Format

Send to

Choose Destination
Cell Rep. 2016 Oct 25;17(5):1318-1329. doi: 10.1016/j.celrep.2016.09.082.

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

Author information

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: scott.snapper@childrens.harvard.edu.
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: fquintana@rics.bwh.harvard.edu.

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.

KEYWORDS:

AHR; IBD; ITE; humanized mice; treg

PMID:
27783946
PMCID:
PMC5106873
DOI:
10.1016/j.celrep.2016.09.082
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center