title: In vivo dioxin favors interleukin-22 production by human CD4+ T cells in an aryl hydrocarbon receptor (AhR)-dependent manner.
abstract: BACKGROUND
  The transcription factor aryl hydrocarbon receptor (AhR) mediates the effects of a group of chemicals known as dioxins, ubiquitously present in our environment. However, it is poorly known how the in vivo exposure to these chemicals affects in humans the adaptive immune response. We therefore assessed the functional phenotype of T cells from an individual who developed a severe cutaneous and systemic syndrome after having been exposed to an extremely high dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
  
  
  RESULTS
  T cells of the TCDD-exposed individual were studied for their capacity to produce cytokines in response to polyclonal and superantigenic stimulation, and for the expression of chemokine receptors involved in skin homing. The supernatants from T cells of the exposed individual contained a substantially increased amount of interleukin (IL)-22 but not of IL-17A, interferon (IFN)-γ or IL-10 when compared to nine healthy controls. In vitro experiments confirmed a direct, AhR-dependent, enhancing effect of TCDD on IL-22 production by CD4+ T cells. The increased production of IL-22 was not dependent on AhR occupancy by residual TCDD molecules, as demonstrated in competition experiments with the specific AhR antagonist CH-223191. In contrast, it was due to an increased frequency of IL-22 single producing cells accompanied by an increased percentage of cells expressing the skin-homing chemokine receptors CCR6 and CCR4, identified through a multiparameter flow cytometry approach. Of interest, the frequency of CD4+CD25(hi)FoxP3+ T regulatory cells was similar in the TCDD-exposed and healthy individuals.
  
  
  CONCLUSIONS
  This case strongly supports the contention that human exposure to persistent AhR ligands in vivo induce a long-lasting effect on the human adaptive immune system and specifically polarizes CD4+ T cells to produce IL-22 and not other T cell cytokines with no effect on T regulatory cells.
authors.affiliation: Department of Immunology and Allergy, Swiss Centre for Applied Human Toxicology, University Hospital and School of Medicine, Geneva, Switzerland. nicolo.brembilla@hcuge.ch
authors.forename: Nicolò Costantino
authors.initials: NC
authors.lastname: Brembilla
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Ramirez
authors.forename: Rachel
authors.initials: R
authors.lastname: Chicheportiche
authors.forename: Olivier
authors.initials: O
authors.lastname: Sorg
authors.forename: Jean-Hilaire
authors.initials: JH
authors.lastname: Saurat
authors.forename: Carlo
authors.initials: C
authors.lastname: Chizzolini
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D000072317:Polychlorinated Dibenzodioxins / Q000506:poisoning*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D007371:Interferon-gamma; D016753:Interleukin-10; D020381:Interleukin-17; D007378:Interleukins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D000097043:Interleukin-22