Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells

Eur J Immunol. 2010 Sep;40(9):2450-9. doi: 10.1002/eji.201040461.


Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo[3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-gamma, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4(+) T cells. The specific AHR-inhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4(+) T cells to produce IL-22 without IL-17 and IFN-gamma. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161(+) Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4(+) T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azo Compounds / pharmacology
  • CD4 Antigens / biosynthesis
  • Carbazoles / pharmacology
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Cytochrome P-450 CYP1A1 / metabolism
  • Dioxins / pharmacology
  • Humans
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism*
  • Interleukin-22
  • Interleukins / genetics
  • Interleukins / immunology
  • Interleukins / metabolism*
  • Lymphocyte Activation / drug effects
  • NK Cell Lectin-Like Receptor Subfamily B / biosynthesis
  • Pyrazoles / pharmacology
  • Receptors, Aryl Hydrocarbon / immunology
  • Receptors, Aryl Hydrocarbon / metabolism*
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocyte Subsets / pathology
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / metabolism*
  • T-Lymphocytes, Helper-Inducer / pathology
  • Transcription Factors / genetics
  • Transcription Factors / immunology
  • Transcription Factors / metabolism
  • Up-Regulation


  • 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide
  • 6-formylindolo(3,2-b)carbazole
  • Azo Compounds
  • CD4 Antigens
  • Carbazoles
  • Dioxins
  • IL17A protein, human
  • Interleukin-17
  • Interleukins
  • NK Cell Lectin-Like Receptor Subfamily B
  • Pyrazoles
  • Receptors, Aryl Hydrocarbon
  • Transcription Factors
  • Interferon-gamma
  • Cytochrome P-450 CYP1A1