Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin.

Mucosal-associated invariant T (MAIT) cells represent an abundant innate-like T cell subtype in the human liver. MAIT cells are assigned crucial roles in regulating immunity and inflammation, yet their role in liver cancer remains elusive. Here, we present a MAIT cell-centered profiling of hepatocellular carcinoma (HCC) using scRNA-seq, flow cytometry, and co-detection by indexing (CODEX) imaging of paired patient samples. These analyses highlight the heterogeneity and dysfunctionality of MAIT cells in HCC and their defective capacity to infiltrate liver tumors. Machine-learning tools were used to dissect the spatial cellular interaction network within the MAIT cell neighborhood. Co-localization in the adjacent liver and interaction between niche-occupying CSF1R+PD-L1+ tumor-associated macrophages (TAMs) and MAIT cells was identified as a key regulatory element of MAIT cell dysfunction. Perturbation of this cell-cell interaction in ex vivo co-culture studies using patient samples and murine models reinvigorated MAIT cell cytotoxicity. These studies suggest that aPD-1/aPD-L1 therapies target MAIT cells in HCC patients.

Mucosa-Associated Invariant T Cell Hypersensitivity to Staphylococcus aureus Leukocidin ED and Its Modulation by Activation.

Mucosa-associated invariant T (MAIT) cells recognize bacterial riboflavin metabolite Ags presented by MHC class Ib-related protein (MR1) and play important roles in immune control of microbes that synthesize riboflavin. This includes the pathobiont Staphylococcus aureus, which can also express a range of virulence factors, including the secreted toxin leukocidin ED (LukED). In this study, we found that human MAIT cells are hypersensitive to LukED-mediated lysis and lost on exposure to the toxin, leaving a T cell population devoid of MAIT cells. The cytolytic effect of LukED on MAIT cells was rapid and occurred at toxin concentrations lower than those required for toxicity against conventional T cells. Furthermore, this coincided with high MAIT cell expression of CCR5, and loss of these cells was efficiently inhibited by the CCR5 inhibitor maraviroc. Interestingly, exposure and preactivation of MAIT cells with IL-12 and IL-18, or activation via TCR triggering, partially protected from LukED toxicity. Furthermore, analysis of NK cells indicated that LukED targeted the mature cytotoxic CD57+ NK cell subset in a CCR5-independent manner. Overall, these results indicate that LukED efficiently eliminates immune cells that can respond rapidly to S. aureus in an innate fashion without the need for clonal expansion, and that MAIT cells are exceptionally vulnerable to this toxin. Thus, the findings support a model where LukED secretion may allow S. aureus to avoid recognition by the rapid cell-mediated responses mediated by MAIT cells and NK cells.

Chronic Obstructive Pulmonary Disease and Cigarette Smoke Lead to Dysregulated Mucosal-associated Invariant T-Cell Activation.

Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation, increased infiltration by CD8+ T lymphocytes, and infection-driven exacerbations. Although cigarette smoke is the leading risk factor for COPD, the mechanisms driving the development of COPD in only a subset of smokers are incompletely understood. Lung-resident mucosal-associated invariant T (MAIT) cells play a role in microbial infections and inflammatory diseases. The role of MAIT cells in COPD pathology is unknown. Here, we examined MAIT cell activation in response to cigarette smoke-exposed primary human bronchial epithelial cells (BECs) from healthy, COPD, or smoker donors. We observed significantly higher baseline MAIT cell responses to COPD BECs than healthy BECs. However, infected COPD BECs stimulated a smaller fold increase in MAIT cell response despite increased microbial infection. For all donor groups, cigarette smoke-exposed BECs elicited reduced MAIT cell responses; conversely, cigarette smoke exposure increased ligand-mediated MR1 surface translocation in healthy and COPD BECs. Our data demonstrate that MAIT cell activation is dysregulated in the context of cigarette smoke and COPD. MAIT cells could contribute to cigarette smoke- and COPD-associated inflammation through inappropriate activation and reduced early recognition of bacterial infection, contributing to microbial persistence and COPD exacerbations.

Mucosal-associated invariant T cells display both pathogenic and protective roles in patients with inflammatory bowel diseases.

An important subtype of the innate-like T lymphocytes is mucosal-associated invariant T (MAIT) cells expressing a semi-invariant T cell receptor α (TCR-α) chain. MAIT cells could be activated mainly by TCR engagement or cytokines. They have been found to have essential roles in various immune mediated. There have been growing preclinical and clinical findings that show an association between MAIT cells and the physiopathology of inflammatory bowel diseases (IBD). Of note, published reports demonstrate contradictory findings regarding the role of MAIT cells in IBD patients. A number of reports suggests a protective effect, whereas others show a pathogenic impact. The present review article aimed to explore and discuss the findings of experimental and clinical investigations evaluating the effects of MAIT cells in IBD subjects and animal models. Findings indicate that MAIT cells could exert opposite effects in the course of IBD, including an anti-inflammatory protective effect of blood circulating MAIT cells and an effector pathogenic effect of colonic MAIT cells. Another important finding is that blood levels of MAIT cells can be considered as a potential biomarker in IBD patients.

MAIT cells are functionally impaired in a Mauritian cynomolgus macaque model of SIV and Mtb co-infection.

Mucosal-associated invariant T (MAIT) cells can recognize and respond to some bacterially infected cells. Several in vitro and in vivo models of Mycobacterium tuberculosis (Mtb) infection suggest that MAIT cells can contribute to control of Mtb, but these studies are often cross-sectional and use peripheral blood cells. Whether MAIT cells are recruited to Mtb-affected granulomas and lymph nodes (LNs) during early Mtb infection and what purpose they might serve there is less well understood. Furthermore, whether HIV/SIV infection impairs MAIT cell frequency or function at the sites of Mtb replication has not been determined. Using Mauritian cynomolgus macaques (MCM), we phenotyped MAIT cells in the peripheral blood and bronchoalveolar lavage (BAL) before and during infection with SIVmac239. To test the hypothesis that SIV co-infection impairs MAIT cell frequency and function within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb Erdman, and necropsied at 6 weeks post Mtb-challenge. MAIT cell frequency and function were examined within the peripheral blood, BAL, and Mtb-affected lymph nodes (LN) and granulomas. MAIT cells did not express markers indicative of T cell activation in response to Mtb in vivo within granulomas in animals infected with Mtb alone. SIV and Mtb co-infection led to increased expression of the activation/exhaustion markers PD-1 and TIGIT, and decreased ability to secrete TNFα when compared to SIV-naïve MCM. Our study provides evidence that SIV infection does not prohibit the recruitment of MAIT cells to sites of Mtb infection, but does functionally impair those MAIT cells. Their impaired function could have impacts, either direct or indirect, on the long-term containment of TB disease.

Mucosal-Associated Invariant T Cell Dysregulation Correlates With Conjugated Bilirubin Level in Chronic HBV Infection.

BACKGROUND AND AIMS: Mucosal-associated invariant T (MAIT) cells are nonconventional T cells restricted to major histocompatibility complex class I-related protein 1 (MR1). They are highly abundant in human liver and activated by T-cell receptor (TCR)-dependent and TCR-independent mechanisms to exhibit rapid, innate-like effector responses. However, the roles of MAIT cells in chronic HBV infection are still open for study. This study aims to test their antiviral potential and investigate their dynamic changes and regulating factors during chronic HBV infection. APPROACH AND RESULTS: Blood samples from 257 chronic HBV-infected patients were enrolled, and nontumor liver specimens were collected from 58 HBV-infected HCC patients. Combining cell-culture experiments and human data, we showed that MAIT cells had strong cytotoxicity against HBV-transfected hepatocytes in an MR1-dependent way. However, circulating and hepatic MAIT cells in HBV-infected patients decreased significantly compared to controls. Correlation analysis suggested that MAIT cell frequency was associated with disease progression and inversely correlated with serum-conjugated bilirubin level. In particular, conjugated bilirubin not only directly promoted MAIT cell activation and apoptosis, but also impaired TCR-induced proliferation and expansion of MAIT cells, which could be partially rescued by IL-2 in the absence of conjugated bilirubin. Despite that MAIT cells from patients with high conjugated bilirubin levels showed decreased cytokine-producing capacity, the increased TCR-dependent antiviral cytokine production suggested MAIT cells as an important guardian of chronic HBV with high conjugated bilirubin. CONCLUSIONS: We reveal the MR1-dependent, anti-HBV potential of MAIT cells and identify conjugated bilirubin as a major factor dysregulating its frequency and function in chronic HBV-infected patients, suggesting a therapeutic target for MAIT-cell-based immunity against chronic HBV infection.

MAIT cell alterations in adults with recent-onset and long-term type 1 diabetes.

AIMS/HYPOTHESIS: Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes expressing an αß T cell antigen receptor that recognises the MHC-related 1 molecule. MAIT cells are altered in children at risk for and with type 1 diabetes, and mouse model studies have shown MAIT cell involvement in type 1 diabetes development. Since several studies support heterogeneity in type 1 diabetes physiopathology according to the age of individuals, we investigated whether MAIT cells were altered in adults with type 1 diabetes. METHODS: MAIT cell frequency, phenotype and function were analysed by flow cytometry, using fresh peripheral blood from 21 adults with recent-onset type 1 diabetes (2-14 days after disease onset) and 47 adults with long-term disease (>2 years after diagnosis) compared with 55 healthy blood donors. We also separately analysed 17 women with long-term type 1 diabetes and an associated autoimmune disease, compared with 30 healthy women and 27 women with long-term type 1 diabetes. RESULTS: MAIT cells from adults with recent-onset type 1 diabetes, compared with healthy adult donors, harboured a strongly activated phenotype indicated by an elevated CD25+ MAIT cell frequency. In adults with long-term type 1 diabetes, MAIT cells displayed an activated and exhausted phenotype characterised by high CD25 and programmed cell death 1 (PD1) expression and a decreased production of proinflammatory cytokines, IL-2, IFN-γ and TNF-α. Even though MAIT cells from these patients showed upregulated IL-17 and IL-4 production, the polyfunctionality of MAIT cells was decreased (median 4.8 vs 13.14% of MAIT cells, p < 0.001) and the frequency of MAIT cells producing none of the effector molecules analysed increased (median 34.40 vs 19.30% of MAIT cells, p < 0.01). Several MAIT cell variables correlated with HbA1c level and more particularly in patients with recent-onset type 1 diabetes. In women with long-term type 1 diabetes, MAIT cell alterations were more pronounced in those with an associated autoimmune disease than in those without another autoimmune disease. In women with long-term type 1 diabetes and an associated autoimmune disease, there was an increase in CD69 expression and a decrease in the survival B-cell lymphoma 2 (BCL-2) (p < 0.05) and CD127 (IL-7R) (p < 0.01) marker expression compared with women without a concomitant autoimmune disorder. Concerning effector molecules, TNF-α and granzyme B production by MAIT cells was decreased. CONCLUSIONS/INTERPRETATION: Alterations in MAIT cell frequency, phenotype and function were more pronounced in adults with long-term type 1 diabetes compared with adults with recent-onset type 1 diabetes. There were several correlations between MAIT cell variables and clinical characteristics. Moreover, the presence of another autoimmune disease in women with long-term type 1 diabetes further exacerbated MAIT cell alterations. Our results suggest that MAIT cell alterations in adults with type 1 diabetes could be associated with two aspects of the disease: impaired glucose homeostasis; and autoimmunity.

Mucosal-associated invariant T cells and Vδ2+ γδ T cells in community acquired pneumonia: association of abundance in sputum with clinical severity and outcome.

Mucosal-associated invariant T (MAIT) cells and Vδ2+ γδ T cells are anti-bacterial innate-like lymphocytes (ILLs) that are enriched in blood and mucosa. ILLs have been implicated in control of infection. However, the role of ILLs in community-acquired pneumonia (CAP) is unknown. Using sputum samples from a well-characterized CAP cohort, MAIT cell and Vδ2+ T cell abundance was determined by quantitative polymerase chain reaction (qPCR). Cytokine and chemokine concentrations in sputum were measured. The capacity of bacteria in sputum to produce activating ligands for MAIT cells and Vδ2+ T cells was inferred by 16S rRNA sequencing. MAIT cell abundance in sputum was higher in patients with less severe pneumonia; duration of hospital admission was inversely correlated with both MAIT and Vδ2+ T cell abundance. The abundance of both ILLs was higher in patients with a confirmed bacterial aetiology; however, there was no correlation with total bacterial load or the predicted capacity of bacteria to produce activating ligands. Sputum MAIT cell abundance was associated with interferon (IFN)-α, IFN-γ, and sputum neutrophil abundance, while Vδ2+ T cell abundance was associated with CXCL11 and IFN-γ. Therefore, MAIT and Vδ2+ T cells can be detected in sputum in CAP, where they may contribute to improved clinical outcome.

Mucosal-associated invariant T (MAIT) cells are activated in the gastrointestinal tissue of patients with combination ipilimumab and nivolumab therapy-related colitis in a pathology distinct from ulcerative colitis.

The aim of this study was to investigate the pathogenesis of combination ipilimumab and nivolumab-associated colitis (IN-COL) by measuring gut-derived and peripheral blood mononuclear cell (GMNC; PBMC) profiles. We studied GMNC and PBMC from patients with IN-COL, IN-treated with no adverse-events (IN-NAE), ulcerative colitis (UC) and healthy volunteers using flow cytometry. In the gastrointestinal-derived cells we found high levels of activated CD8+ T cells and mucosal-associated invariant T (MAIT) cells in IN-COL, changes that were not evident in IN-NAE or UC. UC, but not IN-C, was associated with a high proportion of regulatory T cells (Treg ). We sought to determine if local tissue responses could be measured in peripheral blood. Peripherally, checkpoint inhibition instigated a rise in activated memory CD4+ and CD8+ T cells, regardless of colitis. Low circulating MAIT cells at baseline was associated with IN-COL patients compared with IN-NAE in one of two cohorts. UC, but not IN-COL, was associated with high levels of circulating plasmablasts. In summary, the alterations in T cell subsets measured in IN-COL-affected tissue, characterized by high levels of activated CD8+ T cells and MAIT cells and a low proportion of Treg , reflected a pathology distinct from UC. These tissue changes differed from the periphery, where T cell activation was a widespread on-treatment effect, and circulating MAIT cell count was low but not reliably predictive of colitis.

Mucosal-Associated Invariant T Cells in Chronic Inflammatory Liver Disease.

The broadening field of microbiome research has led to a substantial reappraisal of the gut-liver axis and its role in chronic liver disease. The liver is a central immunologic organ that is continuously exposed to food and microbial-derived antigens from the gastrointestinal tract. Mucosal-associated invariant T (MAIT) cells are enriched in the human liver and can be activated by inflammatory cytokines and microbial antigens. In chronic inflammatory liver disease, MAIT cells are depleted suggesting an impaired MAIT cell-dependent protection against bacterial infections.

Mucosa-associated invariant T cells in malignancies: a faithful friend or formidable foe?

Mucosa-associated invariant T (MAIT) cells are a subset of innate-like T lymphocytes known for their ability to respond to MHC-related protein 1 (MR1)-restricted stimuli and select cytokine signals. They are abundant in humans and especially enriched in mucosal layers, common sites of neoplastic transformation. MAIT cells have been found within primary and metastatic tumors. However, whether they promote malignancy or contribute to anticancer immunity is unclear. On the one hand, MAIT cells produce IL-17A in certain locations and under certain circumstances, which could in turn facilitate neoangiogenesis, intratumoral accumulation of immunosuppressive cell populations, and cancer progression. On the other hand, they can express a potent arsenal of cytotoxic effector molecules, NKG2D and IFN-γ, all of which have established roles in cancer immune surveillance. In this review, we highlight MAIT cells' characteristics as they might pertain to cancer initiation, progression, or control. We discuss recent findings, including our own, that link MAIT cells to cancer, with a focus on colorectal carcinoma, as well as some of the outstanding questions in this active area of research. Finally, we provide a hypothetical picture in which MAIT cells constitute attractive targets in cancer immunotherapy.

Mucosa-associated invariant T cells infiltrate hepatic metastases in patients with colorectal carcinoma but are rendered dysfunctional within and adjacent to tumor microenvironment.

Mucosa-associated invariant T (MAIT) cells are innate-like T lymphocytes that are unusually abundant in the human liver, a common site of colorectal carcinoma (CRC) metastasis. However, whether they contribute to immune surveillance against colorectal liver metastasis (CRLM) is essentially unexplored. In addition, whether MAIT cell functions can be impacted by chemotherapy is unclear. These are important questions given MAIT cells' potent immunomodulatory and inflammatory properties. Herein, we examined the frequencies and functions of peripheral blood, healthy liver tissue, tumor-margin and tumor-infiltrating MAIT cells in 21 CRLM patients who received no chemotherapy, FOLFOX, or a combination of FOLFOX and Avastin before they underwent liver resection. We found that MAIT cells, defined as CD3ε+Vα7.2+CD161++ or CD3ε+MR1 tetramer+ cells, were present within both healthy and tumor-afflicted hepatic tissues. Paired and grouped analyses of samples revealed the physical proximity of MAIT cells to metastatic lesions to drastically influence their functional competence. Accordingly, unlike those residing in the healthy liver compartment, tumor-infiltrating MAIT cells failed to produce IFN-γ in response to a panel of TCR and cytokine receptor ligands, and tumor-margin MAIT cells were only partially active. Furthermore, chemotherapy did not account for intratumoral MAIT cell insufficiencies. Our findings demonstrate for the first time that CRLM-penetrating MAIT cells exhibit wide-ranging functional impairments, which are dictated by their physical location but not by preoperative chemotherapy. Therefore, we propose that MAIT cells may provide an attractive therapeutic target in CRC and that their ligands may be combined with chemotherapeutic agents to treat CRLM.

Neuropathologic, phenotypic and functional analyses of Mucosal Associated Invariant T cells in Multiple Sclerosis.

BACKGROUND: The involvement of Mucosal Associated Invariant T (MAIT) cells, which are anti-microbial semi-invariant T cells, remains elusive in Multiple Sclerosis (MS). OBJECTIVE: Deciphering the potential involvement of MAIT cells in the MS inflammatory process. METHODS: By flow cytometry, blood MAIT cells from similar cohorts of MS patients and healthy volunteers (HV) were compared for frequency, phenotype, activation potential after in vitro TCR engagement by bacterial ligands and transmigration abilities through an in vitro model of blood-brain barrier. MS CNS samples were also studied by immunofluorescent staining and quantitative PCR. RESULTS AND CONCLUSION: Blood MAIT cells from relapsing-remitting MS patients and HV presented similar frequency, ex vivo effector phenotype and activation abilities. MAIT cells represented 0.5% of the total infiltrating T cells on 39 MS CNS lesions. This is low as compared to blood frequency (p<0.001), but consistent with their low transmigration rate. Finally, transcriptional over-expression of MR1 - which presents cognate antigens to MAIT cells - and of the activating cytokines IL-18 and IL-23 was evidenced in MS lesions, suggesting that the CNS microenvironment is suited to activate the few infiltrating MAIT cells. Taken together, these data place MAIT cells from MS patients as minor components of the inflammatory pathological process.

MAIT cells are activated and accumulated in the inflamed mucosa of ulcerative colitis.

BACKGROUND AND AIM: Ulcerative colitis (UC) is a chronic, relapsing and remitting, inflammatory disorder of the large intestine. Mucosal associated invariant T (MAIT) cells are a member of innate-like lymphocytes found abundantly in the mucosal tissue. The contribution of MAIT cells in the pathogenesis of UC is still unclear; therefore, this study aimed at investigating the role of these cells in patients with UC. METHODS: The frequency of MAIT cells, as well as the production of cytokines and expression levels of activation markers by these cells in the peripheral blood of UC patients and healthy controls, was analyzed by flow cytometry. MAIT cells were also quantified in colon biopsies of UC patients using a confocal microscope. RESULTS: There was a significant reduction in MAIT cell frequency in the peripheral blood of UC patients compared with healthy controls (P < 0.0001). MAIT cells from UC patients secreted more interleukin (IL)-17 than healthy controls (P < 0.05). The expression levels of CD69 on these cells were correlated with disease activity and endoscopic scores and plasma levels of IL-18. Furthermore, MAIT cells increased in the inflamed mucosa, and their frequency was correlated with clinical and endoscopic disease activity in UC patients. CONCLUSIONS: The findings from this study indicate that MAIT cells could be associated with UC and may serve as potential biomarkers or therapeutic targets in UC.

MAIT cells are associated with responsiveness to neoadjuvant immunotherapy in COPD-associated NSCLC.

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.

The alterations of circulating mucosal-associated invariant T cells in polycystic ovary syndrome.

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.

Chronic stress physically spares but functionally impairs innate-like invariant T cells.

The deleterious effects of psychological stress on mainstream T lymphocytes are well documented. However, how stress impacts innate-like T cells is unclear. We report that long-term stress surprisingly abrogates both T helper 1 (TH1)- and TH2-type responses orchestrated by invariant natural killer T (iNKT) cells. This is not due to iNKT cell death because these cells are unusually refractory to stress-inflicted apoptosis. Activated iNKT cells in stressed mice exhibit a "split" inflammatory signature and trigger sudden serum interleukin-10 (IL-10), IL-23, and IL-27 spikes. iNKT cell dysregulation is mediated by cell-autonomous glucocorticoid receptor signaling and corrected upon habituation to predictable stressors. Importantly, under stress, iNKT cells fail to potentiate cytotoxicity against lymphoma or to reduce the burden of metastatic melanoma. Finally, stress physically spares mouse mucosa-associated invariant T (MAIT) cells but hinders their TH1-/TH2-type responses. The above findings are corroborated in human peripheral blood and hepatic iNKT/MAIT cell cultures. Our work uncovers a mechanism of stress-induced immunosuppression.

Circulating mucosal-associated invariant T cells in subjects with recurrent urinary tract infections are functionally impaired.

BACKGROUND: Urinary tract infection recurrence is common, particularly in women and immunocompromised patients, such as renal transplant recipients (RTRs). Mucosal-associated invariant T (MAIT) cells play a role in the antibacterial response by recognizing bacterial riboflavin metabolites produced by bacteria such as Escherichia coli. Here, we investigated whether MAIT cells are involved in the pathogenesis of recurrent urinary tract infections (RUTIs). METHODS: Using multichannel flow cytometry, we characterized the MAIT cell phenotype and function in blood from immunocompetent adults with (n = 13) and without RUTIs (n = 10) and in RTRs with (n = 9) and without RUTIs (n = 10). RESULTS: There were no differences in the numbers of MAIT cells between the study groups. MAIT cells in patients with RUTI expressed T-bet more often than those in controls. MAIT cells from immunocompetent RUTI participants required more antigen-presenting cells coincubated with E. coli to evoke a similar cytokine and degranulation response than those from controls. This effect was absent in the RTR with RUTI vs RTR control groups, where the overall percentage of MAIT cells that responded to stimulation was already reduced. CONCLUSION: Circulating MAIT cells in immunocompetent individuals with RUTIs respond to bacterial stimuli with reduced efficacy, which suggests that they are involved in the pathogenesis of RUTIs.

Activation, Deficiency, and Reduced IFN-γ Production of Mucosal-Associated Invariant T Cells in Patients with Inflammatory Bowel Disease.

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.