title: The aryl hydrocarbon receptor promotes IL-10 production by NK cells.
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.
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Sagie
authors.initials: S
authors.lastname: Wagage
authors.forename: Beena
authors.initials: B
authors.lastname: John
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Krock
authors.forename: Aisling O'Hara
authors.initials: AO
authors.lastname: Hall
authors.forename: Louise M
authors.initials: LM
authors.lastname: Randall
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000096:biosynthesis / Q000378:metabolism; D019281:Dimerization; D017930:Genes, Reporter; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000378:metabolism*; D015979:Killer Cells, Lymphokine-Activated / Q000378:metabolism*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D020825:T-Box Domain Proteins / Q000096:biosynthesis; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: C556062:IL10 protein, mouse; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D018336:Receptors, Aryl Hydrocarbon; D011971:Receptors, Immunologic; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016753:Interleukin-10; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D018664:Interleukin-12; D007371:Interferon-gamma