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

Authors: Goettel, Jeremy A; Gandhi, Roopali; Kenison, Jessica E; Yeste, Ada; Murugaiyan, Gopal; Sambanthamoorthy, Sharmila; Griffith, Alexandra E; Patel, Bonny; Shouval, Dror S; Weiner, Howard L; Snapper, Scott B; Quintana, Francisco J

Published In Cell Rep, (2016 Oct 25)

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.

PubMed ID: 27783946

MeSH Terms: Animals; Colitis/immunology*; Colitis/metabolism*; Disease Models, Animal; Forkhead Transcription Factors/metabolism; Humans; Mice; Receptors, Aryl Hydrocarbon/metabolism*; T-Lymphocytes, Regulatory/immunology*; Thiazoles; Transforming Growth Factor beta1/pharmacology; Trinitrobenzenesulfonic Acid