Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells.
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.
Ramirez
Jean-Marie
JM
Immunology and Allergy, Swiss Centre for Applied Human Toxicology, University Hospital and School of Medicine, Geneva, Switzerland.
Brembilla
Nicolò C
NC
Sorg
Olivier
O
Chicheportiche
Rachel
R
Matthes
Thomas
T
Dayer
Jean-Michel
JM
Saurat
Jean-Hilaire
JH
Roosnek
Eddy
E
Chizzolini
Carlo
C
D001391:Azo Compounds / Q000494:pharmacology; D015704:CD4 Antigens / Q000096:biosynthesis; D002227:Carbazoles / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004147:Dioxins / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000096:biosynthesis; D011720:Pyrazoles / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation; D000097043:Interleukin-22
D001391:Azo Compounds; D015704:CD4 Antigens; D002227:Carbazoles; D019363:Cytochrome P-450 CYP1A1; D004147:Dioxins; D007371:Interferon-gamma; D020381:Interleukin-17; D007378:Interleukins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011720:Pyrazoles; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D000097043:Interleukin-22; C511621:2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide; C111855:6-formylindolo(3,2-b)carbazole; C508717:IL17A protein, human