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Tuberculosis (TB) is still an urgent global public health problem. Notably, mucosal‐associated invariant T (MAIT) cells play an important role in early anti‐TB immune response. Targeted control of them may be an effective method to improve vaccine efficacy and TB treatment. However, the biology and signal regulation mechanisms of MAIT cells in TB patients are still poorly understood. Previous studies have been limited by the lack of reagents to specifically identify MAIT cells. In addition, the use of alternative markers may subsume non‐MAIT cell into MAIT cell populations. In this study, the human MR1 tetramer which can specifically identify MAIT cells was used to further explore the effect and mechanism of MAIT cells in anti‐TB immune response. Our results showed that the tetramer+ MAIT cells in peripheral blood of TB patients were mainly CD8+ or CD4−CD8− cells, and very few were CD4+ cells. After BCG infecting autologous antigen‐presenting cells, MAIT cells in patients produced significantly higher levels of cytokines, lysis and proliferation compared with healthy controls. After suppression of mTORC1 by the mTORC1‐specific inhibitor rapamycin, the immune response of MAIT cells in patients was significantly reduced. This study demonstrates that peripheral blood tetramer+ MAIT cells from TB patients have significant anti‐TB immune effect, which is regulated by mTORC1. This could provide ideas and potential therapeutic targets for the development of novel anti‐TB immunotherapy. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T cells (MAIT cells) are a subset of T cells with innate, effector-like properties that play an essential role in the immune response to microbial infections. In humans, MAIT cells are detectable in the blood, liver, and lungs, but little is known about the frequency of these cells in the bone marrow. Also, the pathogenic role, if any, of MAIT cells in the development of aplastic anemia, a disease with an exquisite origin in the bone marrow, is currently unknown. We investigated the frequency and clinical relevance of bone marrow MAIT cells in a cohort of 14 patients (60.6 ± 23 and 57% women) with aplastic anemia. MAIT cells in the bone marrow samples obtained at diagnosis were evaluated by flow cytometry, and their association with various blood cell parameters and the patients' clinical features was analyzed. MAIT cells were detectable in the bone marrow of all patients, with considerable variations among them. Bone marrow MAIT cells expressing the activator receptor natural killer group 2D - NKG2D (NKG2D+ MAIT cells) were significantly more abundant in the specimens of the aplastic anemia patients than in patients with bone marrow failure distinct from aplastic anemia. In addition, the NKG2D+ MAIT cells positively correlated with whole blood cell counts (WBC), platelet counts, and neutrophil counts, as well as with various inflammatory markers, including neutrophil-to-lymphocyte rate (NLR), platelet-to-lymphocyte rate (PLR), and systemic inflammatory index (SII). In functional studies, bone marrow CD34+ hematopoietic cells exposed to phytohemagglutinin or bacterial-derived lipopolysaccharide and acetyl-6-formylpterin upregulated MR1 (major histocompatibility complex, class I-related, known to interact with MAIT cells) and MICA/B (MHC class I chain-related gene A, a ligand of NKG2D) proteins on their cell surface, suggesting that under stress conditions, CD34+ hematopoietic cells are more likely to interact with NKG2D+ MAIT cells. In addition, NKG2D+ MAIT cells upregulated perforin and granzyme B in response to their interaction with recombinant MICA protein in vitro. This study reports for the first time the frequency of MAIT cells in the bone marrow of patients with aplastic anemia and assesses the potential implications of these cells in the pathogenesis or progression of aplastic anemia. [ABSTRACT FROM AUTHOR]

Mucosal‐associated invariant T (MAIT) cells are innate‐like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro‐inflammatory functions and have potentials for use as adoptive cell therapy. However, studies into their anti‐cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we showed that peritumoral injection of in vivo‐expanded MAIT cells into RAG1−/− mice with MC38‐derived tumours inhibits tumour growth compared to control. Multiplex cytokine analyses showed that tumours from the MAIT cell‐treated group have higher expression of markers for eosinophil‐activating cytokines, suggesting a potential association between eosinophil recruitment and tumour inhibition. In a human peripheral leukocyte co‐culture model, we showed that leukocytes stimulated with MAIT ligand showed an increase in eotaxin‐1 production and activation of eosinophils, associated with increased cancer cell killing. In conclusion, we showed that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil‐associated mechanisms. Our results highlight the potential of MAIT cells for non‐donor restricted colon cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells are unconventional T cells with innate-like antimicrobial responsiveness. MAIT cells are known for MR1 (MHC class I-related protein 1)-restricted recognition of microbial riboflavin metabolites giving them the capacity to respond to a broad range of microbes. However, recent progress has shown that MAIT cells can also respond to several viral infections in humans and in mouse models, ranging from HIV-1 and hepatitis viruses to influenza virus and SARS-CoV-2, in a primarily cognate Ag-independent manner. Depending on the disease context MAIT cells can provide direct or indirect antiviral protection for the host and may help recruit other immune cells, but they may also in some circumstances amplify inflammation and aggravate immunopathology. Furthermore, chronic viral infections are associated with varying degrees of functional and numerical MAIT cell impairment, suggesting secondary consequences for host defense. In this review, we summarize recent progress and highlight outstanding questions regarding the emerging role of MAIT cells in antiviral immunity.

Although mucosal-associated invariant T (MAIT) cells provide rapid, innate-like responses, they are not pre-set, and memory-like responses have been described for MAIT cells following infections. The importance of metabolism for controlling these responses, however, is unknown. Here, following pulmonary immunization with a Salmonella vaccine strain, mouse MAIT cells expanded as separate CD127-Klrg1+ and CD127+Klrg1- antigen-adapted populations that differed in terms of their transcriptome, function and localization in lung tissue. These populations remained altered from steady state for months as stable, separate MAIT cell lineages with enhanced effector programmes and divergent metabolism. CD127+ MAIT cells engaged in an energetic, mitochondrial metabolic programme, which was critical for their maintenance and IL-17A synthesis. This programme was supported by high fatty acid uptake and mitochondrial oxidation and relied on highly polarized mitochondria and autophagy. After vaccination, CD127+ MAIT cells protected mice against Streptococcus pneumoniae infection. In contrast, Klrg1+ MAIT cells had dormant but ready-to-respond mitochondria and depended instead on Hif1a-driven glycolysis to survive and produce IFN-γ. They responded antigen independently and participated in protection from influenza virus. These metabolic dependencies may enable tuning of memory-like MAIT cell responses for vaccination and immunotherapies.

Human mucosal-associated invariant T (MAIT) cells are characterized by their expression of an invariant TCR α chain Vα7.2-Jα33/Jα20/Jα12 paired with a restricted TCR β chain. MAIT cells recognize microbial peptides presented by the highly conserved MHC class I-like molecule MR1 and bridge the innate and acquired immune systems to mediate augmented immune responses. Upon activation, MAIT cells rapidly proliferate, produce a variety of cytokines and cytotoxic molecules, and trigger efficient antitumor immunity. Administration of a representative MAIT cell ligand 5-OP-RU effectively activates MAIT cells and enhances their antitumor capacity. In this review, we introduce MAIT cell biology and their importance in antitumor immunity, summarize the current development of peripheral blood mononuclear cell-derived and stem cell-derived MAIT cell products for cancer treatment, and discuss the potential of genetic engineering of MAIT cells for off-the-shelf cancer immunotherapy.

Background: Currently, there is a lack of an objective quantitative measure to comprehensively evaluate the inflammatory activity of axSpA, which poses certain challenges in accurately assessing the disease activity. Objective: To explore the value of combined-parameter models of sacroiliac joints (SIJs) MRI relaxometry and peripheral blood Mucosalassociated invariant T (MAIT) cells in evaluating the inflammatory activity of axial spondyloarthritis (axSpA). Methods: This retrospective clinical study included 88 axSpA patients (median age 31.0 (22.0, 41.8) years, 21.6% females) and 20 controls (median age 28.0 (20.5, 49.5) years, 40.0% females). The axSpA group was classified into active subgroup (n=50) and inactive subgroup (n=38) based on ASDAS-CRP. All participants underwent SIJs MRI examination including T1 and T2* mapping, and peripheral blood flow cytometry analysis of MAIT cells (defined as CD3+Vα7.2+CD161+) and their activation markers (CD69). The T1 and T2* values, as were the percentages of MAIT cells and CD69+MAIT cells were compared between different groups. Combined-parameter models were established using logistic regression, and ROC curves were employed to evaluate the diagnostic efficacy. Results: The T1 values of SIJs and %CD69+MAIT cells in the axSpA group and its subgroup were higher than the control group (p<0.05), while %MAIT cells were lower than the control group (p<0.05). The T1 values and %CD69+MAIT cells correlated positively, while %MAIT cells correlated negatively, with the ASDASCRP (r=0.555, 0.524, -0.357, p<0.001). Between the control and axSpA groups, and between the inactive and active subgroups, the combined-parameter model T1 mapping+%CD69+MAIT cells has the best efficacy (AUC=0.959, 0.879, sensibility=88.6, 70%, specificity=95.0, 94.7%, respectively). Conclusion: The combined-parameter model T1 mapping+%CD69+MAIT cells allows a more accurate evaluation of the level of inflammatory activity. [ABSTRACT FROM AUTHOR]

The dog is valued as a companion animal and increasingly recognized as a model for human disorders. Given the importance of T cells in health and disease, comprehensive knowledge of canine T cells can contribute to our understanding of pathogenesis mechanisms and inform the development of new treatment strategies. However, the diversity of canine T cells is still poorly understood mainly due to the lack of species-reactive antibodies for use in flow cytometry. The aim of this study was to generate a detailed atlas of peripheral blood TCRαβ+ T cells of healthy dogs using single-cell RNA-sequencing (scRNAseq) combined with immune repertoire sequencing. A total of 22 TCRαβ+ T cell clusters were identified, which were classified into three major groups: CD4-dominant (11 clusters), CD8A-dominant (8 clusters), and CD4/CD8A-mixed (3 clusters). Based on differential gene expression, distinct differentiation states (naïve, effector, memory, exhausted) and lineages (e.g. CD4 T helper and regulatory T cells) could be distinguished. Importantly, several T cell populations were identified, which have not been described in dogs before. Of particular note, our data provide first evidence for the existence of canine mucosa-associated invariant T cell (MAIT)-like cells, representing one of three newly identified FCER1G+ innate-like CD8A+ T cell populations in the peripheral blood of healthy dogs. In conclusion, using scRNAseq combined with immune repertoire sequencing we were able to resolve canine TCRαβ+ T cell populations at unprecedented resolution. The peripheral blood TCRαβ+ T cell atlas of healthy dogs generated here represents an important reference data set for future studies and is of relevance for identifying new targets for T cell-specific therapies.

Background: Patients with non‐small cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD) experience worse clinical outcomes but respond better to immunotherapy than patients with NSCLC without COPD. Mucosal‐associated invariant T (MAIT) cells, a versatile population of innate immune T lymphocytes, have a crucial function in the response to infection and tumors. This study investigated the distribution of MAIT cells in COPD‐associated NSCLC and their involvement in the immune response. Methods: Flow cytometry, immunohistochemistry, and immunofluorescence were performed on tissue samples of patients with NSCLC, with or without COPD, treated with or without anti‐programmed death 1 (PD1) immunotherapy. MAIT cells were stimulated with 5‐OP‐RU using a mouse subcutaneous tumor model. Results: Tumors contained significantly more MAIT cells than paraneoplastic tissues, and CD8+ MAIT cells accounted for more than 90% of these cells. Patients with NSCLC and COPD had higher CD8+ MAIT cell counts than those with NSCLC without COPD. Additionally, patients with NSCLC and COPD displayed reduced expression of the activation marker, CD69, and functional markers, granzyme B (GZMB) and interferon γ (IFNγ), and higher expression of the immune exhaustion marker, PD1. Among patients who received immunotherapy, the proportion with a complete or partial response was higher in those with COPD than in those without COPD. In patients with NSCLC and COPD, the major pathologic response (MPR) group had higher MAIT levels than those in the no major pathologic response (NPR) group. In the mouse subcutaneous tumor model stimulation of MAIT cells using 5‐OP‐RU enhanced the antitumor effects of anti‐PD1. Conclusions: In patients with NSCLC and COPD, response to immunotherapy is associated with accumulation of CD8+ MAIT cells showing immune exhaustion. These findings may contribute to innovative approaches for immunotherapy targeting CD8+ MAIT cells. [ABSTRACT FROM AUTHOR]

Background: Mepolizumab treatment improves symptom control and quality of life and reduces exacerbations in patients with severe eosinophilic asthma. However, biomarkers that predict therapeutic effectiveness must be determined for use in precision medicine. Herein, we elucidated the dynamics of various parameters before and after treatment as well as patient characteristics predictive of clinical responsiveness to mepolizumab after 1-year treatment. Methods: Twenty-seven patients with severe asthma were treated with mepolizumab for one year. Asthma control test scores, pulmonary function tests, fractional exhaled nitric oxide levels, and blood samples were evaluated. Additionally, we explored the role of CD69-positive mucosal-associated invariant T (MAIT) cells as a candidate biomarker for predicting treatment effectiveness by evaluating an OVA-induced asthma murine model using MR1 knockout mice, where MAIT cells were absent. Results: The frequencies of CD69-positive group 1 innate lymphoid cells, group 3 innate lymphoid cells, natural killer cells, and MAIT cells decreased after mepolizumab treatment. The frequency of CD69-positive MAIT cells and neutrophils was lower and serum periostin levels were higher in responders than in non-responders. In the OVA-induced asthma murine model, CD69-positive MAIT cell count in the whole mouse lung was significantly higher than that in the control mice. Moreover, OVA-induced eosinophilic airway inflammation was exacerbated in the MAIT cell-deficient MR1 knockout mice. Conclusions: This study shows that circulating CD69-positive MAIT cells, neutrophils, and serum periostin might predict the real-world response after 1-year mepolizumab treatment. Furthermore, MAIT cells potentially have a protective role against type 2 airway inflammation.

Cell-mediated immunity (CMI) is crucial in controlling the highly aggressive and progressive SARS-CoV-2 infection. Despite extensive researches on severe COVID-19 infection, the etiology and/or mechanisms of lymphopenia, decreased T cell-mediated responses in patients, cytokine release storms (CRS), and enhanced pro-inflammatory mediators are not fully understood. Several T cell subpopulations, including innate-like lymphocytes (ILLs) and conventional T cells, are involved in COVID-19 infection; however, their contribution to immunity and complications remains to be more elucidated. CD16+ T cells are among the effective players in the development of T helper1 (Th1) responses in COVID-19 infection, while their robust cytolytic properties contribute to lung tissue damage. While CD56-CD16bright NK cells play a protective role, natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells, and γδ T cells and their roles in COVID-19 require further investigation. The involvement of the other T cell subsets, such as Th17, along with neutrophils, adds to the complexity of the situation. In this review, we presented and discussed the findings of recent studies on T cell responses and the contribution of each type of immune cells to COVID-19.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that are highly abundant in human blood and tissues. Most MAIT cells have an invariant TCRα-chain that uses T cell receptor α-variable 1-2 (TRAV1-2) joined to TRAJ33/20/12 and recognizes metabolites from bacterial riboflavin synthesis bound to the Ag-presenting molecule MHC class I related (MR1). Our attempts to identify alternative MR1-presented Ags led to the discovery of rare MR1-restricted T cells with non-TRAV1-2 TCRs. Because altered Ag specificity likely alters affinity for the most potent known Ag, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), we performed bulk TCRα- and TCRβ-chain sequencing and single-cell-based paired TCR sequencing on T cells that bound the MR1-5-OP-RU tetramer with differing intensities. Bulk sequencing showed that use of V genes other than TRAV1-2 was enriched among MR1-5-OP-RU tetramerlow cells. Although we initially interpreted these as diverse MR1-restricted TCRs, single-cell TCR sequencing revealed that cells expressing atypical TCRα-chains also coexpressed an invariant MAIT TCRα-chain. Transfection of each non-TRAV1-2 TCRα-chain with the TCRβ-chain from the same cell demonstrated that the non-TRAV1-2 TCR did not bind the MR1-5-OP-RU tetramer. Thus, dual TCRα-chain expression in human T cells and competition for the endogenous β-chain explains the existence of some MR1-5-OP-RU tetramerlow T cells. The discovery of simultaneous expression of canonical and noncanonical TCRs on the same T cell means that claims of roles for non-TRAV1-2 TCR in MR1 response must be validated by TCR transfer-based confirmation of Ag specificity.

Anti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from coronavirus disease 2019 (COVID-19) in high-risk populations, such as people with diabetes and the elderly; however, data on their efficacy in these populations are limited. We demonstrate that prophylactic mAb treatment blocks viral replication in both the upper and lower respiratory tracts in aged, type 2 diabetic rhesus macaques. mAb infusion dramatically curtails severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing development of interstitial pneumonia. Furthermore, mAb infusion significantly dampens the greater than 3-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data show that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.

Abstract Background Patients with non‐small cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD) experience worse clinical outcomes but respond better to immunotherapy than patients with NSCLC without COPD. Mucosal‐associated invariant T (MAIT) cells, a versatile population of innate immune T lymphocytes, have a crucial function in the response to infection and tumors. This study investigated the distribution of MAIT cells in COPD‐associated NSCLC and their involvement in the immune response. Methods Flow cytometry, immunohistochemistry, and immunofluorescence were performed on tissue samples of patients with NSCLC, with or without COPD, treated with or without anti‐programmed death 1 (PD1) immunotherapy. MAIT cells were stimulated with 5‐OP‐RU using a mouse subcutaneous tumor model. Results Tumors contained significantly more MAIT cells than paraneoplastic tissues, and CD8+ MAIT cells accounted for more than 90% of these cells. Patients with NSCLC and COPD had higher CD8+ MAIT cell counts than those with NSCLC without COPD. Additionally, patients with NSCLC and COPD displayed reduced expression of the activation marker, CD69, and functional markers, granzyme B (GZMB) and interferon γ (IFNγ), and higher expression of the immune exhaustion marker, PD1. Among patients who received immunotherapy, the proportion with a complete or partial response was higher in those with COPD than in those without COPD. In patients with NSCLC and COPD, the major pathologic response (MPR) group had higher MAIT levels than those in the no major pathologic response (NPR) group. In the mouse subcutaneous tumor model stimulation of MAIT cells using 5‐OP‐RU enhanced the antitumor effects of anti‐PD1. Conclusions In patients with NSCLC and COPD, response to immunotherapy is associated with accumulation of CD8+ MAIT cells showing immune exhaustion. These findings may contribute to innovative approaches for immunotherapy targeting CD8+ MAIT cells.

Mepolizumab treatment improves symptom control and quality of life and reduces exacerbations in patients with severe eosinophilic asthma. However, biomarkers that predict therapeutic effectiveness must be determined for use in precision medicine. Herein, we elucidated the dynamics of various parameters before and after treatment as well as patient characteristics predictive of clinical responsiveness to mepolizumab after 1-year treatment. Twenty-seven patients with severe asthma were treated with mepolizumab for one year. Asthma control test scores, pulmonary function tests, fractional exhaled nitric oxide levels, and blood samples were evaluated. Additionally, we explored the role of CD69-positive mucosal-associated invariant T (MAIT) cells as a candidate biomarker for predicting treatment effectiveness by evaluating an OVA-induced asthma murine model using MR1 knockout mice, where MAIT cells were absent. The frequencies of CD69-positive group 1 innate lymphoid cells, group 3 innate lymphoid cells, natural killer cells, and MAIT cells decreased after mepolizumab treatment. The frequency of CD69-positive MAIT cells and neutrophils was lower and serum periostin levels were higher in responders than in non-responders. In the OVA-induced asthma murine model, CD69-positive MAIT cell count in the whole mouse lung was significantly higher than that in the control mice. Moreover, OVA-induced eosinophilic airway inflammation was exacerbated in the MAIT cell-deficient MR1 knockout mice. This study shows that circulating CD69-positive MAIT cells, neutrophils, and serum periostin might predict the real-world response after 1-year mepolizumab treatment. Furthermore, MAIT cells potentially have a protective role against type 2 airway inflammation. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that mucosal-associated invariant T cells (MAITs) play a crucial role in anti-tumor responses against various cancers. In this study, we investigated the immune characteristics of MAIT cells in patients with acute myeloid leukemia (AML). Using multi-parameter flow cytometry, we performed phenotypic and functional analysis of MAITs in peripheral blood or bone marrow samples collected from 131 patients with AML including 99 newly diagnosed, 18 remission, and 14 relapsed cases, as well as 69 healthy controls. We found that MAITs exhibit signs of aging and exhaustion, particularly in CD8+ MAITs subset, at newly diagnosis. MAITs exhibit an effector memory or terminally differentiated phenotype. Frequency and number of MAITs reflect AML cell genetic features, tumor burden, disease status, and treatment responsiveness. Moreover, MAITs exhibit a highly activated or even exhausted state, as indicated by upregulation of PD-1. Furthermore, impaired production of Th1-type cytokines and increased secretion of Th17-type cytokines, granzyme B, and perforin were observed in MAITs from AML patients. Additionally, MAITs shifted toward producing cytokines that promote tumor progression, such as IL-8. Lower frequency of MAITs was associated with poorer overall survival (OS), and multivariate analysis revealed that MAITs frequency < 2.12% was an independent prognostic factor affecting OS. Collectively, our findings suggest that MAITs may play a role in immune deficiency in AML, emphasizing their potential importance in AML pathogenesis and treatment. These discoveries provide a theoretical basis for the development of novel immunotherapeutic strategies in AML. [ABSTRACT FROM AUTHOR]

Abstract Chimeric antigen receptor (CAR) T cell therapy, in which a patient’s own T lymphocytes are engineered to recognize and kill cancer cells, has achieved striking success in some hematological malignancies in preclinical and clinical trials, resulting in six FDA-approved CAR-T products currently available in the market. Despite impressive clinical outcomes, concerns about treatment failure associated with low efficacy or high cytotoxicity of CAR-T cells remain. While the main focus has been on improving CAR-T cells, exploring alternative cellular sources for CAR generation has garnered growing interest. In the current review, we comprehensively evaluated other cell sources rather than conventional T cells for CAR generation.

BackgroundLiver is enriched in several innate-like unconventional T cells, but their role in alcohol-related liver disease (ALD) is not fully understood. Studies in several acute alcohol feeding models but not in chronic alcoholic steatohepatitis (ASH) model have shown that invariant natural killer T (iNKT) cells play a pathogenic role in ALD. Here, we investigated the activation of iNKT cells in an intragastric (iG) infusion model of chronic ASH as well as the frequency and cytokine phenotype of 3 different unconventional T cells: iNKT, mucosal-associated invariant T (MAIT), and CD8+ CD161hi Vα7.2- cells in peripheral blood of ALD patients.MethodsHepatic iNKT cells were investigated using the iG model of chronic ASH that combines feeding of high-cholesterol/high-fat diet (HCFD) with intragastric feeding of ethanol diet (HCFD + iG Alc). Human iNKT, MAIT, and CD8+ CD161hi Vα7.2- cells were examined by flow cytometry in peripheral blood of patients with severe alcoholic hepatitis (SAH) and chronic alcoholics (ChA) and compared with healthy controls.ResultsIn the iG model of chronic ASH, IFNγ+ iNKT cells accumulate in their livers compared with pair-fed control mice and activated hepatic iNKT cells show high expression of Fas and FasL. Notably, IFNγ+ iNKT cells are also significantly increased in peripheral blood of ChA patients compared with SAH patients. MAIT cells are significantly reduced in all ALD patients, but CD8+ CD161hi Vα7.2- cells are increased in SAH patients. Although MAIT and CD8+ CD161hi Vα7.2- cells displayed a similar cytokine production profile, the production of IFNγ and TNFα is significantly increased in SAH patients, while significant IL-17A production is found in ChA patients.ConclusionsWe found that the 3 unconventional T cells are activated in ALD patients showing interesting differences in their frequency and cytokine production profile between SAH and ChA patients. In the iG murine model of chronic ASH, iNKT cells are also activated secreting proinflammatory cytokines suggesting their involvement in liver disease.

Chimeric antigen receptor (CAR) T cell therapy, in which a patient's own T lymphocytes are engineered to recognize and kill cancer cells, has achieved striking success in some hematological malignancies in preclinical and clinical trials, resulting in six FDA-approved CAR-T products currently available in the market. Despite impressive clinical outcomes, concerns about treatment failure associated with low efficacy or high cytotoxicity of CAR-T cells remain. While the main focus has been on improving CAR-T cells, exploring alternative cellular sources for CAR generation has garnered growing interest. In the current review, we comprehensively evaluated other cell sources rather than conventional T cells for CAR generation. [ABSTRACT FROM AUTHOR]

Aims: It is acknowledged that aberrant liver immunity contributes to the development of type 2 diabetes mellitus (T2DM). Mucosal‐associated invariant T (MAIT) cells, an innate‐like T‐cell subset, are enriched in the human liver. Nevertheless, the characterisation and potential role of hepatic MAIT cells in T2DM remain unclear. Materials and methods: Fourteen newly diagnosed T2DM subjects and 15 controls received liver biopsy. The frequency and cytokine production of MAIT cells were analysed by flow cytometry. The expression of genes involved in glucose metabolism was determined in HepG2 cells co‐cultured with hepatic MAIT cells. Results: Compared with controls, hepatic MAIT cell frequency was significantly increased in T2DM patients (24.66% vs. 14.61%, p = 0.001). There were more MAIT cells producing interferon‐γ (IFN‐γ, 60.49% vs. 33.33%, p = 0.021) and tumour necrosis factor‐α (TNF‐α, 46.84% vs. 5.91%, p = 0.021) in T2DM than in controls, whereas their production of interleukin 17 (IL‐17) was comparable (15.25% vs. 4.55%, p = 0.054). Notably, an IFN‐γ+TNF‐α+IL‐17+/−producing MAIT cell subset was focussed, which showed an elevated proportion in T2DM (42.66% vs. 5.85%, p = 0.021) and positively correlated with plasma glucose levels. A co‐culture experiment further indicated that hepatic MAIT cells from T2DM upregulated the gene expression of pyruvate carboxylase, a key molecule involved in gluconeogenesis, in HepG2 cells, and this response was blocked with neutralising antibodies against IFN‐γ and TNF‐α. Conclusions: Our data implicate an increased Th1‐like MAIT cell subset in the liver of newly diagnosed T2DM subjects, which induces hyperglycaemia by promoting hepatic gluconeogenesis. It provides novel insights into the immune regulation of metabolic homoeostasis. Clinical trial registration number: NCT03296605 (registered at www.clinicaltrials.gov on 12 October 2018). [ABSTRACT FROM AUTHOR]

Mucosa-associated invariant T (MAIT) cell loss in chronic HIV-1 infection is a significant insult to antimicrobial immune defenses. Here we investigate the response of MAIT cells during acute HIV-1 infection utilizing the RV217 cohort with paired longitudinal pre- and post-infection samples. MAIT cells are activated and expand in blood and mucosa coincident with peak HIV-1 viremia, in a manner associated with emerging microbial translocation. This is followed by a phase with elevated function as viral replication is controlled to a set-point level, and later by their functional decline at the onset of chronic infection. Interestingly, enhanced innate-like pathways and characteristics develop progressively in MAIT cells during infection, in parallel with TCR repertoire alterations. These findings delineate the dynamic MAIT cell response to acute HIV-1 infection, and show how the MAIT compartment initially responds and expands with enhanced function, followed by progressive reprogramming away from TCR-dependent antibacterial responses towards innate-like functionality.

Tuberculosis (TB) is the leading cause of mortality from a single infectious agent, Mycobacterium tuberculosis Relevant immune targets of the partially efficacious TB vaccine bacille Calmette-Guérin (BCG) remain poorly defined. Mucosal-associated invariant T (MAIT) cells are MHC-related protein 1 (MR1)-restricted T cells, which are reactive against M. tuberculosis, and underexplored as potential TB vaccine targets. We sought to determine whether BCG vaccination activated mycobacteria-specific MAIT cell responses in humans. We analyzed whole blood samples from M. tuberculosis-infected South African adults who were revaccinated with BCG after a six-month course of isoniazid preventative therapy. In vitro BCG stimulation potently induced IFN-γ expression by phenotypic (CD8+CD26+CD161+) MAIT cells, which constituted the majority (75%) of BCG-reactive IFN-γ-producing CD8+ T cells. BCG revaccination transiently expanded peripheral blood frequencies of BCG-reactive IFN-γ+ MAIT cells, which returned to baseline frequencies a year following vaccination. In another cohort of healthy adults who received BCG at birth, 53% of mycobacteria-reactive-activated CD8 T cells expressed CDR3α TCRs, previously reported as MAIT TCRs, expressing the canonical TRAV1-2-TRAJ33 MAIT TCRα rearrangement. CD26 and CD161 coexpression correlated with TRAV1-2+CD161+ phenotype more accurately in CD8+ than CD4-CD8- MAIT cells. Interestingly, BCG-induced IFN-γ expression by MAIT cells in vitro was mediated by the innate cytokines IL-12 and IL-18 more than MR1-induced TCR signaling, suggesting TCR-independent activation. Collectively, the data suggest that activation of blood MAIT cells by innate inflammatory cytokines is a major mechanism of responsiveness to vaccination with whole cell vaccines against TB or in vitro stimulation with mycobacteria (Clinical trial registration: NCT01119521).

How early-life colonization and subsequent exposure to the microbiota affect long-term tissue immunity remains poorly understood. Here, we show that the development of mucosal-associated invariant T (MAIT) cells relies on a specific temporal window, after which MAIT cell development is permanently impaired. This imprinting depends on early-life exposure to defined microbes that synthesize riboflavin-derived antigens. In adults, cutaneous MAIT cells are a dominant population of interleukin-17A (IL-17A)-producing lymphocytes, which display a distinct transcriptional signature and can subsequently respond to skin commensals in an IL-1-, IL-18-, and antigen-dependent manner. Consequently, local activation of cutaneous MAIT cells promotes wound healing. Together, our work uncovers a privileged interaction between defined members of the microbiota and MAIT cells, which sequentially controls both tissue-imprinting and subsequent responses to injury.

Objective To investigate the change in mucosal-associated invariant T（MAIT） lymphocytes in peripheral blood of children with metabolic associated fatty liver disease（MAFLD） and its clinical significance. Methods A total of 18 children with MAFLD who attended Hunan Children’s Hospital from March to May, 2022, were enrolled as MAFLD group, and 20 normal children who attended the hospital during the same period of time were enrolled as control group. Peripheral blood samples were collected, and flow cytometry was used to measure the percentages of MAIT lymphocytes（CD3+CDl61+TCRVα7.2+ cells）, different MAIT lymphocyte subsets（CD4+CD8- MAIT cells, CD4-CD8- MAIT lymphocytes, CD4-CD8+ MAIT lymphocytes, and CD4+CD8+ MAIT lymphocytes）, and MAIT lymphocytes expressing PD-1, CD69, perforin, CD107α, CXCR3, CXCR6, and CCR6. The correlation of MAIT lymphocyte frequency with liver inflammation, fat content, and fibrosis degree was analyzed. The t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups. The Spearman correlation analysis was used for correlation analysis. Results Compared with the control group, the MAFLD group had significant increases in the percentage of MAIT lymphocytes in peripheral blood, the percentages of MAIT cells expressing PD-1, CD69, CD107α, CXCR3, CXCR6 and CCR6, and the percentages of CD4+CD8- MAIT cells and CD4+CD8+ MAIT lymphocytes among MAIT cell subsets（all P<0.05）, as well as a significant reduction in the percentage of CD4-CD8+ MAIT cells among MAIT cell subsets（P<0.001）. The percentages of CD4+CD8+ MAIT lymphocytes and CD107α-positive MAIT lymphocytes were negatively correlated with alanine aminotransferase（r=-0.474 and-0.550, P=0.047 and 0.018）. Conclusion The migration of peripheral blood MAIT lymphocytes to the liver plays a protective role against liver inflammation in children with MAFLD. [ABSTRACT FROM AUTHOR]

Abstract Background Mucosal-associated invariant T (MAIT) cells are systemically depleted in human immunodeficiency virus type 1 (HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy (cART). This study aimed to identify the mechanism underlying MAIT cell depletion. Methods In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. Results Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D (GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12 (IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro. Conclusions Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients, which could potentiate disease progression and poor immune reconstitution.

IntroductionThe 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).MethodsThrough 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.ResultsHere 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.DiscussionThis 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 represent a population of innate T cells that is highly abundant in humans. MAIT cells recognize metabolites of the microbial vitamin B pathway that are presented by the major histocompatibility complex (MHC) class I-related protein MR1. Upon bacterial infection, activated MAIT cells produce diverse cytokines and cytotoxic effector molecules and accumulate at the site of infection, thus, MAIT cells have been shown to be protective against various bacterial infections. Here, we summarize the current knowledge of the role of MAIT cells in bacterial pulmonary infection models.

Humans have populations of innate-like T lymphocytes with an invariant TCR α-chain that recognize nonpeptide Ags, including invariant NKT (iNKT) cells and mucosal-associated invariant T (MAIT) cells. iNKT cell involvement in human asthma is controversial, whereas there has been little analysis of MAIT cells. Using peripheral blood cells from 110 participants from the Urban Environment and Childhood Asthma (URECA) birth cohort study, these cells were analyzed for number and function. We determined whether iNKT cell or MAIT cell frequency at 1 y is correlated with the cytokine polarization of mainstream CD4+ T cells and/or the development of asthma by age 7 y. Dust samples from 300 houses were tested for iNKT cell antigenic activity. Our results show that a higher MAIT cell frequency at 1 y of age was associated with a decreased risk of asthma by age 7 y. The frequency of MAIT cells was associated with increased production of IFN-γ by activated CD4+ T cells from the URECA cohort. iNKT cell antigenic activity in bedroom dust samples was associated with higher endotoxin concentration and also with reduced risk of asthma. In conclusion, MAIT cell frequency at 1 y may reflect the tendency of the immune system toward Th1 responses and is associated with protection from asthma. Additionally, iNKT cell antigenic activity may be a marker of houses with increased microbial exposures and therefore also with protection from asthma.

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting reproductive age females and an important cause of infertility. Although the etiology is complex and its pathogenesis remains unclear, the pathological process of PCOS is tightly related with the immune dysfunction and gut microbial dysbiosis. Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells which can regulate inflammation through the production of cytokines and play a role in regulating the gut microbiota. We aim to evaluate the correlation between characteristics of PCOS and MAIT cells as well as their impact on cytokine secretion. Methods: Peripheral blood samples were taken from PCOS patients (n=33) and healthy controls (n=30) during 2-5 days of the menstrual period. The frequencies of MAIT cells and T cells were measured by flow cytometry. Cytokines interleukin 17 (IL-17), interleukin 22(IL-22), interferon γ (IFN-γ) and granzyme B were determined by Enzyme-linked immunosorbent assay (ELISA). Results: The frequency of MAIT cells was significantly reduced in the blood of PCOS patients compared with the controls, and negatively correlated with Body Mass Index (BMI), Homeostatic model assessment-insulin resistance (HOMA-IR) index, and Anti Miillerian Hormone (AMH). Thus, the frequencies of MAIT cells decreased in PCOS patients with abnormal weight (BMI=24kg/m2), higher HOMA-IR (=1.5), and excessive AMH (=8ng/ml). The Cytokine IL-17 was significantly higher in PCOS patients and negatively correlated with the frequency of MAIT cells. Even though the IL-22 was lower in PCOS Patients, no correlation with MAIT cells was detected. In subgroup, CD4+MAIT cells correlated with BMI, AMH, and testosterone (T) levels. Conclusion: The frequency change of MAIT cells may play a significant role in the pathogenesis of PCOS. Exploring these interactions with MAIT cells may provide a new target for PCOS treatment and prevention. [ABSTRACT FROM AUTHOR]

Background: Necrotizing enterocolitis (NEC) is a potentially fatal inflammatory gastrointestinal disease in preterm infants with unknown pathogenesis. Mucosal-associated invariant T (MAIT) cells primarily accumulate at sites where exposure to microbes is ubiquitous and regulate immunological responses. As the implications of these cells in NEC development in premature infants remain unknown, we investigated the role and characteristics of MAIT cells in NEC pathogenesis. Methods: The percentage of different MAIT cell subsets in peripheral blood samples of 30 preterm infants with NEC and 22 control subjects was estimated using flow cytometry. The frequency of MAIT cells in the intestinal tissues of five NEC patients and five control subjects was also examined. The level of serum cytokines was estimated using cytometric bead array. Potential associations between the different measurements were analyzed using the Spearman's correlation test. Results: Compared with controls, the NEC patients were found to have significantly reduced percentages of circulating CD161+ CD3+ CD8aa+ T cells and CD161+ CD3+ TCRd-TCRVa7.2+ MAIT cells. In the intestinal tissues, the percentage of MAIT cells was significantly higher in samples from the NEC patients than the controls. Furthermore, the percentage of circulating MAIT cells in the peripheral blood samples was inversely correlated with that in the intestinal tissues of the NEC patients. The percentage of CD8aa+ MAIT cells was found to be significantly reduced in both peripheral blood and intestinal tissues of NEC patients. Following treatment, the frequency of circulating MAIT cells significantly increased in NEC patients and reached a level similar to that in the control subjects. However, there was no difference in the percentage of circulating CD8aa+ MAIT cells before and after treatment in the NEC patients. Conclusion: Our results suggested that during the development of NEC MAIT cells accumulate in the inflammatory intestinal tissues, while the percentage of CD8aa+ MAIT cells is significantly decreased, which may lead to the dysfunction of MAIT cells in gut immunity. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells are evolutionarily conserved innatelike T cells capable of recognizing bacterial and fungal ligands derived from vitamin B biosynthesis. Under different stimulation conditions, MAIT cells can display different immune effector phenotypes, exerting immune regulation and anti-/ protumor responses. Based on basic biological characteristics, including the enrichment of mucosal tissue, the secretion of mucosal repair protective factors (interleukin-17, etc.), and the activation of riboflavin metabolites by intestinal flora, MAIT cells may play an important role in the immune regulation effect of mucosal lesions or inflammation. At the same time, activated MAIT cells secrete granzyme B, perforin, interferon γ, and other toxic cytokines, which can mediate anti-tumor effects. In addition, since a variety of hematological malignancies express the targets of MAIT cell-specific effector molecules, MAIT cells are also a potentially attractive target for cell therapy or immunotherapy for hematological malignancies. In this review, we will provide an overview of MAIT research related to blood system diseases and discuss the possible immunomodulatory or anti-tumor roles that unique biological characteristics or effector phenotypes may play in hematological diseases. [ABSTRACT FROM AUTHOR]

Mucosal‐associated invariant T (MAIT) cells are a major subset of innate‐like T cells mediating protection against bacterial infection through recognition of microbial metabolites derived from riboflavin biosynthesis. Mouse MAIT cells egress from the thymus as two main subpopulations with distinct functions, namely, T‐bet‐expressing MAIT1 and RORγt‐expressing MAIT17 cells. Previously, we reported that inducible T‐cell costimulator and interleukin (IL)‐23 provide essential signals for optimal MHC‐related protein 1 (MR1)‐dependent activation and expansion of MAIT17 cells in vivo. Here, in a model of tularemia, in which MAIT1 responses predominate, we demonstrate that IL‐12 and IL‐23 promote MAIT1 cell expansion during acute infection and that IL‐12 is indispensable for MAIT1 phenotype and function. Furthermore, we showed that the bias toward MAIT1 or MAIT17 responses we observed during different bacterial infections was determined and modulated by the balance between IL‐12 and IL‐23 and that these responses could be recapitulated by cytokine coadministration with antigen. Our results indicate a potential for tailored immunotherapeutic interventions via MAIT cell manipulation. [ABSTRACT FROM AUTHOR]

Abstract Background Alcohol-related liver disease (ALD) is a major cause of chronic liver diseases. Inflammatory response is a basic pathological feature of ALD. Mucosal-associated invariant T(MAIT) cells are a novel population of innate immune cells, which may be depleted in various inflammatory diseases. However, the changes of MAIT cell in ALD remains unclear. Results In this study, the levels of MAIT cell were significantly decreased in patients with alcoholic fatty liver disease, alcoholic cirrhosis, and mixed cirrhosis (alcoholic + viral). Furthermore, the reduction of circulating MAIT cells was correlated with liver function in patients with cirrhosis. Functional changes among circulating MAIT cells in patients with alcoholic cirrhosis, including increased production of IL-17A and perforin, and reduced production of TNF-α. Plasma cytokine and chemokine levels were quantified using multiple immunoassays and ELISA. Serum levels of chemokine IL-8 were correlated with MAIT cell frequency in patients with alcoholic cirrhosis. Moreover, no differences were observed in the expression of CCR6, CXCR6, and PD-1 in circulating MAIT cells of patients with alcoholic cirrhosis. The MAIT cells in patients with alcoholic cirrhosis were prone to apoptosis, which was promoted by IL-12, IL-18, and IL-8. Conclusions Our findings indicate persistent MAIT cell loss during alcohol-related liver disease and suggest that MAIT cells can be promising indicator and therapeutic targets in ALD.

Aim: Mucosal‐associated invariant T (MAIT) cells are known to be resident in oral mucosal tissue, but their roles in periodontitis are unknown. This study aimed to examine the level and function of MAIT cells in periodontitis patients. Materials and Methods: Frequency, activation, and function of MAIT cells from 28 periodontitis patients and 28 healthy controls (HCs) were measured by flow cytometry. Results: Circulating MAIT cells were numerically reduced in periodontitis patients. Moreover, they exhibited higher expression of CD69 and annexin V, together with more increased production of interleukin (IL)‐17 and tumour necrosis factor (TNF)‐α, in periodontitis patients than in HCs. Interestingly, periodontitis patients had higher frequencies of MAIT cells in gingival tissue than in peripheral blood. In addition, circulating MAIT cells had elevated expression of tissue‐homing chemokine receptors such as CCR6 and CXCR6, and the corresponding chemokines (i.e., CCL20 and CXCL16) were more strongly expressed in inflamed gingiva than in healthy gingiva. Conclusions: This study demonstrates that circulating MAIT cells are numerically deficient with an activated profile toward the production of IL‐17 and TNF‐α in periodontitis patients. Furthermore, circulating MAIT cells have the potential to migrate to inflamed gingival tissues. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus type 1 (HIV‐1) infection causes considerable morbidity and mortality worldwide. Although antiretroviral therapy (ART) has largely transformed HIV infection from a fatal disease to a chronic condition, approximately 10%–40% of HIV‐infected individuals who receive effective ART and sustain long‐term viral suppression still cannot achieve optimal immune reconstitution. These patients are called immunological nonresponders, a state associated with poor clinical prognosis. Mucosal‐associated invariant T (MAIT) cells are an evolutionarily conserved unconventional T‐cell subset defined by expression of semi‐invariant αβ T‐cell receptor (TCR), which recognizes metabolites derived from the riboflavin biosynthetic pathway presented on major histocompatibility complex‐related protein‐1. MAIT cells, which are considered to act as a bridge between innate and adaptive immunity, produce a wide range of cytokines and cytotoxic molecules upon activation through TCR‐dependent and TCR‐independent mechanisms, which is of major importance in defense against a variety of pathogens. In addition, MAIT cells are involved in autoimmune and immune‐mediated diseases. The number of MAIT cells is dramatically and irreversibly decreased in the early stage of HIV infection and is not fully restored even after long‐term suppressive ART. In light of the important role of MAIT cells in mucosal immunity and because microbial translocation is inversely associated with CD4+ T‐cell counts, we propose that MAIT cells participate in the maintenance of intestinal barrier integrity and microbial homeostasis, thus further affecting immune reconstitution in HIV‐infected individuals. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Mucosal-associated invariant T cells (MAIT cells) are an abundant population of innate T cells. When activated, MAIT cells rapidly produce a range of cytokines, including IFNγ, TNF-α and IL-17. Several studies have implicated MAIT cells in the development of metabolic dysfunction, but the mechanisms through which this occurs are not fully understood. We hypothesised that MAIT cells are associated with insulin resistance in children with obesity, and affect insulin signalling through their production of IL-17. Methods: In a cross-sectional observational study, we investigated MAIT cell cytokine profiles in a cohort of 30 children with obesity and 30 healthy control participants, of similar age, using flow cytometry. We then used a cell-based model to determine the direct effect of MAIT cells and IL-17 on insulin signalling and glucose uptake. Results: Children with obesity display increased MAIT cell frequencies (2.2% vs 2.8%, p=0.047), and, once activated, these produced elevated levels of both TNF-α (39% vs 28%, p=0.03) and IL-17 (1.25% vs 0.5%, p=0.008). The IL-17-producing MAIT cells were associated with an elevated HOMA-IR (r=0.65, p=0.001). The MAIT cell secretome from adults with obesity resulted in reduced glucose uptake when compared with the secretome from healthy adult control (1.31 vs 0.96, p=0.0002), a defect that could be blocked by neutralising IL-17. Finally, we demonstrated that recombinant IL-17 blocked insulin-mediated glucose uptake via inhibition of phosphorylated Akt and extracellular signal-regulated kinase. Conclusions/interpretations: Collectively, these studies provide further support for the role of MAIT cells in the development of metabolic dysfunction, and suggest that an IL-17-mediated effect on intracellular insulin signalling is responsible. [ABSTRACT FROM AUTHOR]

Background: Mucosal-associated invariant T (MAIT) cells are systemically depleted in human immunodeficiency virus type 1 (HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy (cART). This study aimed to identify the mechanism underlying MAIT cell depletion. Methods: In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. Results: Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D (GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12 (IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro. Conclusions: Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients, which could potentiate disease progression and poor immune reconstitution. [ABSTRACT FROM AUTHOR]

Abstract Background Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear. Case presentation We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology. Conclusions This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can activate either in response to T-cell receptor (TCR) engagement or through activating cytokines and play an important role in autoimmune disorders. The study examined the level and function of MAIT cells in patients with inflammatory bowel disease (IBD). Circulating MAIT cell levels were significantly reduced in IBD patients. This MAIT cell deficiency was correlated with IBD disease activity grades, hemoglobin, and CRP. IFN-γ production of circulating MAIT cells in response to both MHC class 1b-like related protein (MR1)-dependent and -independent stimulations was decreased in IBD patients, which was partially associated with reduced activation of nuclear factor of activated T cells 1 (NFAT1) transcription factor, a main regulator of IFN-γ production. Expression levels of CD69, programmed death-1 (PD-1), and annexin V in MAIT cells were elevated in IBD patients. CCL20, CXCL10, CXCL16, and CCL25 were expressed higher in inflamed intestinal tissues than in noninflamed tissues. This study demonstrates that circulating MAIT cells are activated and numerically and functionally deficient in IBD patients. Furthermore, activated MAIT cells have the potential to migrate to inflamed tissues. These findings suggest an important role of MAIT cells in mucosal immunity in IBD.

Competing Interests: LVK is a member of the scientific advisory board of Isu Abxis Co., Ltd. South Korea. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Prostate cancer is the second most common cancer in men worldwide. Despite an abundance of prostate-specific antigens, immunotherapies have yet to become a standard of care, potentially limited by T-cell dysfunction. Up to 10% of human circulating T-cells, and a significant fraction in the urogenital tract, are mucosal-associated invariant T (MAIT) cells. MAIT cells express stereotyped T-cell receptors that recognize riboflavin metabolites derived from microbes presented by MR-1. We evaluated the number, phenotype and function of circulating MAIT cells, alongside two other innate-like T (ILT) -cell subsets, in men with prostate cancer and age- and sex-matched controls. MAIT cells in men with prostate cancer circulated at similar frequencies to controls, but their cytokine production and proliferation was impaired. In contrast, the function of two other ILT-cell populations (natural killer T-cells and Vγ9Vδ2 T-cells) was not impaired. In both patients and controls, MAIT cells expressed high levels of the immune checkpoint molecule PD-1 at rest, while upregulation of PD-1 in response to the MR-1 ligand 5-amino-6D-ribitylaminouracil (5-A-RU) was greater in patients. 5-A-RU also induced upregulation of PD-L1 and -L2 RNA in primary mononuclear cells. We confirmed that circulating MAIT cell number and function were preserved before and during anti-PD1 therapy with pembrolizumab in a cohort of patients with melanoma. In vitro, 5-A-RU enhanced mononuclear cell cytotoxicity against the PD-L1 positive prostate cancer cell line PC3 in an MR-1-dependent manner. Addition of pembrolizumab enhanced this cytotoxicity, and was associated with increased MAIT cell expression of CD107a and IFN-γ. We conclude that prostate cancer is associated with MAIT-cell dysfunction, and that this might be overcome through the application of potent MR-1 ligands with PD-1 blockade. These findings may have implications for the development of cancer immunotherapies that exploit MAIT cells.

Prostate cancer is the second most common cancer in men worldwide. Despite an abundance of prostate-specific antigens, immunotherapies have yet to become a standard of care, potentially limited by T-cell dysfunction. Up to 10% of human circulating T-cells, and a significant fraction in the urogenital tract, are mucosal-associated invariant T (MAIT) cells. MAIT cells express stereotyped T-cell receptors that recognize riboflavin metabolites derived from microbes presented by MR-1. We evaluated the number, phenotype and function of circulating MAIT cells, alongside two other innate-like T (ILT) -cell subsets, in men with prostate cancer and age- and sex-matched controls. MAIT cells in men with prostate cancer circulated at similar frequencies to controls, but their cytokine production and proliferation was impaired. In contrast, the function of two other ILT-cell populations (natural killer T-cells and Vγ9Vδ2 T-cells) was not impaired. In both patients and controls, MAIT cells expressed high levels of the immune checkpoint molecule PD-1 at rest, while upregulation of PD-1 in response to the MR-1 ligand 5-amino-6D-ribitylaminouracil (5-A-RU) was greater in patients. 5-A-RU also induced upregulation of PD-L1 and -L2 RNA in primary mononuclear cells. We confirmed that circulating MAIT cell number and function were preserved before and during anti-PD1 therapy with pembrolizumab in a cohort of patients with melanoma. In vitro , 5-A-RU enhanced mononuclear cell cytotoxicity against the PD-L1 positive prostate cancer cell line PC3 in an MR-1-dependent manner. Addition of pembrolizumab enhanced this cytotoxicity, and was associated with increased MAIT cell expression of CD107a and IFN-γ. We conclude that prostate cancer is associated with MAIT-cell dysfunction, and that this might be overcome through the application of potent MR-1 ligands with PD-1 blockade. These findings may have implications for the development of cancer immunotherapies that exploit MAIT cells. [ABSTRACT FROM AUTHOR]

Background & Aims: Mucosal-associated invariant T (MAIT) cells are depleted from blood in patients with advanced liver disease and show features of immune dysfunction. Because circulating MAIT cells differ from organ-resident MAIT cells, we aimed to investigate the frequency, phenotype, and function of peritoneal MAIT cells from patients with cirrhosis and spontaneous bacterial peritonitis (SBP). Methods: MAIT cells in blood and ascitic fluid from patients with cirrhosis were characterized using flow cytometry. Healthy individuals and noncirrhotic patients undergoing peritoneal dialysis served as controls. MAIT cell migration was studied in transwell assays. Cytokine release in response to infected ascitic fluid and bacterial products was assessed in vitro. Results: Peritoneal CD3+ CD161hi Vα7.2+ T cells had an inflammatory, tissue retention phenotype, expressing the alpha E integrin, the chemokine receptors CCR5 and CXCR3, and the activation marker CD69 at higher levels than their circulating equivalents. Seventy-seven percent bound to MR1 tetramers loaded with the pyrimidine intermediate 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil. The ratio of peritoneal to blood MAIT cell frequency increased from 1.3 in the absence of SBP to 2.6 at diagnosis and decreased by day 3. MAIT cells migrated toward infected ascitic fluid containing CCL5 and CCL20 and released cytokines in an MR1-restricted fashion. Whereas the depleted circulating MAIT cell pool displayed features of immune exhaustion, peritoneal MAIT cells remained competent producers of inflammatory cytokines in response to bacterial products. Peritoneal MAIT activation correlated with systemic inflammation, suggesting a possible link between peritoneal and systemic immunity. Conclusions: Peritoneal MAIT cells phenotypically and functionally differ from circulating MAIT cells in decompensated cirrhosis and redistribute to the peritoneum during SBP.

Background: Alcohol-related liver disease (ALD) is a major cause of chronic liver diseases. Inflammatory response is a basic pathological feature of ALD. Mucosal-associated invariant T(MAIT) cells are a novel population of innate immune cells, which may be depleted in various inflammatory diseases. However, the changes of MAIT cell in ALD remains unclear. Results: In this study, the levels of MAIT cell were significantly decreased in patients with alcoholic fatty liver disease, alcoholic cirrhosis, and mixed cirrhosis (alcoholic + viral). Furthermore, the reduction of circulating MAIT cells was correlated with liver function in patients with cirrhosis. Functional changes among circulating MAIT cells in patients with alcoholic cirrhosis, including increased production of IL-17A and perforin, and reduced production of TNF-α. Plasma cytokine and chemokine levels were quantified using multiple immunoassays and ELISA. Serum levels of chemokine IL-8 were correlated with MAIT cell frequency in patients with alcoholic cirrhosis. Moreover, no differences were observed in the expression of CCR6, CXCR6, and PD-1 in circulating MAIT cells of patients with alcoholic cirrhosis. The MAIT cells in patients with alcoholic cirrhosis were prone to apoptosis, which was promoted by IL-12, IL-18, and IL-8. Conclusions: Our findings indicate persistent MAIT cell loss during alcohol-related liver disease and suggest that MAIT cells can be promising indicator and therapeutic targets in ALD. [ABSTRACT FROM AUTHOR]

Objective To investigate the role of mouse hepatic mucosal-associated T (MAIT) cells in type 2 diabetes mellitus. Methods Five-week-old male C57BL/6 mice were randomly divided into normal control group (n=5) and model group (n=5). The model of type 2 diabetic mice was established via 16 weeks of high-fat-diet feeding. Hepatic lymphocytes were separated from liver samples using density gradient centrifugation. The frequency of hepatic MAIT cells and cytokine expressions of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-17 and IL-4 in hepatic MAIT cells were analyzed by flow cytometry. The gene expressions of key molecules involved in hepatic glucose metabolism [glucose-6-phosphatase (G6pc), pyruvate kinase M1/2 (PKm), 6-phosphofructokinase 1 (Pfk1)] were evaluated in primary hepatocytes co-cultured with hepatic MAIT cells sorted from diabetic mice. Independent-samples t test was used to compare between two groups. Results Compared with the normal control group, the body weight [(49.87± 0.99) vs. (26.41±0.81) g, respectively, t=36.76, P<0.05) and fasting blood glucose [(11.52±0.46) vs. (6.12±0.48) mmol/L, respectively, t=16.22, P<0.05] were increased significantly in the model group. The hepatic steatosis was obvious in the model group. Compared with the normal control group, the frequency of hepatic MAIT cells was increased significantly [(1.06±0.46) % vs. (0.42±0.20) %, respectively, t=2.85, P<0.05] and the expression of IFN-γ in hepatic MAIT cells was elevated significantly [(27.18±13.14) % vs. (47.56±13.08) %, respectively, t=2.46, P<0.05] in the model group. In vitro co-culture experiments showed that hepatic MAIT cells from diabetes predominantly upregulated mRNA levels of G6pc (t=14.60, P<0.01) and downregulated mRNA levels of Pkm (t= 22.27, P<0.01) and Pfk1 (t=4.28, P<0.05) of primary hepatocytes. Conclusions Hepatic MAIT cells of diabetic mouse are elevated in frequency and IFN-γ expression, and contributed to the excessive hepatic output of glucose, which is highly correlated with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background Mucosal‐associated invariant T (MAIT) cells have been associated with inflammation in several autoimmune diseases. However, their relation to ischemic stroke remains unclear. This study attempted to elucidate the role of MAIT cells in acute ischemic stroke in mice. Methods and Results We used MR1 knockout C57BL/6 (MR1−/−) mice and wild‐type littermates (MR1+/+). After performing a transient middle cerebral artery occlusion (tMCAO), we evaluated the association with inflammation and prognosis in the acute cerebral ischemia. Furthermore, we analyzed the tMCAO C57BL/6 mice administered with the suppressive MR1 ligand and the vehicle control. We also evaluated the infiltration of MAIT cells into the ischemic brain by flow cytometry. Results showed a reduction of infarct volume and an improvement of neurological impairment in MR1−/− mice (n=8). There was a reduction in the number of infiltrating microglia/macrophages (n=3–5) and in their activation (n=5) in the peri‐infarct area of MR1−/− mice. The cytokine levels of interleukin‐6 and interleukin‐17 at 24 hours after tMCAO (n=3–5), and for interleukin‐17 at 72 hours after tMCAO (n=5), were lower in the MR1−/− mice. The administration of the suppressive MR1 ligand reduced the infarct volume and improved functional impairment (n=5). Flow cytometric analysis demonstrated there was a reduction of MAIT cells infiltrating into the ischemic brain at 24 hours after tMCAO (n=17). Conclusions Our results showed that MAIT cells play an important role in neuroinflammation after focal cerebral ischemia and the use of MAIT cell regulation has a potential role as a novel neuroprotectant for the treatment of acute ischemic stroke.