Dysregulation and impaired anti-bacterial potential of mucosal-associated invariant T cells in autoimmune liver diseases.

Autoimmune liver diseases (AILD) encompass a group of conditions in which the immune system mistakenly attacks the liver tissue. Mucosal-associated invariant T (MAIT) cells are enriched in the liver, where they play crucial roles in antibacterial defense and inflammation regulation. Compared to other autoimmune conditions affecting the synovium of the joints, MAIT cells from AILD exhibited a greater deficiency in ratio, elevated activation markers, increased apoptosis, and higher pro-inflammatory cytokines production. However, the frequency of MAIT cells in AILD was negatively correlated with anti-bacterial indexes, and their impaired responsiveness and weakened anti-bacterial potential were evidenced by reduced expansion ability, lower maximal IFN-γ production, and diminished E. coli-induced cytotoxic mediators release. Similar shifts in MAIT cell ratios and phenotypes were observed in both primary biliary cirrhosis and autoimmune hepatitis, linked to upregulation of bile acid components in the affected tissue. Specifically, ursodeoxycholic acid, a metabolic intermediate and traditional anti-primary biliary cirrhosis drug, inhibited TCR-mediated expansion and downregulated pro-inflammatory cytokines and anti-bacterial-related mediators in MAIT cells. These findings underscore the intricate interplay between hepatic pathology and MAIT cells, and highlight the importance of antibacterial monitoring during ursodeoxycholic acid treatment in AILD.

Gut redox and microbiome: charting the roadmap to T-cell regulation.

The gastrointestinal (GI) tract redox environment, influenced by commensal microbiota and bacterial-derived metabolites, is crucial in shaping T-cell responses. Specifically, metabolites from gut microbiota (GM) exhibit robust anti-inflammatory effects, fostering the differentiation and regulation of CD8+ tissue-resident memory (TRM) cells, mucosal-associated invariant T (MAIT) cells, and stabilizing gut-resident Treg cells. Nitric oxide (NO), a pivotal redox mediator, emerges as a central regulator of T-cell functions and gut inflammation. NO impacts the composition of the gut microbiome, driving the differentiation of pro-inflammatory Th17 cells and exacerbating intestinal inflammation, and supports Treg expansion, showcasing its dual role in immune homeostasis. This review delves into the complex interplay between GI redox balance and GM metabolites, elucidating their profound impact on T-cell regulation. Additionally, it comprehensively emphasizes the critical role of GI redox, particularly reactive oxygen species (ROS) and NO, in shaping T-cell phenotype and functions. These insights offer valuable perspectives on disease mechanisms and potential therapeutic strategies for conditions associated with oxidative stress. Understanding the complex cross-talk between GI redox, GM metabolites, and T-cell responses provides valuable insights into potential therapeutic avenues for immune-mediated diseases, underscoring the significance of maintaining GI redox balance for optimal immune health.

A shotgun proteomic dataset of human mucosal-associated invariant T cells.

Mucosal-associated invariant T (MAIT) cells represent a unique unconventional T cell population important in eliciting immunomodulatory responses in a range of diseases, including infectious diseases, autoimmunity and cancer. This innate-like T cell subset predominantly express CD8 in humans. Unlike conventional CD8+ T cells, which recognize peptide antigen presented by polymorphic major histocompatibility complex (MHC) molecules, MAIT cells are restricted by MR1, a non-polymorphic antigen-presenting molecule widely expressed in multiple tissues. Thus, identification of proteomic signature of MAIT cells in relation to conventional T cells is pivotal in understanding it's specific functional characteristics. The high-resolution dataset presents here comprehensively describes and compare the whole cell proteomes of MAIT (TCRVα7.2+CD161+) and conventional/non-MAIT T cells (TCR Vα7.2-CD161-) in humans. The dataset was generated using the proteomic samples prepared from matched T cell subsets sorted from peripheral blood mononuclear cells (PBMC) of three healthy volunteers. Peptides obtained from trypsin-digested cell lysates were analysed using Data-Dependent Mass Spectrometry (DDA-MS). Label-free quantitation of DDA-MS data using MaxQuant and MaxLFQ software identified 4,442 proteins at a 1 % false discovery rate. Of them, 3680 proteins that were detected with single UniProt accession and a minimum of 2 unique or razor peptides were assessed to identify differentially abundant proteins between MAIT cells and conventional T cells, including total T cells and CD8+ T cells. The dataset comprises high-quality label-free quantitative proteomic data that can be used to compare the expression pattern of whole cell proteomes between the above-mentioned T cell populations. Further, this can be used as a reference proteome of human MAIT cells for the in-depth understanding of the MAIT cell behaviour among T cells and to discover potential therapeutic targets to modulate MAIT cell function.

Mucosal associated invariant T cells: Powerhouses of the lung.

The lungs face constant environmental challenges from harmless molecules, airborne pathogens and harmful agents that can damage the tissue. The lungs' immune system includes numerous tissue-resident lymphocytes that contribute to maintain tissue homeostasis and to the early initiation of immune responses. Amongst tissue-resident lymphocytes, Mucosal Associated Invariant T (MAIT) cells are present in human and murine lungs and emerging evidence supports their contribution to immune responses during infections, chronic inflammatory disorders and cancer. This review explores the mechanisms underpinning MAIT cell functions in the airways, their impact on lung immunity and the potential for targeting pulmonary MAIT cells in a therapeutic context.

Circulating MAIT cells in multiple sclerosis and amyotrophic lateral sclerosis.

Neurological disorders, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), may be associated with alterations in blood cell composition and phenotype. Here, we focused our attention on circulating mucosal-associated invariant T (MAIT) cells, a CD8+ T cell memory population expressing the invariant Vα7.2 region in the T cell receptor and high surface levels of the CD161 marker. Transcriptomics data relative to peripheral blood mononuclear cells (PBMC) highlighted downregulation of CD161 and other MAIT-associated markers in progressive MS and not relapsing remitting (RR)-MS when gene expressions relative to each disease course were compared to those from healthy controls. Multiparametric flow cytometry of freshly isolated PBMC samples from untreated RR-MS, primary or secondary progressive MS (PP- or SP-MS), ALS and age- and sex-matched healthy controls revealed specific loss of circulating CD8+ MAIT cells in PP-MS and no other MS courses or another neurological disorder such as ALS. Overall, these observations point to the existence of immunological changes in blood specific for the primary progressive course of MS that may support clinical definition of disease.

Increased pathogenicity and pro-inflammatory capabilities of mucosal-associated invariant T cells involved in Oral Lichen Planus.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells assume pivotal roles in numerous autoimmune inflammatory maladies. However, scant knowledge exists regarding their involvement in the pathological progression of oral lichen planus (OLP). The focus of our study was to explore whether MAIT cells were altered across distinct clinical types of OLP. METHODS: The frequency, phenotype, and partial functions of MAIT cells were performed by flow cytometry, using peripheral blood from 18 adults with non-erosive OLP and 22 adults with erosive OLP compared with 15 healthy adults. We also studied the changes in MAIT cells in 15 OLP patients receiving and 10 not receiving corticosteroids. Surface proteins including CD4, CD8, CD69, CD103, CD38, HLA-DR, Tim-3, Programmed Death Molecule-1 (PD-1), and related factors released by MAIT cells such as Granzyme B (GzB), interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-17A, and IL-22 were detected. RESULTS: Within non-erosive OLP patients, MAIT cells manifested an activated phenotype, evident in an elevated frequency of CD69+ CD38+ MAIT cells (p < 0.01). Conversely, erosive OLP patients displayed an activation and depletion phenotype in MAIT cells, typified by elevated CD69 (p < 0.01), CD103 (p < 0.05), and PD-1 expression (p < 0.01). Additionally, MAIT cells exhibited heightened cytokine production, encompassing GzB, IFN-γ, and IL-17A in erosive OLP patients. Notably, the proportion of CD103+ MAIT cells (p < 0.05) and GzB secretion (p < 0.01) by MAIT cells diminished, while the proportion of CD8+ MAIT cells (p < 0.05) rose in OLP patients with corticosteroid therapy. CONCLUSIONS: MAIT cells exhibit increased pathogenicity and pro-inflammatory capabilities in OLP. Corticosteroid therapy influences the expression of certain phenotypes and functions of MAIT cells in the peripheral blood of OLP patients.

A Comprehensive Investigation of Stimulatory Agents on MAIT and Vα7.2+/CD161- T Cell Response and Effects of Immunomodulatory Drugs.

Mucosal-associated invariant T (MAIT) cells, a subset of Vα7.2+ T cells, are a crucial link between innate and adaptive immunity, responding to various stimuli through TCR-dependent and independent pathways. We investigated the responses of MAIT cells and Vα7.2+/CD161- T cells to different stimuli and evaluated the effects of Cyclosporin A (CsA) and Vitamin D3 (VitD). Peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with various agents (PMA/Ionomycin, 5-OP-RU, 5-OP-RU/IL-12/IL-33) with or without CsA and VitD. Flow cytometric analysis assessed surface markers and intracellular cytokine production. Under steady-state conditions, MAIT cells displayed elevated expression of CCR6 and IL-13. They showed upregulated activation and exhaustion markers after activation, producing IFNγ, TNFα, and TNFα/GzB. CsA significantly inhibited MAIT cell activation and cytokine production. Conversely, Vα7.2+/CD161- T cells exhibited distinct responses, showing negligible responses to 5-OP-RU ligand but increased cytokine production upon PMA stimulation. Our study underscores the distinct nature of MAIT cells compared to Vα7.2+/CD161- T cells, which resemble conventional T cells. CsA emerges as a potent immunosuppressive agent, inhibiting proinflammatory cytokine production in MAIT cells. At the same time, VitD supports MAIT cell activation and IL-13 production, shedding light on potential therapeutic avenues for immune modulation.

Human Immunodeficiency Virus-Human Pegivirus Coinfected Individuals Display Functional Mucosal-Associated Invariant T Cells and Follicular T Cells Irrespective of PD-1 Expression.

Human pegivirus (HPgV) appears to alter the prognosis of HIV disease by modulating T cell homeostasis, chemokine/cytokine production, and T cell activation. In this study, we evaluated if HPgV had any 'favorable' impact on the quantity and quality of T cells in HIV-infected individuals. T cell subsets such as CD4lo, CD4hi, and CD8+ T cells, CD4+ MAIT cells, CD8+ MAIT cells, follicular helper T (TFH) cells, and follicular cytotoxic T (TFC) cells were characterized based on the expression of markers associated with immune activation (CD69, ICOS), proliferation (ki67), cytokine production (TNF-α, IFN-γ), and exhaustion (PD-1). HIV+HPgV+ individuals had lower transaminase SGOT (liver) and GGT (biliary) in the plasma than those who were HPgV-. HIV/HPgV coinfection was significantly associated with increased absolute CD4+ T cell counts. HIV+HPgV+ and HIV+HPgV- individuals had highly activated T cell subsets with high expression of CD69 and ICOS on bulk CD4+ and CD8+ T cells, CD4+ MAIT cells, CD8+ MAIT cells, and CXCR5+CD4+ T cells and CXCR5+CD8+ T cells compared with healthy controls. Irrespective of immune activation markers, these cells also displayed higher levels of PD-1 on CD4+ T and CD8+ T cells . Exploring effector functionality based on mitogen stimulation demonstrated increased cytokine production by CD4+ MAIT and CD8+ MAIT cells. Decrease in absolute CD4+ T cell counts correlated positively with intracellular IFN-γ levels by CD4lo T cells, whereas increase of the same correlated negatively with TNF-α in the CD4lo T cells of HIV+HPgV+ individuals. HIV/HPgV coinfected individuals display functional CD4+ and CD8+ MAIT, TFH, and TFC cells irrespective of PD-1 expression.

Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome.

A substantial number of patients recovering from acute SARS-CoV-2 infection present serious lingering symptoms, often referred to as long COVID (LC). However, a subset of these patients exhibits the most debilitating symptoms characterized by ongoing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). We specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R). ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes. Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients. LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC. The expansion of immunosuppressive CD71+ erythroid cells (CECs) was noted. These cells may modulate the immune response and contribute to increased ARTN concentration, which correlated with pain and cognitive impairment. Serology revealed an elevation in a variety of autoantibodies in LC. Intriguingly, we found that the frequency of 2B4+CD160+ and TIM3+CD160+ CD8+ T cells completely separated LC patients from the R group. Our further analyses using a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-ß and MAIT cells can distinguish LC from the R group. Our findings provide a new paradigm in the pathogenesis of ME/CFS to identify strategies for its prevention and treatment.

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

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.

Systematic analysis of mucosal-associated invariant T cells in haematological malignancies.

Mucosal-associated invariant T-cells (MAIT) are unconventional T-cells with cytotoxic and pro-inflammatory properties. Previous research has reported contradictory findings on their role in cancerogenesis with data being even scarcer in haematological malignancies. Here, we report the results of a systematic analysis of MAIT cells in treatment-naïve patients with a broad range of haematological malignancies. We analysed peripheral blood of 204 patients and 50 healthy subjects. The pool of haematological patients had a statistically significant lower both the absolute value (median values, 0.01 × 109/L vs. 0.05 × 109/L) of MAIT cells and their percentage (median values 0.94% vs. 2.56%) among T-cells compared to the control group. Separate analysis showed that the decrease in the absolute number of MAIT cells is significant in patients with acute myeloid leukaemia, myeloproliferative neoplasms, plasma cell myeloma, B-cell non-Hodgkin lymphomas, otherwise not specified, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma compared to the control population. Furthermore, in haematological malignancies, MAIT cells overexpress PD-1 (average values, 51.7% vs. 6.7%), HLA-DR (average values, 40.2% vs. 7%), CD38 (average values, 25.9% vs. 4.9%) and CD69 (average values, 40.2% vs. 9.2%). Similar results were obtained when comparing patients with individual malignancies to the control population. Our data show that the depletion of circulating MAIT cells is a common observation in a broad spectrum of haematological malignancies. In addition to their reduced numbers, MAIT cells acquire an activated/exhausted phenotype.

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

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).

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

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

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

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

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

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

The immune system in neurological diseases: What innate-like T cells have to say.

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.

Dysregulation of mucosal-associated invariant T cells correlates with altered placental microenvironment in preterm birth.

Preterm birth (PTB) is a major problem affecting perinatal health, directly increasing the mortality risk of mother and infant that often results from the breakdown of the maternal-fetal immune balance. Increasing evidence shows the essential role of mucosal-associated invariant T (MAIT) cells to balance antibacterial function and immune tolerance function during pregnancy. However, the phenotype and function of placental MAIT cells and their specific mechanisms in PTB remain unclear. Here, we report that MAIT cells in placentas from PTBs show increased activation levels and decreased IFN-γ secretion capacity compared with those from normal pregnancies. Moreover, our data indicate gravidity is a factor affecting placental MAIT cells during pregnancies. Multi-omics analysis indicated aberrant immune activation and abnormal increase of lipids and lipid-like metabolites in the PTB placental microenvironment. Moreover, the proportion and activation of MAIT cells were positively correlated with the abnormal increase of lipids and lipid-like metabolites. Together, our work revealed that abnormal activation and impaired function of MAIT cells may be related to abnormal elevation of lipids and lipid-like metabolites in PTB.

Mice Generated with Induced Pluripotent Stem Cells Derived from Mucosal-Associated Invariant T Cells.

The function of mucosal-associated invariant T (MAIT) cells, a burgeoning member of innate-like T cells abundant in humans and implicated in many diseases, remains obscure. To explore this, mice with a rearranged T cell receptor (TCR) α or ß locus, specific for MAIT cells, were generated via induced pluripotent stem cells derived from MAIT cells and were designated Vα19 and Vß8 mice, respectively. Both groups of mice expressed large numbers of MAIT cells. The MAIT cells from these mice were activated by cytokines and an agonist to produce IFN-γ and IL-17. While Vß8 mice showed resistance in a cancer metastasis model, Vα19 mice did not. Adoptive transfer of MAIT cells from the latter into the control mice, however, recapitulated the resistance. These mice present an implication for understanding the role of MAIT cells in health and disease and in developing treatments for the plethora of diseases in which MAIT cells are implicated.

Corrigendum: The paradigm of IL-23-independent production of IL-17F and IL-17A and their role in chronic inflammatory diseases.

[This corrects the article DOI: 10.3389/fimmu.2023.1191782.].

Current Perspectives and Challenges of MAIT Cell-Directed Therapy for Tuberculosis Infection.

Mucosal-associated invariant T (MAIT) cells are a distinct population of non-conventional T cells that have been preserved through evolution and possess properties of both innate and adaptive immune cells. They are activated through the recognition of antigens presented by non-polymorphic MR1 proteins or, alternately, can be stimulated by specific cytokines. These cells are multifaceted and exert robust antimicrobial activity against bacterial and viral infections, direct the immune response through the modulation of other immune cells, and exhibit a specialized tissue homeostasis and repair function. These distinct characteristics have instigated interest in MAIT cell biology for immunotherapy and vaccine development. This review describes the current understanding of MAIT cell activation, their role in infections and diseases with an emphasis on tuberculosis (TB) infection, and perspectives on the future use of MAIT cells in immune-mediated therapy.