title: AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice.
abstract: Existing therapies for inflammatory bowel disease that are based on broad suppression of inflammation result in variable clinical benefit and unwanted side effects. A potential therapeutic approach for promoting immune tolerance is the in vivo induction of regulatory T cells (Tregs). Here we report that activation of the aryl hydrocarbon receptor using the non-toxic agonist 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) induces human Tregs in vitro that suppress effector T cells through a mechanism mediated by CD39 and Granzyme B. We then developed a humanized murine system whereby human CD4+T cells drive colitis upon exposure to 2,4,6-trinitrobenzenesulfonic acid and assessed ITE as a potential therapeutic. ITE administration ameliorated colitis in humanized mice with increased CD39, Granzyme B, and IL10-secreting human Tregs. These results develop an experimental model to investigate human CD4+T responses in vivo and identify the non-toxic AHR agonist ITE as a potential therapy for promoting immune tolerance in the intestine.
authors: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors: Jeremy A
authors: JA
authors: Goettel
authors: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Roopali
authors: R
authors: Gandhi
authors: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Jessica E
authors: JE
authors: Kenison
authors: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Ada
authors: A
authors: Yeste
authors: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Gopal
authors: G
authors: Murugaiyan
authors: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Sharmila
authors: S
authors: Sambanthamoorthy
authors: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.
authors: Alexandra E
authors: AE
authors: Griffith
authors: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Bonny
authors: B
authors: Patel
authors: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors: Dror S
authors: DS
authors: Shouval
authors: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Howard L
authors: HL
authors: Weiner
authors: Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: scott.snapper@childrens.harvard.edu.
authors: Scott B
authors: SB
authors: Snapper
authors: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA; The Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA. Electronic address: fquintana@rics.bwh.harvard.edu.
authors: Francisco J
authors: FJ
authors: Quintana
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D051379:Mice; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013844:Thiazoles; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018336:Receptors, Aryl Hydrocarbon; D013844:Thiazoles; D053773:Transforming Growth Factor beta1; D014302:Trinitrobenzenesulfonic Acid
keywords: AHR; IBD; ITE; humanized mice; treg