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AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice.

Authors
  • Goettel, Jeremy A1
  • Gandhi, Roopali2
  • Kenison, Jessica E2
  • Yeste, Ada2
  • Murugaiyan, Gopal2
  • Sambanthamoorthy, Sharmila2
  • Griffith, Alexandra E3
  • Patel, Bonny2
  • Shouval, Dror S1
  • Weiner, Howard L2
  • Snapper, Scott B4
  • Quintana, Francisco J5
  • 1 Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
  • 2 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.
  • 3 Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA.
  • 4 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: [email protected]
  • 5 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: [email protected]
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Oct 25, 2016
Volume
17
Issue
5
Pages
1318–1329
Identifiers
DOI: 10.1016/j.celrep.2016.09.082
PMID: 27783946
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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