Die Kämpfe únd schláchten-the struggles and battles of innate-like effector T lymphocytes with microbes.

The large majority of lymphocytes belong to the adaptive immune system, which are made up of B2 B cells and the αß T cells; these are the effectors in an adaptive immune response. A multitudinous group of lymphoid lineage cells does not fit the conventional lymphocyte paradigm; it is the unconventional lymphocytes. Unconventional lymphocytes-here called innate/innate-like lymphocytes, include those that express rearranged antigen receptor genes and those that do not. Even though the innate/innate-like lymphocytes express rearranged, adaptive antigen-specific receptors, they behave like innate immune cells, which allows them to integrate sensory signals from the innate immune system and relay that umwelt to downstream innate and adaptive effector responses. Here, we review natural killer T cells and mucosal-associated invariant T cells-two prototypic innate-like T lymphocytes, which sense their local environment and relay that umwelt to downstream innate and adaptive effector cells to actuate an appropriate host response that confers immunity to infectious agents.

Immunometabolism of Immune Cells in Mucosal Environment Drives Effector Responses against Mycobacterium tuberculosis.

Tuberculosis remains a major threat to global public health, with more than 1.5 million deaths recorded in 2020. Improved interventions against tuberculosis are urgently needed, but there are still gaps in our knowledge of the host-pathogen interaction that need to be filled, especially at the site of infection. With a long history of infection in humans, Mycobacterium tuberculosis (Mtb) has evolved to be able to exploit the microenvironment of the infection site to survive and grow. The immune cells are not only reliant on immune signalling to mount an effective response to Mtb invasion but can also be orchestrated by their metabolic state. Cellular metabolism was often overlooked in the past but growing evidence of its importance in the functions of immune cells suggests that it can no longer be ignored. This review aims to gain a better understanding of mucosal immunometabolism of resident effector cells, such as alveolar macrophages and mucosal-associated invariant T cells (MAIT cells), in response to Mtb infection and how Mtb manipulates them for its survival and growth, which could address our knowledge gaps while opening up new questions, and potentially be applied for future vaccination and therapeutic strategies.

Identification of Distinct Immune Cell Subsets Associated With Asymptomatic Infection, Disease Severity, and Viral Persistence in COVID-19 Patients.

The cell-mediated protective and pathogenic immune responses to SARS-CoV-2 infection remain largely elusive. Here we identified 76 distinct cell subsets in the PBMC samples that were associated with various clinical presentations of COVID-19 using scRNA-seq technology coupled with a deep and comprehensive analysis of unique cell surface markers and differentially expressed genes. We revealed that (TRAV1-2+CD8+)MAIT cells and (NCAM1hiCD160+)NK cells significantly enriched in the asymptomatic subjects whereas (LAG3+CD160+CD8+)NKT cells increased in the symptomatic patients. We also observed that (CD68-CSF1R-IL1BhiCD14+)classical monocytes were positively correlated with the disease severity. Moreover, (CD33-HLA-DMA-CD14+)classical monocytes and (CLEC10A-S100A9lo)pDC were associated with the viral persistence. The GO and KEGG analyses identified enriched pathways related to immune responses, inflammation, and apoptosis. These findings may enhance our understanding of the immunopathogenesis of COVID-19 and help develop novel strategies against SARS-CoV-2 infection.

MAIT cell counts are associated with the risk of hospitalization in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation associated with chronic inflammation in the airways. Mucosal-associated invariant T (MAIT) cells are unconventional, innate-like T cells highly abundant in mucosal tissues including the lung. We hypothesized that the characteristics of MAIT cells in circulation may be prospectively associated with COPD morbidity. METHODS: COPD subjects (n = 61) from the Tools for Identifying Exacerbations (TIE) study were recruited when in stable condition. At study entry, forced expiratory volume in 1 s (FEV1) was measured and peripheral blood mononuclear cells were cryopreserved for later analysis by flow cytometry. Patients were followed for 3 years to record clinically meaningful outcomes. RESULTS: Patients who required hospitalization at one or more occasions during the 3-year follow-up (n = 21) had lower MAIT cell counts in peripheral blood at study inclusion, compared with patients who did not get hospitalized (p = 0.036). In contrast, hospitalized and never hospitalized patients did not differ in CD8 or CD4 T cell counts (p = 0.482 and p = 0.221, respectively). Moreover, MAIT cells in hospitalized subjects showed a more activated phenotype with higher CD38 expression (p = 0.014), and there was a trend towards higher LAG-3 expression (p = 0.052). Conventional CD4 and CD8 T cells were similar between the groups. Next we performed multi-variable logistic regression analysis with hospitalizations as dependent variable, and FEV1, GOLD 2017 group, and quantity or activation of MAIT and conventional T cells as independent variables. MAIT cell count, CD38 expression on MAIT cells, and LAG-3 expression on both MAIT and CD8 T cells were all independently associated with the risk of hospitalization. CONCLUSIONS: These findings suggest that MAIT cells might reflect a novel, FEV1-independent immunological dimension in the complexity of COPD. The potential implication of MAIT cells in COPD pathogenesis and MAIT cells' prognostic potential deserve further investigation.

MAIT Cells in Respiratory Viral Infections in Mouse and Human.

Mucosal associated invariant T (MAIT) cells were first identified as specific for bacterial, mycobacterial, and fungal organisms, which detect microbially-derived biosynthetic ligands presented by MHC-related protein 1 (MR1). More recently two unexpected, additional roles have been identified for these ancient and abundant cells: a TCR-depen-dent role in tissue repair and a TCR-independent role in antiviral host defence. Data from several classes of viral disease shows their capability for activation by the cytokines interleukin (IL)-12, IL-15, IL-18, and type I interferon. MAIT cells are abundant at mucosal surfaces, particularly in the lung, and it seems likely a primary reason for their striking evolutionary conservation is an important role in early innate defence against respiratory infections, including both bacteria and viruses. Here we review evidence for their TCR-independent activation, observational human data for their activation in influenza A virus, and in vivo murine evidence of their protection against severe influenza A infection, mediated at least partially via IFN-gamma. We then survey evidence emerging from other respiratory viral infections including recent evidence for an important adjuvant role in adenovirus infection, specifically chimpanzee adenoviruses used in recent coronavirus vaccines, and data for strong associations between MAIT cell responses and adverse outcomes from coronavirus-19 (COVID-19) disease. We speculate on potential translational implications of these findings, either using corticosteroids or inhibitory ligands to suppress deleterious MAIT cell responses, or the potential utility of stimulatory MR1 ligands to boost MAIT cell frequencies to enhance innate viral defences.

MAIT cell compartment characteristics are associated with the immune response magnitude to the BNT162b2 mRNA anti-SARS-CoV-2 vaccine.

Mucosa-associated invariant T (MAIT) cells are unconventional T cells with innate-like capacity to rapidly respond to microbial infection via MR1-restricted antigen recognition. Emerging evidence indicate that they can also act as rapid sensors of viral infection via innate cytokine activation. However, their possible role in the immune response to mRNA vaccination is unknown. Here, we evaluated the involvement of MAIT cells in individuals vaccinated with the BNT162b2 mRNA SARS-CoV-2 vaccine. MAIT cell levels, phenotype and function in circulation were preserved and unperturbed through day 35 post-vaccination in healthy donor (HD) vaccinees, as well as people living with HIV (PLWH) or with primary immunodeficiency (PID). Unexpectedly, pre-vaccination and post-vaccination levels of MAIT cells correlated positively with the magnitude of the SARS-CoV-2 spike protein-specific CD4 T cell and antibody responses in the HD vaccinees. This pattern was largely preserved in the PID group, but less so in the PLWH group. Furthermore, in the HD vaccinees levels of MAIT cell activation and cytolytic potential correlated negatively to the adaptive antigen-specific immune responses. These findings indicate an unexpected association between MAIT cell compartment characteristics and the immune response magnitude to the BNT162b2 mRNA vaccine.

Immune Response in Severe and Non-Severe Coronavirus Disease 2019 (COVID-19) Infection: A Mechanistic Landscape.

The mechanisms underlying the immune remodeling and severity response in coronavirus disease 2019 (COVID-19) are yet to be fully elucidated. Our comprehensive integrative analyses of single-cell RNA sequencing (scRNAseq) data from four published studies, in patients with mild/moderate and severe infections, indicate a robust expansion and mobilization of the innate immune response and highlight mechanisms by which low-density neutrophils and megakaryocytes play a crucial role in the cross talk between lymphoid and myeloid lineages. We also document a marked reduction of several lymphoid cell types, particularly natural killer cells, mucosal-associated invariant T (MAIT) cells, and gamma-delta T (γδT) cells, and a robust expansion and extensive heterogeneity within plasmablasts, especially in severe COVID-19 patients. We confirm the changes in cellular abundances for certain immune cell types within a new patient cohort. While the cellular heterogeneity in COVID-19 extends across cells in both lineages, we consistently observe certain subsets respond more potently to interferon type I (IFN-I) and display increased cellular abundances across the spectrum of severity, as compared with healthy subjects. However, we identify these expanded subsets to have a more muted response to IFN-I within severe disease compared to non-severe disease. Our analyses further highlight an increased aggregation potential of the myeloid subsets, particularly monocytes, in COVID-19. Finally, we provide detailed mechanistic insights into the interaction between lymphoid and myeloid lineages, which contributes to the multisystemic phenotype of COVID-19, distinguishing severe from non-severe responses.

Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients.

Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49-14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08-18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 -a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.

Suppressive Monocytes Impair MAIT Cells Response via IL-10 in Patients with Severe COVID-19.

Immune cell responses are strikingly altered in patients with severe coronavirus disease 2019 (COVID-19), but the immunoregulatory process in these individuals is not fully understood. In this study, 23 patients with mild and 22 patients with severe COVID-19 and 6 asymptomatic carriers of COVID-19 were enrolled, along with 44 healthy controls (HC). Peripheral immune cells in HC and patients with COVID-19 were comprehensively profiled using mass cytometry. We found that in patients with severe COVID-19, the number of HLA-DRlow/- monocytes was significantly increased, but that of mucosal-associated invariant T (MAIT) cells was greatly reduced. MAIT cells were highly activated but functionally impaired in response to Escherichia coli and IL-12/IL-18 stimulation in patients with severe COVID-19, especially those with microbial coinfection. Single-cell transcriptome analysis revealed that IFN-stimulated genes were significantly upregulated in peripheral MAIT cells and monocytes from patients with severe COVID-19. IFN-α pretreatment suppressed MAIT cells' response to E. coli by triggering high levels of IL-10 production by HLA-DRlow/--suppressive monocytes. Blocking IFN-α or IL-10 receptors rescued MAIT cell function in patients with severe COVID-19. Moreover, plasma from patients with severe COVID-19 inhibited HLA-DR expression by monocytes through IL-10. These data indicate a unique pattern of immune dysregulation in severe COVID-19, which is characterized by enrichment of suppressive HLA-DRlow/- monocytes associated with functional impairment of MAIT cells through the IFN/IL-10 pathway.

Single-Cell Transcriptomic Profiling of MAIT Cells in Patients With COVID-19.

Background: Mucosal-associated invariant T (MAIT) cells are considered to participate of the host immune response against acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, single-cell transcriptomic profiling of MAIT cells in patients with COVID-19 remains unexplored. Methods: We performed single-cell RNA sequencing analyses on peripheral MAIT cells from 13 patients with COVID-19 and 5 healthy donors. The transcriptional profiles of MAIT cells, together with assembled T-cell receptor sequences, were analyzed. Flow cytometry analysis was also performed to investigate the properties of MAIT cells. Results: We identified that differentially expressed genes (DEGs) of MAIT cells were involved in myeloid leukocyte activation and lymphocyte activation in patients with COVID-19. In addition, in MAIT cells from severe cases, more DEGs were enriched in adaptive cellular and humoral immune responses compared with those in moderate cases. Further analysis indicated that the increase of cell cytotoxicity (killing), chemotaxis, and apoptosis levels in MAIT cells were consistent with disease severity and displayed the highest levels in patients with severe disease. Interestingly, flow cytometry analysis showed that the frequencies of pyroptotic MAIT cells, but not the frequencies of apoptotic MAIT cells, were increased significantly in patients with COVID-19, suggesting pyroptosis is one of leading causes of MAIT cell deaths during SARS-CoV-2 infection. Importantly, there were more clonal expansions of MAIT cells in severe cases than in moderate cases. Conclusions: The results of the present study suggest that MAIT cells are likely to be involved in the host immune response against SARS-CoV-2 infection. Simultaneously, the transcriptomic data from MAIT cells provides a deeper understanding of the immune pathogenesis of the disease.

In vitro Interleukin-7 treatment partially rescues MAIT cell dysfunction caused by SARS-CoV-2 infection.

MAIT cells have been shown to be activated upon several viral infections in a TCR-independent manner by responding to inflammatory cytokines secreted by antigen-presenting cells. Recently, a few studies have shown a similar activation of MAIT cells in response to severe acute respiratory coronavirus 2 (SARS-CoV-2) infection. In this study, we investigate the effect of SARS-CoV-2 infection on the frequency and phenotype of MAIT cells by flow cytometry, and we test in vitro stimulation conditions on the capacity to enhance or rescue the antiviral function of MAIT cells from patients with coronavirus disease 2019 (COVID-19). Our study, in agreement with recently published studies, confirmed the decline in MAIT cell frequency of hospitalized donors in comparison to healthy donors. MAIT cells of COVID-19 patients also had lower expression levels of TNF-alpha, perforin and granzyme B upon stimulation with IL-12 + IL-18. 24 h' incubation with IL-7 successfully restored perforin expression levels in COVID-19 patients. Combined, our findings support the growing evidence that SARS-CoV-2 is dysregulating MAIT cells and that IL-7 treatment might improve their function, rendering them more effective in protecting the body against the virus.

Mucosal-associated invariant T cell responses differ by sex in COVID-19.

BACKGROUND: Sexual dimorphisms in immune responses contribute to coronavirus disease 2019 (COVID-19) outcomes, but the mechanisms governing this disparity remain incompletely understood. METHODS: We carried out sex-balanced sampling of peripheral blood mononuclear cells from hospitalized and non-hospitalized individuals with confirmed COVID-19, uninfected close contacts, and healthy control individuals for 36-color flow cytometry and single-cell RNA sequencing. FINDINGS: Our results revealed a pronounced reduction of circulating mucosal-associated invariant T (MAIT) cells in infected females. Integration of published COVID-19 airway tissue datasets suggests that this reduction represented a major wave of MAIT cell extravasation during early infection in females. Moreover, MAIT cells from females possessed an immunologically active gene signature, whereas cells from males were pro-apoptotic. CONCLUSIONS: Our findings uncover a female-specific protective MAIT cell profile, potentially shedding light on reduced COVID-19 susceptibility in females. FUNDING: This work was supported by NIH/NIAID (U01AI066569 and UM1AI104681), the Defense Advanced Projects Agency (DARPA; N66001-09-C-2082 and HR0011-17-2-0069), the Veterans Affairs Health System, and Virology Quality Assurance (VQA; 75N93019C00015). The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. COVID-19 samples were processed under Biosafety level 2 (BSL-2) with aerosol management enhancement or BSL-3 in the Duke Regional Biocontainment Laboratory, which received partial support for construction from NIH/NIAID (UC6AI058607).

Natural killer cells and unconventional T cells in COVID-19.

NK cells and diverse populations of unconventional T cells, such as MAIT cells, γδ T cells, invariant NKT cells, and DNTÉ‘ß cells are important early effector lymphocytes. While some of these cells, such as NK cell and MAIT cells, have well-established roles in antiviral defense, the function of other populations remains more elusive. Here, we summarize and discuss current knowledge on NK cell and unconventional T cell responses to SARS-CoV-2 infection. Also covered is the role of these cells in the pathogenesis of severe COVID-19. Understanding the early, both systemic and local (lung), effector lymphocyte response in this novel disease will likely aid ongoing efforts to combat the pandemic.

The role of unconventional T cells in COVID-19.

COVID-19 is a respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It was first documented in late 2019, but within months, a worldwide pandemic was declared due to the easily transmissible nature of the virus. Research to date on the immune response to SARS-CoV-2 has focused largely on conventional B and T lymphocytes. This review examines the emerging role of unconventional T cell subsets, including γδ T cells, invariant natural killer T (iNKT) cells and mucosal associated invariant T (MAIT) cells in human SARS-CoV-2 infection.Some of these T cell subsets have been shown to play protective roles in anti-viral immunity by suppressing viral replication and opsonising virions of SARS-CoV. Here, we explore whether unconventional T cells play a protective role in SARS-CoV-2 infection as well. Unconventional T cells are already under investigation as cell-based immunotherapies for cancer. We discuss the potential use of these cells as therapeutic agents in the COVID-19 setting. Due to the rapidly evolving situation presented by COVID-19, there is an urgent need to understand the pathogenesis of this disease and the mechanisms underlying its immune response. Through this, we may be able to better help those with severe cases and lower the mortality rate by devising more effective vaccines and novel treatment strategies.

Title of article: Mucosal-associated invariant T cells in lung diseases.

The lungs are directly connected to the external environment, which makes them more vulnerable to infection and injury. They are protected by the respiratory epithelium and immune cells to maintain a dynamic balance. Both innate and adaptive immune cells are involved in the pathogenesis of lung diseases. Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T cells, which have attracted increasing attention in recent years. Although MAIT cells account for a small part of the total immune cells in the lungs, evidence suggests that these cells are activated by T cell receptors and/or cytokine receptors and mediate immune response. They play an important role in immunosurveillance and immunity against microbial infection, and recent studies have shown that subsets of MAIT cells play a role in promoting pulmonary inflammation. Emerging data indicate that MAIT cells are involved in the immune response against SARS-CoV-2 and possible immunopathogenesis in COVID-19. Here, we introduce MAIT cell biology to clarify their role in the immune response. Then we review MAIT cells in human and murine lung diseases, including asthma, chronic obstructive pulmonary disease, pneumonia, pulmonary tuberculosis and lung cancer, and discuss their possible protective and pathological effects. MAIT cells represent an attractive marker and potential therapeutic target for disease progression, thus providing new strategies for the treatment of lung diseases.

MAIT cell activation augments adenovirus vector vaccine immunogenicity.

Mucosal-associated invariant T (MAIT) cells are innate sensors of viruses and can augment early immune responses and contribute to protection. We hypothesized that MAIT cells may have inherent adjuvant activity in vaccine platforms that use replication-incompetent adenovirus vectors. In mice and humans, ChAdOx1 (chimpanzee adenovirus Ox1) immunization robustly activated MAIT cells. Activation required plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-α and monocyte-derived interleukin-18. IFN-α-induced, monocyte-derived tumor necrosis factor was also identified as a key secondary signal. All three cytokines were required in vitro and in vivo. Activation of MAIT cells positively correlated with vaccine-induced T cell responses in human volunteers and MAIT cell-deficient mice displayed impaired CD8+ T cell responses to multiple vaccine-encoded antigens. Thus, MAIT cells contribute to the immunogenicity of adenovirus vectors, with implications for vaccine design.