IL-15 dependent induction of IL-18 secretion as a feedback mechanism controlling human MAIT-cell effector functions

Eur J Immunol. 2015 Aug;45(8):2286-98. doi: 10.1002/eji.201445313. Epub 2015 Jun 22.


Mucosal-associated invariant T (MAIT) cells are characterized by an invariant TCRVα7.2 chain recognizing microbial vitamin B metabolites presented by the MHC-Ib molecule MR1. They are mainly detectable in the CD8(+) and CD8(-) CD4(-) "double negative" T-cell compartments of mammals and exhibit both Th1- and Th17-associated features. As MAIT cells show a tissue-homing phenotype and operate at mucosal surfaces with myriads of pathogenic encounters, we wondered how IL-15, a multifaceted cytokine being part of the intestinal mucosal barrier, impacts on their functions. We demonstrate that in the absence of TCR cross-linking, human MAIT cells secrete IFN-γ, increase perforin expression and switch on granzyme B production in response to IL-15. As this mechanism was dependent on the presence of CD14(+) cells and sensitive to IL-18 blockade, we identified IL-15 induced IL-18 production by monocytes as an inflammatory, STAT5-dependent feedback mechanism predominantly activating the MAIT-cell population. IL-15 equally affects TCR-mediated MAIT-cell functions since it dramatically amplifies bacteria-induced IFN-γ secretion, granzyme production, and cytolytic activity at early time points, an effect being most pronounced under suboptimal TCR stimulation conditions. Our data reveal a new quality of IL-15 as player in an inflammatory cytokine network impacting on multiple MAIT-cell functions.

Keywords: Cytokines; IL-15; Inflammation; MAIT-cells; T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Humans
  • Immunologic Capping
  • Interferon-gamma / immunology
  • Interleukin-15 / immunology*
  • Interleukin-18 / immunology*
  • Lymphocyte Activation / physiology*
  • Male
  • Mucous Membrane / cytology
  • Mucous Membrane / immunology
  • Receptors, Antigen, T-Cell / immunology*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*


  • IFNG protein, human
  • IL15 protein, human
  • IL18 protein, human
  • Interleukin-15
  • Interleukin-18
  • Receptors, Antigen, T-Cell
  • Interferon-gamma