MAIT cell activation is reduced by direct and microbiota-mediated exposure to bisphenols

ABSTRACTMucosa-associated invariant T (MAIT) cells are an innate-like T cell subset in mammals that recognize microbial vitamin B metabolites presented by the evolutionarily conserved major histocompatibility complex class I (MHC I)-related molecule, MR1. Emerging data suggest that MAIT cells may be an attractive target for vaccine-induced protection against bacterial infections because of their rapid cytotoxic responses at mucosal services to a widely conserved bacterial ligand. In this study, we tested whether a MAIT cell priming strategy could protect against aerosol Mycobacterium tuberculosis infection in mice. Intranasal costimulation with the lipopeptide Toll-like receptor (TLR)2/6 agonist, Pam2Cys (P2C), and the synthetic MR1 ligand, 5-OP-RU, resulted in robust expansion of MAIT cells in the lung. Although MAIT cell priming significantly enhanced MAIT cell activation and expansion early after M. tuberculosis challenge, these MAIT cells did not restrict M. tuberculosis bacterial load. MAIT cells were depleted by the onset of the adaptive immune response, with decreased detection of granzyme B+ and gamma interferon (IFN-γ)+ MAIT cells relative to that in uninfected P2C/5-OP-RU-treated mice. Decreasing the infectious inoculum, varying the time between priming and aerosol infection, and testing MAIT cell priming in nitric oxide synthase 2 (NOS2)-deficient mice all failed to reveal an effect of P2C/5-OP-RU-induced MAIT cells on M. tuberculosis control. We conclude that intranasal MAIT cell priming in mice induces early MAIT cell activation and expansion after M. tuberculosis exposure, without attenuating M. tuberculosis growth, suggesting that MAIT cell enrichment in the lung is not sufficient to control M. tuberculosis infection.

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MAIT cell activation and dynamics associated with COVID-19 disease severity

Science Immunology ◽

10.1126/sciimmunol.abe1670 ◽

2020 ◽

Vol 5 (51) ◽

pp. eabe1670 ◽

Cited By ~ 8

Author(s):

Tiphaine Parrot ◽

Jean-Baptiste Gorin ◽

Andrea Ponzetta ◽

Kimia T. Maleki ◽

Tobias Kammann ◽

...

Keyword(s):

Immune Responses ◽

Cell Activation ◽

Severe Disease ◽

Poor Clinical Outcome ◽

Cell Compartment ◽

Mait Cells ◽

Antiviral Responses ◽

Unsupervised Analysis ◽

Cell Enrichment ◽

Mait Cell

Severe COVID-19 is characterized by excessive inflammation of the lower airways. The balance of protective versus pathological immune responses in COVID-19 is incompletely understood. Mucosa-associated invariant T (MAIT) cells are antimicrobial T cells that recognize bacterial metabolites, and can also function as innate-like sensors and mediators of antiviral responses. Here, we investigated the MAIT cell compartment in COVID-19 patients with moderate and severe disease, as well as in convalescence. We show profound and preferential decline in MAIT cells in the circulation of patients with active disease paired with strong activation. Furthermore, transcriptomic analyses indicated significant MAIT cell enrichment and pro-inflammatory IL-17A bias in the airways. Unsupervised analysis identified MAIT cell CD69high and CXCR3low immunotypes associated with poor clinical outcome. MAIT cell levels normalized in the convalescent phase, consistent with dynamic recruitment to the tissues and later release back into the circulation when disease is resolved. These findings indicate that MAIT cells are engaged in the immune response against SARS-CoV-2 and suggest their possible involvement in COVID-19 immunopathogenesis.

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Influenza A Virus Infection v1

10.17504/protocols.io.bmgyk3xw ◽

2020 ◽

Author(s):

Timothy S C Hinks ◽

Bonnie van Wilgenburg ◽

Huimeng Wang ◽

Liyen Loh ◽

Marios Koutsakos ◽

...

Keyword(s):

Influenza A ◽

Cell Activation ◽

Viral Infections ◽

Intracellular Cytokine Staining ◽

Cell Receptor ◽

Type I ◽

Independent Manner ◽

Mait Cells ◽

Mait Cell

This is part 3.3 of the "Study of MAIT Cell Activation in Viral Infections In Vivo" collection of protocols. Collection Abstract: MAIT cells are abundant, highly evolutionarily conserved innate-like lymphocytes expressing a semi-invariant T cell receptor (TCR), which recognizes microbially derived small intermediate molecules from the riboflavin biosynthetic pathway. However, in addition to their TCR-mediated functions they can also be activated in a TCR-independent manner via cytokines including IL-12, -15, -18, and type I interferon. Emerging data suggest that they are expanded and activated by a range of viral infections, and significantly that they can contribute to a protective anti-viral response. Here we describe methods used to investigate these anti-viral functions in vivo in murine models. To overcome the technical challenge that MAIT cells are rare in specific pathogen-free laboratory mice, we describe how pulmonary MAIT cells can be expanded using intranasal bacterial infection or a combination of synthetic MAIT cell antigen and TLR agonists. We also describe protocols for adoptive transfer of MAIT cells, methods for lung homogenization for plaque assays, and surface and intracellular cytokine staining to determine MAIT cell activation.

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MAIT cells are minimally responsive to Mycobacterium tuberculosis within granulomas, but are functionally impaired by SIV in a macaque model of SIV and Mtb co-infection

10.1101/2020.01.07.897447 ◽

2020 ◽

Author(s):

Amy L. Ellis-Connell ◽

Alexis J. Balgeman ◽

Erica C. Larson ◽

Mark A. Rodgers ◽

Cassaundra Ameel ◽

...

Keyword(s):

Peripheral Blood ◽

Cell Activation ◽

Cell Function ◽

Ex Vivo ◽

Cynomolgus Macaque ◽

Cross Sectional ◽

In Vivo Models ◽

Mait Cells ◽

Mait Cell

ABSTRACTMucosal associated invariant T (MAIT) cells recognize and can directly destroy bacterially infected cells. While a role for MAIT cells has been suggested in several in vitro and in vivo models of M.tuberculosis (Mtb) infection, these studies have often focused on MAIT cells within the peripheral blood or are cross-sectional studies rather than longitudinal studies. The role of MAIT cells within granulomas and other sites of Mtb infection is relatively unknown. Furthermore, how HIV/SIV infection might impair MAIT cells at the sites of Mtb infection has not been determined. Using a Mauritian cynomolgus macaque (MCM) model system, we phenotyped MAIT cells in the peripheral blood and BAL prior to and during infection with SIVmac239. To characterize the role of MAIT cells within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb for 6 weeks. MAIT cell frequency and function was examined within the peripheral blood, distal airways, as well as within Mtb-affected lymph nodes (LN) and tissues. Surprisingly, we found no evidence of MAIT cell responsiveness to Mtb within granulomas. Additionally, MAIT cells only minimally responded to mycobacterial stimulus in ex vivo functional assays. In contrast, most MAIT cell activation seemed to occur in samples with highly active SIV replication, including blood and SIV-infected LN. Finally, the ability of MAIT cells to secrete TNFα (TNF) was impaired during SIV and Mtb co-infection, indicating that the two pathogens together could have a synergistically deleterious effect on MAIT cell function. The effect of this functional impairment on overall TB disease burden was unclear, but might be deleterious if MAIT cells are needed to fully activate antimycobacterial immune cells within the granulomas.

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Legionella protection and vaccination mediated by Mucosal Associated Invariant T (MAIT) cells

10.1101/231472 ◽

2017 ◽

Cited By ~ 1

Author(s):

Huimeng Wang ◽

Criselle D’Souza ◽

Xin Yi Lim ◽

Lyudmila Kostenko ◽

Troi J Pediongco ◽

...

Keyword(s):

Cell Activation ◽

Cell Protection ◽

Gm Csf ◽

Mait Cells ◽

Cell Immunity ◽

Tnf Α ◽

Ifn Γ ◽

Clinically Significant ◽

Riboflavin Synthesis ◽

Mait Cell

AbstractMucosal associated invariant T (MAIT) cells recognize conserved microbial metabolites from riboflavin synthesis. Striking evolutionary conservation and pulmonary abundance implicate them in antibacterial host defense, yet their roles in protection against clinically significant pathogens are unknown. Murine Legionella infection induced MR1-dependent MAIT cell activation and rapid pulmonary accumulation of MAIT cells associated with immune protection detectable in fully immunocompetent host animals. MAIT cell protection was more evident in mice lacking CD4+ cells, whilst profoundly immunodeficient RAG2−/−γC−/− mice were substantially rescued from uniformly lethal Legionella infection by adoptively-transferred MAIT cells. This protection was dependent on MR1, IFN-γ and GM-CSF, but not IL-17, TNF-α or perforin. Protection was enhanced and observed earlier post-infection in mice that were Ag-primed to boost MAIT cells before infection. Our findings define a significant role for MAIT cells in protection against a major human pathogen and indicate a potential role for vaccination to enhance MAIT cell immunity.

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Outcome of SARS-CoV-2 infection linked to MAIT cell activation and cytotoxicity: evidence for an IL-18 dependent mechanism

10.1101/2020.08.31.20185082 ◽

2020 ◽

Cited By ~ 4

Author(s):

Héloïse Flament ◽

Matthieu Rouland ◽

Lucie Beaudoin ◽

Amine Toubal ◽

Léo Bertrand ◽

...

Keyword(s):

Disease Severity ◽

Cell Activation ◽

Viral Infections ◽

Immune Cell ◽

Dependent Manner ◽

Mait Cells ◽

Inflammatory Phase ◽

Immune System Dysfunction ◽

Cell Counts ◽

Mait Cell

Immune system dysfunction is paramount in Coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in a cohort of 182 patients including patients at various stages of disease activity. A profound decrease of MAIT cell counts in blood of critically ill patients was observed. These cells showed a strongly activated and cytotoxic phenotype that positively correlated with circulating pro-inflammatory cytokines, notably IL-18. MAIT cell alterations markedly correlated with disease severity and patient mortality. SARS-CoV-2-infected macrophages activated MAIT cells in a cytokine-dependent manner involving an IFNα-dependent early phase and an IL-18-induced later phase. Therefore, altered MAIT cell phenotypes represent valuable biomarkers of disease severity and their therapeutic manipulation might prevent the inflammatory phase involved in COVID-19 aggravation.

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Altered distribution and enhanced osteoclastogenesis of mucosal-associated invariant T cells in gouty arthritis

Rheumatology ◽

10.1093/rheumatology/keaa020 ◽

2020 ◽

Vol 59 (8) ◽

pp. 2124-2134

Author(s):

Young-Nan Cho ◽

Hae-Seong Jeong ◽

Ki-Jeong Park ◽

Hyung-Seok Kim ◽

Eun-Hee Kim ◽

...

Keyword(s):

Cell Activation ◽

Mononuclear Cells ◽

Gouty Arthritis ◽

Bone Destruction ◽

Peripheral Blood Mononuclear ◽

Mait Cells ◽

Tnf Α ◽

Mait Cell ◽

Msu Crystals

Abstract Objective This study was designed to investigate the role of mucosal-associated invariant T (MAIT) cells in gouty arthritis (GA) and their effects on osteoclastogenesis. Methods Patients with GA (n = 61), subjects with hyperuricaemia (n = 11) and healthy controls (n = 30) were enrolled in this study. MAIT cells, cytokines, CD69, programmed death-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) levels were measured by flow cytometry. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells in the presence of M-CSF and RANK ligand. Results Circulating MAIT cell levels were significantly reduced in GA patients. However, their capacities for IFN-γ, IL-17 and TNF-α production were preserved. Expression levels of CD69, PD-1 and LAG-3 in MAIT cells were found to be elevated in GA patients. In particular, CD69 expression in circulating MAIT cells was increased by stimulation with MSU crystals, suggesting that deposition of MSU crystals might contribute to MAIT cell activation. Interestingly, MAIT cells were found to be accumulated in synovial fluid and infiltrated into gouty tophus tissues within joints. Furthermore, activated MAIT cells secreted pro-resorptive cytokines (i.e. IL-6, IL-17 and TNF-α) and facilitated osteoclastogenesis. Conclusion This study demonstrates that circulating MAIT cells are activated and numerically deficient in GA patients. In addition, MAIT cells have the potential to migrate to inflamed tissues and induce osteoclastogenesis. These findings provide an important role of MAIT cells in the pathogenesis of inflammation and bone destruction in GA patients.

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Sustained IFN-I stimulation impairs MAIT cell responses to bacteria by inducing IL-10 during chronic HIV-1 infection

Science Advances ◽

10.1126/sciadv.aaz0374 ◽

2020 ◽

Vol 6 (8) ◽

pp. eaaz0374 ◽

Cited By ~ 4

Author(s):

X. Tang ◽

S. Zhang ◽

Q. Peng ◽

L. Ling ◽

H. Shi ◽

...

Keyword(s):

Cell Activation ◽

Surface Protein ◽

Interleukin 10 ◽

Mait Cells ◽

Cell Dysfunction ◽

Cell Responses ◽

High Level ◽

Hiv 1 ◽

Mait Cell

Mucosal-associated invariant T (MAIT) cells in HIV-1–infected individuals are functionally impaired by poorly understood mechanisms. Single-cell transcriptional and surface protein analyses revealed that peripheral MAIT cells from HIV-1–infected subjects were highly activated with the up-regulation of interferon (IFN)–stimulated genes as compared to healthy individuals. Sustained IFN-α treatment suppressed MAIT cell responses to Escherichia coli by triggering high-level interleukin-10 (IL-10) production by monocytes, which subsequently inhibited the secretion of IL-12, a crucial costimulatory cytokine for MAIT cell activation. Blocking IFN-α or IL-10 receptors prevented MAIT cell dysfunction induced by HIV-1 exposure in vitro. Moreover, blocking the IL-10 receptor significantly improved anti–Mycobacterium tuberculosis responses of MAIT cells from HIV-1–infected patients. Our findings demonstrate the central role of the IFN-I/IL-10 axis in MAIT cell dysfunction during HIV-1 infection, which has implications for the development of anti–IFN-I/IL-10 strategies against bacterial coinfections in HIV-1–infected patients.

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