The aryl hydrocarbon receptor promotes IL-10 production by NK cells

J Immunol. 2014 Feb 15;192(4):1661-70. doi: 10.4049/jimmunol.1300497. Epub 2014 Jan 8.

Abstract

The cytokine IL-10 has an important role in limiting inflammation in many settings, including toxoplasmosis. In the present studies, an IL-10 reporter mouse was used to identify the sources of this cytokine following challenge with Toxoplasma gondii. During infection, multiple cell types expressed the IL-10 reporter but NK cells were a major early source of this cytokine. These IL-10 reporter(+) NK cells expressed high levels of the IL-12 target genes T-bet, KLRG1, and IFN-γ, and IL-12 depletion abrogated reporter expression. However, IL-12 signaling alone was not sufficient to promote NK cell IL-10, and activation of the aryl hydrocarbon receptor (AHR) was also required for maximal IL-10 production. NK cells basally expressed the AHR, relevant chaperone proteins, and the AHR nuclear translocator, which heterodimerizes with the AHR to form a competent transcription factor. In vitro studies revealed that IL-12 stimulation increased NK cell AHR levels, and the AHR and AHR nuclear translocator were required for optimal production of IL-10. Additionally, NK cells isolated from T. gondii-infected Ahr(-/-) mice had impaired expression of IL-10, which was associated with increased resistance to this infection. Taken together, these data identify the AHR as a critical cofactor involved in NK cell production of IL-10.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator / biosynthesis
  • Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
  • Dimerization
  • Genes, Reporter
  • Inflammation / immunology
  • Interferon-gamma / biosynthesis
  • Interleukin-10 / biosynthesis*
  • Interleukin-12 / metabolism*
  • Killer Cells, Lymphokine-Activated / metabolism*
  • Lectins, C-Type
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Receptors, Aryl Hydrocarbon / deficiency
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Receptors, Immunologic / biosynthesis
  • Signal Transduction / immunology
  • T-Box Domain Proteins / biosynthesis
  • Toxoplasma / immunology*
  • Toxoplasmosis, Animal / immunology

Substances

  • IL10 protein, mouse
  • Klrg1 protein, mouse
  • Lectins, C-Type
  • Receptors, Aryl Hydrocarbon
  • Receptors, Immunologic
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Interleukin-10
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • Interleukin-12
  • Interferon-gamma