cells mounted a more rigorous TNF-α response post-FMT. In conclusion, FMT improves MAIT cell functions, which should serve patients well in subsequent microbial challenges in the face of cancer-elicited immunosuppression. Trial Registration: https://clinicaltrials.gov/ Identifier: NCT04163289 (registration date: November 14, 2019).

Mucosal-associated invariant T (MAIT) cells are restricted by MR1 and are known to protect against bacterial and viral infections. Our understanding of the role of MAIT cells in parasitic infections, such as visceral leishmaniasis (VL) caused by protozoan parasites of Leishmania donovani, is limited. This study showed that in response to L. infantum, human peripheral blood MAIT cells from children with leishmaniasis produced TNF and IFN-γ in an MR1-dependent manner. The overall frequency of MAIT cells was inversely correlated with alanine aminotransferase levels, a specific marker of liver damage strongly associated with severe hepatic involvement in VL. In addition, there was a positive correlation between total protein levels and the frequency of IL-17A+ CD8+ MAIT cells, whereby reduced total protein levels are a marker of liver and kidney damage. Furthermore, the frequencies of IFN-γ+ and IL-10+ MAIT cells were inversely correlated with hemoglobin levels, a marker of severe anemia. In asymptomatic individuals and VL patients after treatment, MAIT cells also produced IL-17A, a cytokine signature associated with resistance to visceral leishmaniasis, suggesting that MAIT cells play important role in protecting against VL. In summary, these results broaden our understanding of MAIT-cell immunity to include protection against parasitic infections, with implications for MAIT-cell-based therapeutics and vaccines. At last, this study paves the way for the investigation of putative MAIT cell antigens that could exist in the context of Leishmania infection.