T cell antigen receptor recognition of antigen-presenting molecules.

The Major Histocompatibility Complex (MHC) locus encodes classical MHC class I and MHC class II molecules and nonclassical MHC-I molecules. The architecture of these molecules is ideally suited to capture and present an array of peptide antigens (Ags). In addition, the CD1 family members and MR1 are MHC class I-like molecules that bind lipid-based Ags and vitamin B precursors, respectively. These Ag-bound molecules are subsequently recognized by T cell antigen receptors (TCRs) expressed on the surface of T lymphocytes. Structural and associated functional studies have been highly informative in providing insight into these interactions, which are crucial to immunity, and how they can lead to aberrant T cell reactivity. Investigators have determined over thirty unique TCR-peptide-MHC-I complex structures and twenty unique TCR-peptide-MHC-II complex structures. These investigations have shown a broad consensus in docking geometry and provided insight into MHC restriction. Structural studies on TCR-mediated recognition of lipid and metabolite Ags have been mostly confined to TCRs from innate-like natural killer T cells and mucosal-associated invariant T cells, respectively. These studies revealed clear differences between TCR-lipid-CD1, TCR-metabolite-MR1, and TCR-peptide-MHC recognition. Accordingly, TCRs show remarkable structural and biological versatility in engaging different classes of Ag that are presented by polymorphic and monomorphic Ag-presenting molecules of the immune system.

Targeting BMI-1 in B cells restores effective humoral immune responses and controls chronic viral infection.

Ineffective antibody-mediated responses are a key characteristic of chronic viral infection. However, our understanding of the intrinsic mechanisms that drive this dysregulation are unclear. Here, we identify that targeting the epigenetic modifier BMI-1 in mice improves humoral responses to chronic lymphocytic choriomeningitis virus. BMI-1 was upregulated by germinal center B cells in chronic viral infection, correlating with changes to the accessible chromatin landscape, compared to acute infection. B cell-intrinsic deletion of Bmi1 accelerated viral clearance, reduced splenomegaly and restored splenic architecture. Deletion of Bmi1 restored c-Myc expression in B cells, concomitant with improved quality of antibody and coupled with reduced antibody-secreting cell numbers. Specifically, BMI-1-deficiency induced antibody with increased neutralizing capacity and enhanced antibody-dependent effector function. Using a small molecule inhibitor to murine BMI-1, we could deplete antibody-secreting cells and prohibit detrimental immune complex formation in vivo. This study defines BMI-1 as a crucial immune modifier that controls antibody-mediated responses in chronic infection.

DNA architectural protein CTCF facilitates subset-specific chromatin interactions to limit the formation of memory CD8+ T cells.

Although the importance of genome organization for transcriptional regulation of cell-fate decisions and function is clear, the changes in chromatin architecture and how these impact effector and memory CD8+ T cell differentiation remain unknown. Using Hi-C, we studied how genome configuration is integrated with CD8+ T cell differentiation during infection and investigated the role of CTCF, a key chromatin remodeler, in modulating CD8+ T cell fates through CTCF knockdown approaches and perturbation of specific CTCF-binding sites. We observed subset-specific changes in chromatin organization and CTCF binding and revealed that weak-affinity CTCF binding promotes terminal differentiation of CD8+ T cells through the regulation of transcriptional programs. Further, patients with de novo CTCF mutations had reduced expression of the terminal-effector genes in peripheral blood lymphocytes. Therefore, in addition to establishing genome architecture, CTCF regulates effector CD8+ T cell heterogeneity through altering interactions that regulate the transcription factor landscape and transcriptome.

Infection induces tissue-resident memory NK cells that safeguard tissue health.

Tissue health is dictated by the capacity to respond to perturbations and then return to homeostasis. Mechanisms that initiate, maintain, and regulate immune responses in tissues are therefore essential. Adaptive immunity plays a key role in these responses, with memory and tissue residency being cardinal features. A corresponding role for innate cells is unknown. Here, we have identified a population of innate lymphocytes that we term tissue-resident memory-like natural killer (NKRM) cells. In response to murine cytomegalovirus infection, we show that circulating NK cells were recruited in a CX3CR1-dependent manner to the salivary glands where they formed NKRM cells, a long-lived, tissue-resident population that prevented autoimmunity via TRAIL-dependent elimination of CD4+ T cells. Thus, NK cells develop adaptive-like features, including long-term residency in non-lymphoid tissues, to modulate inflammation, restore immune equilibrium, and preserve tissue health. Modulating the functions of NKRM cells may provide additional strategies to treat inflammatory and autoimmune diseases.

Microbiota-Derived Short-Chain Fatty Acids Promote the Memory Potential of Antigen-Activated CD8+ T Cells.

Interactions with the microbiota influence many aspects of immunity, including immune cell development, differentiation, and function. Here, we examined the impact of the microbiota on CD8+ T cell memory. Antigen-activated CD8+ T cells transferred into germ-free mice failed to transition into long-lived memory cells and had transcriptional impairments in core genes associated with oxidative metabolism. The microbiota-derived short-chain fatty acid (SCFA) butyrate promoted cellular metabolism, enhanced memory potential of activated CD8+ T cells, and SCFAs were required for optimal recall responses upon antigen re-encounter. Mechanistic experiments revealed that butyrate uncoupled the tricarboxylic acid cycle from glycolytic input in CD8+ T cells, which allowed preferential fueling of oxidative phosphorylation through sustained glutamine utilization and fatty acid catabolism. Our findings reveal a role for the microbiota in promoting CD8+ T cell long-term survival as memory cells and suggest that microbial metabolites guide the metabolic rewiring of activated CD8+ T cells to enable this transition.

T Cell LEGO: Identifying the Master Builders and What They Do.

Understanding how cell fate decisions are made during cellular differentiation and the mechanisms that drive them is a holy grail of cell biology. In this issue of Immunity, Hu et al. (2018) and Johnson et al. (2018) demonstrate that key transcriptional regulators and global changes in nuclear architecture underlie differentiation decisions during T cell development.

Th1 Cells Alter the Inflammatory Signature of IL-6 by Channeling STAT Transcription Factors to Alu-like Retroelements.

Cytokines that signal via STAT1 and STAT3 transcription factors instruct decisions affecting tissue homeostasis, antimicrobial host defense, and inflammation-induced tissue injury. To understand the coordination of these activities, we applied RNA sequencing, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing to identify the transcriptional output of STAT1 and STAT3 in peritoneal tissues from mice during acute resolving inflammation and inflammation primed to drive fibrosis. Bioinformatics focused on the transcriptional signature of the immunomodulatory cytokine IL-6 in both settings and examined how profibrotic IFN-γ-secreting CD4+ T cells altered the interpretation of STAT1 and STAT3 cytokine cues. In resolving inflammation, STAT1 and STAT3 cooperated to drive stromal gene expression affecting antimicrobial immunity and tissue homeostasis. The introduction of IFN-γ-secreting CD4+ T cells altered this transcriptional program and channeled STAT1 and STAT3 to a previously latent IFN-γ activation site motif in Alu-like elements. STAT1 and STAT3 binding to this conserved sequence revealed evidence of reciprocal cross-regulation and gene signatures relevant to pathophysiology. Thus, we propose that effector T cells retune the transcriptional output of IL-6 by shaping a regulatory interplay between STAT1 and STAT3 in inflammation.

Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli.

Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-deficient microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1(creER) increased the lifespan of otherwise Mecp2-null mice. These data suggest that Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages might contribute to the systemic pathologies observed in Rett syndrome.

High 3He/4He in central Panama reveals a distal connection to the Galápagos plume.

It is well established that mantle plumes are the main conduits for upwelling geochemically enriched material from Earth's deep interior. The fashion and extent to which lateral flow processes at shallow depths may disperse enriched mantle material far (>1,000 km) from vertical plume conduits, however, remain poorly constrained. Here, we report He and C isotope data from 65 hydrothermal fluids from the southern Central America Margin (CAM) which reveal strikingly high 3He/4He (up to 8.9RA) in low-temperature (≤50 °C) geothermal springs of central Panama that are not associated with active volcanism. Following radiogenic correction, these data imply a mantle source 3He/4He >10.3RA (and potentially up to 26RA, similar to Galápagos hotspot lavas) markedly greater than the upper mantle range (8 ± 1RA). Lava geochemistry (Pb isotopes, Nb/U, and Ce/Pb) and geophysical constraints show that high 3He/4He values in central Panama are likely derived from the infiltration of a Galápagos plume-like mantle through a slab window that opened ∼8 Mya. Two potential transport mechanisms can explain the connection between the Galápagos plume and the slab window: 1) sublithospheric transport of Galápagos plume material channeled by lithosphere thinning along the Panama Fracture Zone or 2) active upwelling of Galápagos plume material blown by a "mantle wind" toward the CAM. We present a model of global mantle flow that supports the second mechanism, whereby most of the eastward transport of Galápagos plume material occurs in the shallow asthenosphere. These findings underscore the potential for lateral mantle flow to transport mantle geochemical heterogeneities thousands of kilometers away from plume conduits.

Dog ownership in infancy is protective for persistent wheeze in 17q21 asthma-risk carriers.

BACKGROUND: Asthma-associated single nucleotide polymorphisms from large genome-wide association studies only explain a fraction of genetic heritability. Likely causes of the missing heritability include broad phenotype definitions and gene-environment interactions (GxE). The mechanisms underlying GxE in asthma are poorly understood. Previous GxE studies on pet ownership showed discordant results. OBJECTIVES: We sought to study the GxE between the 17q12-21 locus and pet ownership in infancy in relation to wheeze. METHODS: Wheezing classes derived from 5 UK-based birth cohorts (latent class analysis) were used to study GxE between the 17q12-21 asthma-risk variant rs2305480 and dog and cat ownership in infancy, using multinomial logistic regression. A total of 9149 children had both pet ownership and genotype data available. Summary statistics from individual analyses were meta-analyzed. RESULTS: rs2305480 G allele was associated with increased risk of persistent wheeze (additive model odds ratio, 1.37; 95% CI, 1.25-1.51). There was no evidence of an association between dog or cat ownership and wheeze. We found significant evidence of a GxE interaction between rs2305480 and dog ownership (P = 8.3 × 10-4) on persistent wheeze; among dog owners, the G allele was no longer associated with an increased risk of persistent wheeze (additive model odds ratio, 0.95; 95% CI, 0.73-1.24). For those without pets, G allele was associated with increased risk of persistent wheeze (odds ratio, 1.61; 95% CI, 1.40-1.86). Among cat owners, no such dampening of the genetic effect was observed. CONCLUSIONS: Among dog owners, rs2305480 G was no longer associated with an increased risk of persistent wheeze (or asthma). Early-life environmental exposures may therefore attenuate likelihood of asthma in those carrying 17q12-21 risk alleles.

E-liquids and vanillin flavoring disrupts retinoic acid signaling and causes craniofacial defects in Xenopus embryos.

Environmental teratogens such as smoking are known risk factors for developmental disorders such as cleft palate. While smoking rates have declined, a new type of smoking, called vaping is on the rise. Vaping is the use of e-cigarettes to vaporize and inhale an e-liquid containing nicotine and food-like flavors. There is the potential that, like smoking, vaping could also pose a danger to the developing human. Rather than waiting for epidemiological and mammalian studies, we have turned to an aquatic developmental model, Xenopus laevis, to more quickly assess whether e-liquids contain teratogens that could lead to craniofacial malformations. Xenopus, like zebrafish, has the benefit of being a well-established developmental model and has also been effective in predicting whether a chemical could be a teratogen. We have determined that embryonic exposure to dessert flavored e-liquids can cause craniofacial abnormalities, including an orofacial cleft in Xenopus. To better understand the underlying mechanisms contributing to these defects, transcriptomic analysis of the facial tissues of embryos exposed to a representative dessert flavored e-liquid vapor extract was performed. Analysis of differentially expressed genes in these embryos revealed several genes associated with retinoic acid metabolism or the signaling pathway. Consistently, retinoic acid receptor inhibition phenocopied the craniofacial defects as those embryos exposed to the vapor extract of the e-liquid. Such malformations also correlated with a group of common differentially expressed genes, two of which are associated with midface birth defects in humans. Further, e-liquid exposure sensitized embryos to forming craniofacial malformations when they already had depressed retinoic acid signaling. Moreover, 13-cis-retinoic acid treatment could significantly reduce the e-liquid induced malformation in the midface. Such results suggest the possibility of an interaction between retinoic acid signaling and e-liquid exposure. One of the most popular and concentrated flavoring chemicals in dessert flavored e-liquids is vanillin. Xenopus embryos exposed to this chemical closely resembled embryos exposed to dessert-like e-liquids and a retinoic acid receptor antagonist. In summary, we determined that e-liquid chemicals, in particular vanillin, can cause craniofacial defects potentially by dysregulating retinoic acid signaling. This work warrants the evaluation of vanillin and other such flavoring additives in e-liquids on mammalian development.

Genetic Architecture of Gene Expression in European and African Americans: An eQTL Mapping Study in GENOA.

Most existing expression quantitative trait locus (eQTL) mapping studies have been focused on individuals of European ancestry and are underrepresented in other populations including populations with African ancestry. Lack of large-scale well-powered eQTL mapping studies in populations with African ancestry can both impede the dissemination of eQTL mapping results that would otherwise benefit individuals with African ancestry and hinder the comparable analysis for understanding how gene regulation is shaped through evolution. We fill this critical knowledge gap by performing a large-scale in-depth eQTL mapping study on 1,032 African Americans (AA) and 801 European Americans (EA) in the GENOA cohort. We identified a total of 354,931 eSNPs in AA and 371,309 eSNPs in EA, with 112,316 eSNPs overlapped between the two. We found that eQTL harboring genes (eGenes) are enriched in metabolic pathways and tend to have higher SNP heritability compared to non-eGenes. We found that eGenes that are common in the two populations tend to be less conserved than eGenes that are unique to one population, which are less conserved than non-eGenes. Through conditional analysis, we found that eGenes in AA tend to harbor more independent eQTLs than eGenes in EA, suggesting potentially diverse genetic architecture underlying expression variation in the two populations. Finally, the large sample sizes in GENOA allow us to construct accurate expression prediction models in both AA and EA, facilitating powerful transcriptome-wide association studies. Overall, our results represent an important step toward revealing the genetic architecture underlying expression variation in African Americans.

Global Incidence and Prevalence of Eosinophilic Esophagitis, 1976-2022: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Owing to 2018 expanded diagnostic criteria for eosinophilic esophagitis (EoE) and thus a possible increase in diagnosis, previous studies on the global incidence and prevalence of EoE may need to be updated. We aimed to describe global, regional, and national trends in the incidence and prevalence of EoE from 1976 to 2022 and analyze their associations with geographic, demographic, and social factors through a systematic review. METHODS: We searched the PubMed/MEDLINE, Embase, CINAHL, Google Scholar, and Cochrane databases from their inception dates to December 20, 2022, for studies that reported the incidence or prevalence of EoE in the general population. We calculated the global incidence and prevalence of EoE using pooled estimates with 95% confidence intervals (CIs) and performed subgroup analysis based on age, sex, race, geographical area, World Bank income group, and diagnostic criteria of EoE. RESULTS: Forty studies met the eligibility criteria, including over 288 million participants and 147,668 patients with EoE from 15 countries across the five continents. The global pooled incidence and prevalence of EoE were 5.31 cases per 100,000 inhabitant-years (95% CI, 3.98-6.63; number of studies, 27; sample population, 42,191,506) and 40.04 cases per 100,000 inhabitant-years (95% CI, 31.10-48.98; number of studies, 20; sample population, 30,467,177), respectively. The pooled incidence of EoE was higher in high-income countries (vs low- or middle-income countries), males, and North America (vs Europe and Asia). The global prevalence of EoE followed a similar pattern. The pooled prevalence of EoE gradually increased from 1976 to 2022 (1976-2001; 8.18; 95% CI, 3.67-12.69 vs 2017-2022; 74.42; 95% CI, 39.66-109.19 cases per 100,000 inhabitant-years). CONCLUSIONS: The incidence and prevalence of EoE have increased substantially and vary widely across the world. Further research is needed to evaluate the incidence and prevalence of EoE in Asia, South America, and Africa.

Best step-up treatments for children with uncontrolled asthma: a systematic review and network meta-analysis of individual participant data.

BACKGROUND: There is uncertainty about the best treatment option for children/adolescents with uncontrolled asthma despite inhaled corticosteroids (ICS) and international guidelines make different recommendations. We evaluated the pharmacological treatments to reduce asthma exacerbations and symptoms in uncontrolled patients age <18 years on ICS. METHODS: We searched MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Embase, Web of Science, National Institute for Health and Care Excellence Technology Appraisals, National Institute for Health and Care Research Health Technology Assessment series, World Health Organization International Clinical Trials Registry, conference abstracts and internal clinical trial registers (1 July 2014 to 5 May 2023) for randomised controlled trials of participants age <18 years with uncontrolled asthma on any ICS dose alone at screening. Studies before July 2014 were retrieved from previous systematic reviews/contact with authors. Patients had to be randomised to any dose of ICS alone or combined with long-acting ß2-agonists (LABA) or combined with leukotriene receptor antagonists (LTRA), LTRA alone, theophylline or placebo. Primary outcomes were exacerbation and asthma control. The interventions evaluated were ICS (low/medium/high dose), ICS+LABA, ICS+LTRA, LTRA alone, theophylline and placebo. RESULTS: Of the 4708 publications identified, 144 trials were eligible. Individual participant data were obtained from 29 trials and aggregate data were obtained from 19 trials. Compared with ICS Low, ICS Medium+LABA was associated with the lowest odds of exacerbation (OR 0.44, 95% credibility interval (95% CrI) 0.19-0.90) and with an increased forced expiratory volume in 1 s (mean difference 0.71, 95% CrI 0.35-1.06). Treatment with LTRA was the least preferred. No apparent differences were found for asthma control. CONCLUSIONS: Uncontrolled children/adolescents on low-dose ICS should be recommended a change to medium-dose ICS+LABA to reduce the risk for exacerbation and improve lung function.

A semi-invariant Vα10+ T cell antigen receptor defines a population of natural killer T cells with distinct glycolipid antigen-recognition properties.

Type I natural killer T cells (NKT cells) are characterized by an invariant variable region 14-joining region 18 (V(α)14-J(α)18) T cell antigen receptor (TCR) α-chain and recognition of the glycolipid α-galactosylceramide (α-GalCer) restricted to the antigen-presenting molecule CD1d. Here we describe a population of α-GalCer-reactive NKT cells that expressed a canonical V(α)10-J(α)50 TCR α-chain, which showed a preference for α-glucosylceramide (α-GlcCer) and bacterial α-glucuronic acid-containing glycolipid antigens. Structurally, despite very limited TCRα sequence identity, the V(α)10 TCR-CD1d-α-GlcCer complex had a docking mode similar to that of type I TCR-CD1d-α-GalCer complexes, although differences at the antigen-binding interface accounted for the altered antigen specificity. Our findings provide new insight into the structural basis and evolution of glycolipid antigen recognition and have notable implications for the scope and immunological role of glycolipid-specific T cell responses.

Identification of eczema clusters and their association with filaggrin and atopic comorbidities: analysis of five birth cohorts.

BACKGROUND: Longitudinal modelling of the presence/absence of current eczema through childhood has identified similar phenotypes, but their characteristics often differ between studies. OBJECTIVES: To demonstrate that a more comprehensive description of longitudinal pattern of symptoms may better describe trajectories than binary information on eczema presence. METHODS: We derived six multidimensional variables of eczema spells from birth to 18 years of age (including duration, temporal sequencing and the extent of persistence/recurrence). Spells were defined as consecutive observations of eczema separated by no eczema across 5 epochs in five birth cohorts: infancy (first year); early childhood (age 2-3 years); preschool/early school age (4-5 years); middle childhood (8-10 years); adolescence (14-18 years). We applied Partitioning Around Medoids clustering on these variables to derive clusters of the temporal patterns of eczema. We then investigated the stability of the clusters, within-cluster homogeneity and associated risk factors, including FLG mutations. RESULTS: Analysis of 7464 participants with complete data identified five clusters: (i) no eczema (51.0%); (ii) early transient eczema (21.6%); (iii) late-onset eczema (LOE; 8.1%); (iv) intermittent eczema (INT; 7.5%); and (v) persistent eczema (PE; 11.8%). There was very-high agreement between the assignment of individual children into clusters when using complete or imputed (n = 15 848) data (adjusted Rand index = 0.99; i.e. the clusters were very stable). Within-individual symptom patterns across clusters confirmed within-cluster homogeneity, with consistent patterns of symptoms among participants within each cluster and no overlap between the clusters. Clusters were characterized by differences in associations with risk factors (e.g. parental eczema was associated with all clusters apart from LOE; sensitization to inhalant allergens was associated with all clusters, with the highest risk in the PE cluster). All clusters apart from LOE were associated with FLG mutations. Of note, the strongest association was for PE [relative risk ratio (RRR) 2.70, 95% confidence interval (CI) 2.24-3.26; P < 0.001] followed by INT (RRR 2.29, 95% CI 1.82-2.88; P < 0.001). CONCLUSIONS: Clustering of multidimensional variables identified stable clusters with different genetic architectures. Using multidimensional variables may capture eczema development and derive stable and internally homogeneous clusters. However, deriving homogeneous symptom clusters does not necessarily mean that these are underpinned by completely unique mechanisms.

Granzyme B promotes cytotoxic lymphocyte transmigration via basement membrane remodeling.

Granzyme B (GzmB) is a protease with a well-characterized intracellular role in targeted destruction of compromised cells by cytotoxic lymphocytes. However, GzmB also cleaves extracellular matrix components, suggesting that it influences the interplay between cytotoxic lymphocytes and their environment. Here, we show that GzmB-null effector T cells and natural killer (NK) cells exhibited a cell-autonomous homing deficit in mouse models of inflammation and Ectromelia virus infection. Intravital imaging of effector T cells in inflamed cremaster muscle venules revealed that GzmB-null cells adhered normally to the vessel wall and could extend lamellipodia through it but did not cross it efficiently. In vitro migration assays showed that active GzmB was released from migrating cytotoxic lymphocytes and enabled chemokine-driven movement through basement membranes. Finally, proteomic analysis demonstrated that GzmB cleaved basement membrane constituents. Our results highlight an important role for GzmB in expediting cytotoxic lymphocyte diapedesis via basement membrane remodeling.

Distinct epigenetic signatures delineate transcriptional programs during virus-specific CD8(+) T cell differentiation.

The molecular mechanisms that regulate the rapid transcriptional changes that occur during cytotoxic T lymphocyte (CTL) proliferation and differentiation in response to infection are poorly understood. We have utilized ChIP-seq to assess histone H3 methylation dynamics within naive, effector, and memory virus-specific T cells isolated directly ex vivo after influenza A virus infection. Our results show that within naive T cells, codeposition of the permissive H3K4me3 and repressive H3K27me3 modifications is a signature of gene loci associated with gene transcription, replication, and cellular differentiation. Upon differentiation into effector and/or memory CTLs, the majority of these gene loci lose repressive H3K27me3 while retaining the permissive H3K4me3 modification. In contrast, immune-related effector gene promoters within naive T cells lacked the permissive H3K4me3 modification, with acquisition of this modification occurring upon differentiation into effector/memory CTLs. Thus, coordinate transcriptional regulation of CTL genes with related functions is achieved via distinct epigenetic mechanisms.

Mucosal-Associated Invariant T Cell Effector Function Is an Intrinsic Cell Property That Can Be Augmented by the Metabolic Cofactor α-Ketoglutarate.

Mucosal-associated invariant T (MAIT) cells are an innate-like population of unconventional T cells that respond rapidly to microbial metabolite Ags or cytokine stimulation. Because of this reactivity and surface expression of CD45RO+, CD45RA-, and CD127+, they are described as effector memory cells. Yet, there is heterogeneity in MAIT cell effector response. It is unclear what factors control MAIT cell effector capacity, whether it is fixed or can be modified and if this differs based on whether activation is TCR dependent or independent. To address this, we have taken a systematic approach to examine human MAIT cell effector capacity across healthy individuals in response to ligand and cytokine stimulation. We demonstrate the heterogenous nature of MAIT cell effector capacity and that the ability to produce an effector response is not directly attributable to TCR clonotype or coreceptor expression. Global gene transcription analysis revealed that the MAIT cell effector capacity produced in response to TCR stimulation is associated with increased expression of the epigenetic regulator lysine demethylase 6B (KDM6B). Addition of a KDM6B inhibitor did not alter MAIT cell effector function to Ag or cytokine stimulation. However, addition of the KDM6B cofactor α-ketoglutarate greatly enhanced MAIT cell effector capacity to TCR-dependent stimulation in a partially KDM6B-dependent manner. These results demonstrate that the TCR-dependent effector response of MAIT cells is epigenetically regulated and dependent on the availability of metabolic cofactors.