A major population of mucosal memory CD4+ T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality

Mucosal Immunol. 2015 May;8(3):545-58. doi: 10.1038/mi.2014.87. Epub 2014 Oct 1.

Abstract

Mucosal tissues contain large numbers of memory CD4(+) T cells that, through T-cell receptor-dependent interactions with antigen-presenting cells, are believed to have a key role in barrier defense and maintenance of tissue integrity. Here we identify a major subset of memory CD4(+) T cells at barrier surfaces that coexpress interleukin-18 receptor alpha (IL-18Rα) and death receptor-3 (DR3), and display innate lymphocyte functionality. The cytokines IL-15 or the DR3 ligand tumor necrosis factor (TNF)-like cytokine 1A (TL1a) induced memory IL-18Rα(+)DR3(+)CD4(+) T cells to produce interferon-γ, TNF-α, IL-6, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-22 in the presence of IL-12/IL-18. TL1a synergized with IL-15 to enhance this response, while suppressing IL-15-induced IL-10 production. TL1a- and IL-15-mediated cytokine induction required the presence of IL-18, whereas induction of IL-5, IL-13, GM-CSF, and IL-22 was IL-12 independent. IL-18Rα(+)DR3(+)CD4(+) T cells with similar functionality were present in human skin, nasal polyps, and, in particular, the intestine, where in chronic inflammation they localized with IL-18-producing cells in lymphoid aggregates. Collectively, these results suggest that human memory IL-18Rα(+)DR3(+) CD4(+) T cells may contribute to antigen-independent innate responses at barrier surfaces.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • Crohn Disease / genetics
  • Crohn Disease / immunology*
  • Crohn Disease / pathology
  • Epithelial Cells / immunology
  • Epithelial Cells / pathology
  • Gene Expression Regulation
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Humans
  • Immunity, Innate*
  • Immunity, Mucosal
  • Immunologic Memory
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interleukin-13 / genetics
  • Interleukin-13 / immunology
  • Interleukin-15 / genetics
  • Interleukin-15 / immunology
  • Interleukin-5 / genetics
  • Interleukin-5 / immunology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Interleukins / genetics
  • Interleukins / immunology
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / pathology
  • Nasal Polyps / genetics
  • Nasal Polyps / immunology*
  • Nasal Polyps / pathology
  • Primary Cell Culture
  • Receptors, Interleukin-18 / genetics
  • Receptors, Interleukin-18 / immunology*
  • Receptors, Tumor Necrosis Factor, Member 25 / genetics
  • Receptors, Tumor Necrosis Factor, Member 25 / immunology*
  • Signal Transduction
  • Skin / cytology
  • Skin / immunology
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / genetics
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / immunology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • IL15 protein, human
  • IL5 protein, human
  • IL6 protein, human
  • Interleukin-13
  • Interleukin-15
  • Interleukin-5
  • Interleukin-6
  • Interleukins
  • Receptors, Interleukin-18
  • Receptors, Tumor Necrosis Factor, Member 25
  • TNFRSF25 protein, human
  • TNFSF15 protein, human
  • Tumor Necrosis Factor Ligand Superfamily Member 15
  • Tumor Necrosis Factor-alpha
  • interleukin-13, human
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • interleukin-22