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Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells.
- Source :
-
European journal of immunology [Eur J Immunol] 2010 Sep; Vol. 40 (9), pp. 2450-9. - Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- 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
Interleukins genetics
Interleukins immunology
Lymphocyte Activation drug effects
NK Cell Lectin-Like Receptor Subfamily B biosynthesis
Pyrazoles pharmacology
Receptors, Aryl Hydrocarbon immunology
T-Lymphocyte Subsets drug effects
T-Lymphocyte Subsets immunology
T-Lymphocyte Subsets pathology
T-Lymphocytes, Helper-Inducer drug effects
T-Lymphocytes, Helper-Inducer immunology
T-Lymphocytes, Helper-Inducer pathology
Transcription Factors genetics
Transcription Factors immunology
Transcription Factors metabolism
Up-Regulation
Interleukin-22
Interleukin-17 metabolism
Interleukins metabolism
Receptors, Aryl Hydrocarbon metabolism
T-Lymphocyte Subsets metabolism
T-Lymphocytes, Helper-Inducer metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-4141
- Volume :
- 40
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- European journal of immunology
- Publication Type :
- Academic Journal
- Accession number :
- 20706985
- Full Text :
- https://doi.org/10.1002/eji.201040461