title: Differential regulation of Th17 and T regulatory cell differentiation by aryl hydrocarbon receptor dependent xenobiotic response element dependent and independent pathways.
abstract: The aryl hydrocarbon receptor (AHR) is regarded as an environmental sensor and has been shown to link environmental stresses with chronic inflammatory and autoimmune diseases. The AHR can be activated to regulate both the X/DRE (xenobiotic or dioxin response elements) as well as a non-X/DRE mediated pathway. Selective AHR modulators (SAhRMs) are recently identified compounds that activate non-X/DRE mediated pathway without activating the X/DRE-driven responses. Here, we have used 3 classes of AHR ligands; agonist, antagonist, and a SAhRM, to delineate the role of these AHR-driven pathways in T helper 17 (Th17)/T regulatory (Treg) regulation. We show that Th17 differentiation is primarily dependent on X/DRE-driven responses, whereas Treg differentiation can be suppressed by inhibiting non-X/DRE pathway. Using a model of Citrobacter rodentium infection, we further show that AHR agonist enhances Th17 production and promoted resolution of infection, whereas a SAhRM inhibited Th17 mediated responses with reduced resolution of infection. These data indicate that Th17/Treg function may be differentially regulated by SAhRMs that differentially activate the X/DRE and non-X/DRE mediated pathways, and point to a therapeutic strategy to leverage AHR function in the treatment of chronic inflammatory and autoimmune disease.
authors.affiliation: *Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853, Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033 and Center for Molecular Toxicology, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16801.
authors.forename: Sonia
authors.initials: S
authors.lastname: Mohinta
authors.affiliation: *Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853, Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033 and Center for Molecular Toxicology, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16801.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Kannan
authors.affiliation: *Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853, Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033 and Center for Molecular Toxicology, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16801.
authors.forename: Krishne
authors.initials: K
authors.lastname: Gowda
authors.affiliation: *Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853, Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033 and Center for Molecular Toxicology, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16801.
authors.forename: Shantu G
authors.initials: SG
authors.lastname: Amin
authors.affiliation: *Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853, Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033 and Center for Molecular Toxicology, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16801.
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
authors.affiliation: *Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853, Department of Pharmacology, Pennsylvania State College of Medicine, Hershey, Pennsylvania 17033 and Center for Molecular Toxicology, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania 16801 averyaugust@cornell.edu.
authors.forename: Avery
authors.initials: A
authors.lastname: August
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D044082:Citrobacter rodentium / Q000472:pathogenicity; D004195:Disease Models, Animal; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000382:microbiology; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D013997:Time Factors
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D020381:Interleukin-17; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse; C098680:Il17a protein, mouse
keywords: AHR; SAhRMs; Th17; Treg