scholarly journals Efficient 5-OP-RU-Induced Enrichment of Mucosa-Associated Invariant T Cells in the Murine Lung Does Not Enhance Control of Aerosol Mycobacterium tuberculosis Infection

2020 ◽  
Vol 89 (1) ◽  
pp. e00524-20 ◽  
Author(s):  
Charles Kyriakos Vorkas ◽  
Olivier Levy ◽  
Miroslav Skular ◽  
Kelin Li ◽  
Jeffrey Aubé ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Infections ◽  
Cell Activation ◽  
Bacterial Load ◽  
Cell Subset ◽  
Mycobacterium Tuberculosis Infection ◽  
Class I Mhc ◽  
Content Type ◽  
Mait Cells ◽  
Mait Cell

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.

scholarly journals Efficient 5-OP-RU-induced enrichment of Mucosal-associated invariant T cells in the murine lung does not enhance control of aerosol Mycobacterium tuberculosis infection

2020 ◽  
Author(s):  
Charles Kyriakos Vorkas ◽  
Olivier Levy ◽  
Miroslav Skular ◽  
Kelin Li ◽  
Jeffrey Aubé ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Infections ◽  
Cell Activation ◽  
Bacterial Load ◽  
Cell Subset ◽  
Mycobacterium Tuberculosis Infection ◽  
Mhc I ◽  
Mait Cells ◽  
Aerosol Infection ◽  
Mait Cell

AbstractMucosal-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 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 (Mtb) infection in mice. Intranasal co-stimulation with the lipopeptide TLR 2/6 agonist, Pam2Cys (P2C), and the synthetic MR1 ligand, 5-OP-RU, resulted in robust expansion of MAIT cells in lung. Although MAIT cell priming significantly enhanced MAIT cell activation and expansion early after Mtb challenge, these MAIT cells did not restrict Mtb bacterial load. MAIT cells were depleted later in infection, with decreased detection of granzyme B+ and IFNγ+ MAIT cells relative to 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 NOS2 deficient mice all failed to reveal an effect of P2C/5-OP-RU induced MAIT cells on Mtb control. We conclude that intranasal MAIT cell priming in mice induces early MAIT cell activation and expansion after Mtb exposure, without attenuating M. tuberculosis growth, suggesting that Mtb evades MAIT cell-dependent immunity.

scholarly journals Absence of mucosal-associated invariant T cells in a person with a homozygous point mutation in MR1

2020 ◽  
Vol 5 (49) ◽  
pp. eabc9492 ◽  
Author(s):  
Lauren J. Howson ◽  
Wael Awad ◽  
Anouk von Borstel ◽  
Hui Jing Lim ◽  
Hamish E. G. McWilliam ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Immunity ◽  
Bacterial Infections ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Mait Cells ◽  
History Of ◽  
Antigen Presenting ◽  
Mait Cell

The role unconventional T cells play in protective immunity in humans is unclear. Mucosal-associated invariant T (MAIT) cells are an unconventional T cell subset restricted to the antigen-presenting molecule MR1. Here, we report the discovery of a patient homozygous for a rare Arg31His (R9H in the mature protein) mutation in MR1 who has a history of difficult-to-treat viral and bacterial infections. MR1R9H was unable to present the potent microbially derived MAIT cell stimulatory ligand. The MR1R9H crystal structure revealed that the stimulatory ligand cannot bind due to the mutation lying within, and causing structural perturbation to, the ligand-binding domain of MR1. While MR1R9H could bind and be up-regulated by a MAIT cell inhibitory ligand, the patient lacked circulating MAIT cells. This shows the importance of the stimulatory ligand for MAIT cell selection in humans. The patient had an expanded γδ T cell population, indicating a compensatory interplay between these unconventional T cell subsets.

scholarly journals MAIT cell-directed therapy of Mycobacterium tuberculosis infection

2020 ◽  
Vol 14 (1) ◽  
pp. 199-208 ◽  
Author(s):  
Shunsuke Sakai ◽  
Keith D. Kauffman ◽  
Sangmi Oh ◽  
Christine E. Nelson ◽  
Clifton E. Barry ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd4 T Cell ◽  
Mycobacterium Tuberculosis Infection ◽  
Mait Cells ◽  
T Cell Priming ◽  
Draining Lymph Nodes ◽  
Mait Cell

AbstractMucosal-associated invariant T (MAIT) cells are potential targets of vaccination and host-directed therapeutics for tuberculosis, but the role of MAIT cells during Mycobacterium tuberculosis (Mtb) infection in vivo is not well understood. Here we find that following Mtb infection MAIT cells mount minimal responses, and MAIT cell-deficient MR1−/− mice display normal survival. Preinfection expansion of MAIT cells through 5-OP-RU vaccination fails to protect against subsequent Mtb challenge. In fact, 5-OP-RU vaccination delays Mtb-specific CD4 T cell priming in lung-draining lymph nodes, and conversely MR1 deficiency or blockade accelerates T cell priming. The MAIT cell-mediated delay in T cell priming is partly dependent on TGF-β. Surprisingly, 5-OP-RU treatment during chronic infection drives MAIT cell expansion and an IL-17A-dependent reduction in bacterial loads. Thus, during early infection MAIT cells directly contribute to the notoriously slow priming of CD4 T cells, but later during infection MAIT cell stimulation may be an effective host-directed therapy for tuberculosis.

scholarly journals Interleukin-18 Is Critical for Mucosa-Associated Invariant T Cell Gamma Interferon Responses toFrancisellaSpeciesIn Vitrobut NotIn Vivo

2018 ◽  
Vol 86 (5) ◽  
Author(s):  
Eric Jesteadt ◽  
Irma Zhang ◽  
Huifeng Yu ◽  
Anda Meierovics ◽  
Wei-Jen Chua Yankelevich ◽  
...  
Keyword(s):  
Pulmonary Infection ◽  
Gamma Interferon ◽  
Interleukin 18 ◽  
Class I Mhc ◽  
Content Type ◽  
Mait Cells ◽  
Ifn Γ ◽  
Mait Cell

ABSTRACTMucosa-associated invariant T (MAIT) cells are a subset of innate T cells that express a semi-invariant Vα chain paired with limited Vβ chains. MAIT cells are activated by riboflavin metabolite derivatives presented by the nonpolymorphic major histocompatibility complex class I (MHC-I)-like molecule MR1. The precise mechanisms required to activate MAIT cells are an area of intense interest. Here we used two closely related intracellular pathogens with distinct inflammasome activation phenotypes to probe the role of innate cytokines in MAIT cell activation. Using anin vitroassay containing transgenic murine MAIT cells, we show that macrophages infected withFrancisella novicida, a strong inflammasome activator, released high levels of interleukin-18 (IL-18) and stimulated high levels of MAIT cell gamma interferon (IFN-γ) through a partially MR1-independent pathway. In contrast, macrophages infected withFrancisella tularensislive vaccine strain (LVS), a weak inflammasome activator, generated little IL-18 and stimulated low MAIT cell IFN-γ through an MR1-dependent pathway. By manipulating the quantities of IL-18 in these cultures, we show that the IL-18 concentration is sufficient to influence the magnitude of MAIT cell IFN-γ production. Correspondingly, infected IL-18-deficient macrophages failed to induce substantial MAIT cell IFN-γ. In contrast, we found that MAIT cell IFN-γ production in the lungs of IL-18-deficient mice was not significantly different from that in WT mice duringF. tularensisLVS pulmonary infection. Overall, we demonstrate that while IL-18 is essential for the MAIT cell IFN-γ responsein vitro, it is not essential for MAIT cell IFN-γ production duringin vivoLVS pulmonary infection, suggesting that additional signals can drive MAIT cell IFN-γ productionin vivo.

scholarly journals Limited Pulmonary Mucosal-Associated Invariant T Cell Accumulation and Activation during Mycobacterium tuberculosis Infection in Rhesus Macaques

2018 ◽  
Vol 86 (12) ◽  
Author(s):  
Keith D. Kauffman ◽  
Michelle A. Sallin ◽  
Stella G. Hoft ◽  
Shunsuke Sakai ◽  
Rashida Moore ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd4 T Cells ◽  
Rhesus Macaques ◽  
Intracellular Cytokine Staining ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type ◽  
Mait Cells ◽  
Cd69 Expression

ABSTRACT Mucosal-associated invariant T cells (MAITs) are positioned in airways and may be important in the pulmonary cellular immune response against Mycobacterium tuberculosis infection, particularly prior to priming of peptide-specific T cells. Accordingly, there is interest in the possibility that boosting MAITs through tuberculosis (TB) vaccination may enhance protection, but MAIT responses in the lungs during tuberculosis are poorly understood. In this study, we compared pulmonary MAIT and peptide-specific CD4 T cell responses in M. tuberculosis-infected rhesus macaques using 5-OP-RU-loaded MR-1 tetramers and intracellular cytokine staining of CD4 T cells following restimulation with an M. tuberculosis-derived epitope megapool (MTB300), respectively. Two of four animals showed a detectable increase in the number of MAIT cells in airways at later time points following infection, but by ∼3 weeks postexposure, MTB300-specific CD4 T cells arrived in the airways and greatly outnumbered MAITs thereafter. In granulomas, MTB300-specific CD4 T cells were ∼20-fold more abundant than MAITs. CD69 expression on MAITs correlated with tissue residency rather than bacterial loads, and the few MAITs found in granulomas poorly expressed granzyme B and Ki67. Thus, MAIT accumulation in the airways is variable and late, and MAITs display little evidence of activation in granulomas during tuberculosis in rhesus macaques.

scholarly journals Neither Primary nor Memory Immunity to Mycobacterium tuberculosis Infection Is Compromised in Mice with Chronic Enteric Helminth Infection

2015 ◽  
Vol 83 (3) ◽  
pp. 1217-1223 ◽  
Author(s):  
Wasiulla Rafi ◽  
Kamlesh Bhatt ◽  
William C. Gause ◽  
Padmini Salgame
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Regulatory Cells ◽  
Helminth Infection ◽  
Treg Cells ◽  
Helminth Species ◽  
Nippostrongylus Brasiliensis ◽  
T Regulatory Cell ◽  
Chronic Infections ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type

Previously we had reported thatNippostrongylus brasiliensis, a helminth with a lung migratory phase, affected host resistance againstMycobacterium tuberculosisinfection through the induction of alternatively activated (M2) macrophages. Several helminth species do not have an obligatory lung migratory phase but establish chronic infections in the host that include potent immune downregulatory effects, in part mediated through induction of a FoxP3+T regulatory cell (Treg) response. Treg cells exhibit duality in their functions in host defense againstM. tuberculosisinfection since their depletion leads to enhanced priming of T cells in the lymph nodes and attendant improved control ofM. tuberculosisinfection, while their presence in the lung granuloma protects against excessive inflammation.Heligmosomoides polygyrusis a strictly murine enteric nematode that induces a strong FoxP3 Treg response in the host. Therefore, in this study we investigated whether host immunity toM. tuberculosisinfection would be modulated in mice with chronicH. polygyrusinfection. We report that neither primary nor memory immunity conferred byMycobacterium bovisBCG vaccination was affected in mice with chronic enteric helminth infection, despite a systemic increase in FoxP3+T regulatory cells. The findings indicate that anti-M. tuberculosisimmunity is not similarly affected by all helminth species and highlight the need to consider this inequality in human coinfection studies.

scholarly journals Disparate Effects of Metformin on Mycobacterium tuberculosis Infection in Diabetic and Nondiabetic Mice

2020 ◽  
Vol 65 (1) ◽  
pp. e01422-20
Author(s):  
Harindra D. Sathkumara ◽  
Karyna Hansen ◽  
Socorro Miranda-Hernandez ◽  
Brenda Govan ◽  
Catherine M. Rush ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mycobacterium Tuberculosis ◽  
Disease Burden ◽  
Low Dose ◽  
Diabetic Mice ◽  
Antidiabetic Drug ◽  
Mycobacterium Tuberculosis Infection ◽  
Therapeutic Concentration ◽  
Content Type

ABSTRACTComorbid type 2 diabetes poses a great challenge to the global control of tuberculosis. Here, we assessed the efficacy of metformin (MET), an antidiabetic drug, in mice infected with a very low dose of Mycobacterium tuberculosis. In contrast to diabetic mice, infected nondiabetic mice that received the same therapeutic concentration of MET presented with significantly higher disease burden. This warrants further studies to investigate the disparate efficacy of MET against tuberculosis in diabetic and nondiabetic individuals.

scholarly journals Monitoring Tuberculosis Drug Activity in Live Animals by Using Near-Infrared Fluorescence Imaging

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Raphael Sommer ◽  
Stewart T. Cole
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Near Infrared ◽  
Imaging System ◽  
Limit Of Detection ◽  
Bacterial Load ◽  
Genetically Engineered ◽  
Fluorescent Imaging ◽  
Effective Vaccine ◽  
Content Type ◽  
Immunodeficient Mice

ABSTRACT Worldwide, tuberculosis (TB) is the leading cause of death due to infection with a single pathogenic agent, Mycobacterium tuberculosis. In the absence of an effective vaccine, new, more powerful antibiotics are required to halt the growing spread of multidrug-resistant strains and to shorten the duration of TB treatment. However, assessing drug efficacy at the preclinical stage remains a long and fastidious procedure that delays the progression of drugs down the pipeline and towards the clinic. In this investigation, we report the construction, optimization, and characterization of genetically engineered near-infrared (NIR) fluorescent reporter strains of the pathogens Mycobacterium marinum and Mycobacterium tuberculosis that enable the direct visualization of bacteria in infected zebrafish and mice, respectively. Fluorescence could be measured precisely in infected immunodeficient mice, while its intensity appeared to be below the limit of detection in immunocompetent mice, probably because of the lower bacterial load obtained in these animals. Furthermore, we show that the fluorescence level accurately reflects the bacterial load, as determined by CFU enumeration, thus enabling the efficacy of antibiotic treatment to be assessed in live animals in real time. The NIR fluorescent imaging system disclosed here is a valuable resource for TB research and can serve to accelerate drug development.

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

2020 ◽  
Vol 5 (51) ◽  
pp. eabe1670 ◽  
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.

scholarly journals Interleukin 12 (IL-12) Is Crucial to the Development of Protective Immunity in Mice Intravenously Infected with Mycobacterium tuberculosis

1997 ◽  
Vol 186 (1) ◽  
pp. 39-45 ◽  
Author(s):  
Andrea M. Cooper ◽  
Jeanne Magram ◽  
Jessica Ferrante ◽  
Ian M. Orme
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
T Cell Activation ◽  
Bacterial Growth ◽  
Cell Activation ◽  
Interferon Γ ◽  
Delayed Type Hypersensitivity ◽  
Interleukin 12 ◽  
Mycobacterium Tuberculosis Infection ◽  
Ifn Γ

Immunity to Mycobacterium tuberculosis infection is associated with the emergence of protective CD4 T cells that secrete cytokines, resulting in activation of macrophages and the recruitment of monocytes to initiate granuloma formation. The cytokine-mediating macrophage activation is interferon-γ (IFN-γ), which is largely dependent on interleukin-12 (IL-12) for its induction. To address the role of IL-12 in immunity to tuberculosis, IL-12 p40−/− mice were infected with M. tuberculosis and their capacity to control bacterial growth and other characteristics of their immune response were determined. The IL-12 p40−/− mice were unable to control bacterial growth and this appeared to be linked to the absence of both innate and acquired sources of IFN-γ. T cell activation as measured by delayed type hypersensitivity and lymphocyte accumulation at the site of infection were both markedly reduced in the IL-12 p40−/− mice. Therefore, IL-12 is essential to the generation of a protective immune response to M. tuberculosis, with its main functions being the induction of the expression of IFN-γ and the activation of antigen-specific lymphocytes capable of creating a protective granuloma.

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