Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation

Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10133-8. doi: 10.1073/pnas.1610750113. Epub 2016 Aug 19.

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.

Keywords: H7N9; IL-18; MAIT cells; influenza virus; monocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Cell Communication / immunology
  • Coculture Techniques
  • Gene Expression
  • Granzymes / genetics
  • Granzymes / immunology
  • Humans
  • Immunity, Innate
  • Immunity, Mucosal*
  • Immunophenotyping
  • Influenza A Virus, H7N9 Subtype / immunology
  • Influenza A Virus, H7N9 Subtype / pathogenicity*
  • Influenza, Human / immunology*
  • Influenza, Human / mortality
  • Influenza, Human / pathology
  • Influenza, Human / virology
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interleukin-18 / genetics
  • Interleukin-18 / immunology*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / virology
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / virology
  • Lymphocyte Activation
  • Monocytes / immunology
  • Monocytes / virology
  • Mucosal-Associated Invariant T Cells / immunology*
  • Mucosal-Associated Invariant T Cells / virology
  • NK Cell Lectin-Like Receptor Subfamily B / genetics
  • NK Cell Lectin-Like Receptor Subfamily B / immunology
  • Pneumonia, Viral / immunology*
  • Pneumonia, Viral / mortality
  • Pneumonia, Viral / pathology
  • Pneumonia, Viral / virology
  • Signal Transduction
  • Survival Analysis

Substances

  • IL18 protein, human
  • Interleukin-18
  • KLRB1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily B
  • Interferon-gamma
  • Granzymes