title: Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation.
abstract: Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to elicit potent immunity to a broad range of bacteria, mainly via the rapid production of inflammatory cytokines. Whether MAIT cells contribute to antiviral immunity is less clear. Here we asked whether MAIT cells produce cytokines/chemokines during severe human influenza virus infection. Our analysis in patients hospitalized with avian H7N9 influenza pneumonia showed that individuals who recovered had higher numbers of CD161(+)Vα7.2(+) MAIT cells in peripheral blood compared with those who succumbed, suggesting a possible protective role for this lymphocyte population. To understand the mechanism underlying MAIT cell activation during influenza, we cocultured influenza A virus (IAV)-infected human lung epithelial cells (A549) and human peripheral blood mononuclear cells in vitro, then assayed them by intracellular cytokine staining. Comparison of influenza-induced MAIT cell activation with the profile for natural killer cells (CD56(+)CD3(-)) showed robust up-regulation of IFNγ for both cell populations and granzyme B in MAIT cells, although the individual responses varied among healthy donors. However, in contrast to the requirement for cell-associated factors to promote NK cell activation, the induction of MAIT cell cytokine production was dependent on IL-18 (but not IL-12) production by IAV-exposed CD14(+) monocytes. Overall, this evidence for IAV activation via an indirect, IL-18-dependent mechanism indicates that MAIT cells are protective in influenza, and also possibly in any human disease process in which inflammation and IL-18 production occur.
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia;
authors.forename: Liyen
authors.initials: L
authors.lastname: Loh
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia;
authors.forename: Zhongfang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia;
authors.forename: Sneha
authors.initials: S
authors.lastname: Sant
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia;
authors.forename: Marios
authors.initials: M
authors.lastname: Koutsakos
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; National Institute of Allergy and Infectious Diseases, Bethesda, MD 20852;
authors.forename: Sinthujan
authors.initials: S
authors.lastname: Jegaskanda
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia;
authors.forename: Alexandra J
authors.identifier: 0000-0003-1618-4337
authors.initials: AJ
authors.lastname: Corbett
authors.affiliation: Centre for Inflammation Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia;
authors.forename: Ligong
authors.initials: L
authors.lastname: Liu
authors.affiliation: Centre for Inflammation Disease Research and ARC Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia;
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.affiliation: Deepdene Surgery, Deepdene, VIC 3103, Australia;
authors.forename: Jane
authors.initials: J
authors.lastname: Crowe
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia;
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College of Fudan University, Shanghai 201508, China;
authors.forename: Jianqing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105 pcd@unimelb.edu.au kkedz@unimelb.edu.au.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia;
authors.forename: James
authors.identifier: 0000-0002-8597-815X
authors.initials: J
authors.lastname: McCluskey
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; pcd@unimelb.edu.au kkedz@unimelb.edu.au.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
mesh_terms: D000072283:A549 Cells; D002450:Cell Communication / Q000276:immunology; D018920:Coculture Techniques; D015870:Gene Expression; D053804:Granzymes / Q000235:genetics / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D016130:Immunophenotyping; D064766:Influenza A Virus, H7N9 Subtype / Q000276:immunology / Q000472:pathogenicity*; D007251:Influenza, Human / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000821:virology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D008213:Lymphocyte Activation; D009000:Monocytes / Q000276:immunology / Q000821:virology; D000072336:Mucosal-Associated Invariant T Cells / Q000276:immunology* / Q000821:virology; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000235:genetics / Q000276:immunology; D011024:Pneumonia, Viral / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000821:virology; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: C000589760:IL18 protein, human; D020382:Interleukin-18; C527203:KLRB1 protein, human; D055651:NK Cell Lectin-Like Receptor Subfamily B; D007371:Interferon-gamma; D053804:Granzymes
keywords: H7N9; IL-18; MAIT cells; influenza virus; monocytes