MAIT cells and viruses Ussher, James E; Willberg, Christian B; Klenerman, Paul
Immunology and cell biology,
July 2018, Volume:
96, Issue:
6
Journal Article
Peer reviewed
Open access
Mucosal associated invariant T cells (MAIT cells) bear a T cell receptor (TCR) that specifically targets microbially derived metabolites. Functionally, they respond to bacteria and yeasts, which ...possess the riboflavin pathway, essential for production of such metabolites and which are presented on MR1. Viruses cannot generate these ligands, so a priori, they should not be recognized by MAIT cells and indeed this is true when considering recognition through the TCR. However, MAIT cells are distinctive in another respect, since they respond quite sensitively to non‐TCR signals, especially in the form of inflammatory cytokines. Thus, a number of groups have shown that virus infection can be “sensed” by MAIT cells and a functional response invoked. Since MAIT cells are abundant in humans, especially in tissues such as the liver, the question has arisen as to whether this TCR‐independent MAIT cell triggering by viruses plays any role in vivo. In this review, we will discuss the evidence for this phenomenon and some common features which emerge across different recent studies in this area.
MAIT cells are abundant in humans and have been shown to respond to viruses. In this article, we explore the mechanisms behind this and what the implications are in vivo.
The ability of innate immune cells to sense and respond to impending danger varies by anatomical location. The liver is considered tolerogenic but is still capable of mounting a successful immune ...response to clear various infections. To understand whether hepatic immune cells tune their response to different infectious challenges, we probed mononuclear cells purified from human healthy and diseased livers with distinct pathogen-associated molecules. We discovered that only the TLR8 agonist ssRNA40 selectively activated liver-resident innate immune cells to produce substantial quantities of IFN-γ. We identified CD161(Bright) mucosal-associated invariant T (MAIT) and CD56(Bright) NK cells as the responding liver-resident innate immune cells. Their activation was not directly induced by the TLR8 agonist but was dependent on IL-12 and IL-18 production by ssRNA40-activated intrahepatic monocytes. Importantly, the ssRNA40-induced cytokine-dependent activation of MAIT cells mirrored responses induced by bacteria, i.e., generating a selective production of high levels of IFN-γ, without the concomitant production of TNF-α or IL-17A. The intrahepatic IFN-γ production could be detected not only in healthy livers, but also in HBV- or HCV-infected livers. In conclusion, the human liver harbors a network of immune cells able to modulate their immunological responses to different pathogen-associated molecules. Their ability to generate a strong production of IFN-γ upon stimulation with TLR8 agonist opens new therapeutic opportunities for the treatment of diverse liver pathologies.
The C-type lectin CD161 is expressed by a large proportion of human T lymphocytes of all lineages, including a population known as mucosal-associated invariant T (MAIT) cells. To understand whether ...different T cell subsets expressing CD161 have similar properties, we examined these populations in parallel using mass cytometry and mRNA microarray approaches. The analysis identified a conserved CD161++/MAIT cell transcriptional signature enriched in CD161+CD8+ T cells, which can be extended to CD161+ CD4+ and CD161+TCRγδ+ T cells. Furthermore, this led to the identification of a shared innate-like, TCR-independent response to interleukin (IL)-12 plus IL-18 by different CD161-expressing T cell populations. This response was independent of regulation by CD161, which acted as a costimulatory molecule in the context of T cell receptor stimulation. Expression of CD161 hence identifies a transcriptional and functional phenotype, shared across human T lymphocytes and independent of both T cell receptor (TCR) expression and cell lineage.
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•CD161 expression defines specific T cell subsets, including CD8+, CD4+, and TCRγδ+•CD161-expressing lymphocytes possess a conserved transcriptional signature•CD161-expressing lymphocytes display a shared innate response to IL-12+18•CD161 can act as a costimulatory receptor
T lymphocytes are conventionally divided into subsets based on expression of coreceptors, cytokines, and surface molecules. Using CyTOF and mRNA microarray analysis, Fergusson et al. identify T lymphocytes that express the C-type lectin CD161 to share a transcriptional profile and innate function across these previously defined subsets.
Mucosal-associated invariant T (MAIT) cells can be activated via either their T cell receptor (TCR), which recognizes MR1-bound pyrimidines derived from microbial riboflavin biosynthesis, or via ...cytokines. These two modes of activation may act in concert or independently, depending upon the stimulus. It is unknown, however, how MAIT cell responses differ with the mode of activation. Here, we define transcriptional and effector responses of human CD8+ MAIT cells to TCR and cytokine stimulation. We report that MAIT cells rapidly respond to TCR stimulation, producing multiple cytokines and chemokines, altering their cytotoxic granule content and transcription factor expression, and upregulating co-stimulatory proteins. In contrast, cytokine-mediated activation is slower and results in a more limited response. Therefore, we propose that, in infections by riboflavin-synthesizing bacteria, MAIT cells play a key early role in effecting and coordinating immune responses, while in the absence of TCR stimulation, their role is likely to differ.
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•RNA sequencing of MAIT cells following stimulation via T cell receptor or cytokines•TCR and cytokines induce distinct transcriptome with different modes of activation•TCR stimuli result in a rapid, polyfunctional, proinflammatory response•Cytokine stimulation results in a slower, more restricted response
Lamichhane et al. compare the response of human CD8+ mucosal-associated invariant T (MAIT) cells to T cell receptor (TCR) and cytokine stimuli, demonstrating distinct transcriptional responses. Early TCR-stimulated MAIT cells are polyfunctional and produce multiple proinflammatory cytokines and chemokines. In contrast, response to cytokine stimulation is more restricted.
Mucosal-associated invariant T (MAIT) cells are an innate-like T-cell population involved in anti-bacterial immunity. In human beings, MAIT cells are abundant, comprising ~10% of the CD8(+) T-cell ...compartment in blood. They are enriched at mucosal sites and are particularly prevalent within the liver. MAIT cells are defined by the expression of a semi-invariant T-cell receptor (Vα7.2-Jα33/12/20) and are restricted by the non-polymorphic, highly evolutionarily conserved MHC class Ib molecule, MHC-related protein (MR)1. MR1 has recently been shown to present an unstable pyrimidine intermediate derived from a biosynthetic precursor of riboflavin; riboflavin biosynthesis occurs in many bacteria but not in human beings. Consistent with this, MAIT cells are responsive to riboflavin-metabolizing bacteria, including Salmonella. In mouse models, MAIT cells have been shown to play a non-redundant role in anti-bacterial immunity, including against Escherichia coli, Klebsiella pneumoniae, and Mycobacterium bovis BCG. In human beings, MAIT cells are decreased in frequency in the blood of patients with tuberculosis or pneumonia, and their frequency has been inversely correlated with the risk of subsequent systemic bacterial infection in patients in intensive care. Intriguingly, MAIT cells are also depleted from the blood early in HIV infection and fail to recover with anti-retroviral therapy, which may contribute to the susceptibility of patients infected with HIV to certain bacterial infections, including non-typhoidal Salmonella. In this review, we will discuss what is currently known about MAIT cells, the role that Salmonella has played in elucidating MAIT cell restriction and function, and the role MAIT cells might play in the control of Salmonella infection.
HIV infection is associated with immune dysfunction, perturbation of immune-cell subsets and opportunistic infections. CD161++CD8+ T cells are a tissue-infiltrating population that produce IL17A, ...IL22, IFNγ, and TNFα, cytokines important in mucosal immunity. In adults they dominantly express the semi-invariant TCR Vα7.2, the canonical feature of mucosal associated invariant T (MAIT) cells and have been recently implicated in host defense against pathogens. We analyzed the frequency and function of CD161++/MAIT cells in peripheral blood and tissue from patients with early stage or chronic-stage HIV infection. We show that the CD161++/MAIT cell population is significantly decreased in early HIV infection and fails to recover despite otherwise successful treatment. We provide evidence that CD161++/MAIT cells are not preferentially infected but may be depleted through diverse mechanisms including accumulation in tissues and activation-induced cell death. This loss may impact mucosal defense and could be important in susceptibility to specific opportunistic infections in HIV.
•The frequency of CD161++ MAIT cells is dramatically decreased in the blood of HIV-infected patients, and they are nonrecoverable with HAART.•Gut sequestration and apoptosis in response to bacterial signals may, amongst others, be mechanisms that contribute to this.
At the end of 2019 a newly emerged betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of an outbreak of severe pneumonia, subsequently termed ...COVID-19, in a number of patients in Wuhan, China. Subsequently, SARS-CoV-2 rapidly spread globally, resulting in a pandemic that has to date infected over 200 million individuals and resulted in more than 4.3 million deaths. While SARS-CoV-2 results in severe disease in 13.8%, with increasing frequency of severe disease with age, over 80% of infections are asymptomatic or mild. The immune response is an important determinant of outcome following SARS-CoV-2 infection. While B cell and T cell responses are associated with control of infection and protection against subsequent challenge with SARS-CoV-2, failure to control viral replication and the resulting hyperinflammation are associated with severe COVID-19. Towards the end of 2020, several variants of concern emerged that demonstrate increased transmissibility and/or evasion of immune responses from prior SARS-CoV-2 infection. This article reviews what is known about the humoral and cellular immune responses to SARS-CoV-2 and how mutation and structural/functional changes in the emerging variants of concern impact upon the immune protection from prior infection or vaccination.
Human mucosal-associated invariant T (MAIT) cells are an important T cell subset that are enriched in tissues and possess potent effector functions. Typically such cells are marked by their ...expression of Vα7.2-Jα33/Jα20/Jα12 T cell receptors, and functionally they are major histocompatibility complex class I-related protein 1 (MR1)-restricted, responding to bacterially derived riboflavin synthesis intermediates. MAIT cells are contained within the CD161++ Vα7.2+ T cell population, the majority of which express the CD8 receptor (CD8+), while a smaller fraction expresses neither CD8 or CD4 coreceptor (double negative; DN) and a further minority are CD4+. Whether these cells have distinct homing patterns, phenotype and functions have not been examined in detail. We used a combination of phenotypic staining and functional assays to address the similarities and differences between these CD161++ Vα7.2+ T cell subsets. We find that most features are shared between CD8+ and DN CD161++ Vα7.2+ T cells, with a small but detectable role evident for CD8 binding in tuning functional responsiveness. By contrast, the CD4+ CD161++ Vα7.2+ T cell population, although showing MR1-dependent responsiveness to bacterial stimuli, display reduced T helper 1 effector functions, including cytolytic machinery, while retaining the capacity to secrete interleukin-4 (IL-4) and IL-13. This was consistent with underlying changes in transcription factor (TF) expression. Although we found that only a proportion of CD4+ CD161++ Vα7.2+ T cells stained for the MR1-tetramer, explaining some of the heterogeneity of CD4+ CD161++ Vα7.2+ T cells, these differences in TF expression were shared with CD4+ CD161++ MR1-tetramer+ cells. These data reveal the functional diversity of human CD161++ Vα7.2+ T cells and indicate potentially distinct roles for the different subsets
.
Mucosal-associated invariant T (MAIT) cells, defined as CD161
TCR iVα7.2
T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in ...chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3
CD161
TCR iVα7.2
MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVα7.2
CD161
MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4
T cells and MAIT cells and with CD57 on CD8
T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iVα7.2
MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1.
Data on causes of community-onset bloodstream infection in Myanmar are scarce. We aimed to identify etiological agents of bloodstream infections and patterns of antimicrobial resistance among febrile ...adolescents and adults attending Yangon General Hospital (YGH), Yangon, Myanmar. We recruited patients ≥12 years old with fever ≥38°C who attended YGH from 5 October 2015 through 4 October 2016. A standardized clinical history and physical examination was performed. Provisional diagnoses and vital status at discharge was recorded. Blood was collected for culture, bloodstream isolates were identified, and antimicrobial susceptibility testing was performed. Using whole-genome sequencing, we identified antimicrobial resistance mechanisms of Enterobacteriaceae and sequence types of Enterobacteriaceae and Streptococcus agalactiae. Among 947 participants, 90 (9.5%) had bloodstream infections (BSI) of which 82 (91.1%) were of community-onset. Of 91 pathogens isolated from 90 positive blood cultures, we identified 43 (47.3%) Salmonella enterica including 33 (76.7%) serovar Typhi and 10 (23.3%) serovar Paratyphi A; 20 (22.0%) Escherichia coli; 7 (7.7%) Klebsiella pneumoniae; 6 (6.6%), Staphylococcus aureus; 4 (4.4%) yeasts; and 1 (1.1%) each of Burkholderia pseudomallei and Streptococcus agalactiae. Of 70 Enterobacteriaceae, 62 (88.6%) were fluoroquinolone-resistant. Among 27 E. coli and K. pneumoniae, 18 (66.6%) were extended-spectrum beta-lactamase (ESBL)-producers, and 1 (3.7%) each were AmpC beta-lactamase- and carbapenemase-producers. Fluoroquinolone resistance was associated predominantly with mutations in the quinolone resistance-determining region. blaCTX-M-15 expression was common among ESBL-producers. Methicillin-resistant S. aureus was not detected. Fluoroquinolone-resistant, but not multiple drug-resistant, typhoidal S. enterica was the leading cause of community-onset BSI at a tertiary hospital in Yangon, Myanmar. Fluoroquinolone and extended-spectrum cephalosporin resistance was common among other Enterobactericeae. Our findings inform empiric management of severe febrile illness in Yangon and indicate that measures to prevent and control enteric fever are warranted. We suggest ongoing monitoring and efforts to mitigate antimicrobial resistance among community-onset pathogens.
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