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

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...

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Vydáno v:	Cell reports (Cambridge) Ročník 17; číslo 5; s. 1318 - 1329
Hlavní autoři:	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.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 25.10.2016 Elsevier
Témata:	AHR Animals Colitis - immunology Colitis - metabolism Disease Models, Animal Forkhead Transcription Factors - metabolism humanized mice Humans IBD ITE Mice Receptors, Aryl Hydrocarbon - metabolism T-Lymphocytes, Regulatory - immunology Thiazoles Transforming Growth Factor beta1 - pharmacology treg Trinitrobenzenesulfonic Acid IBD AHR ITE treg humanized mice
ISSN:	2211-1247, 2211-1247
On-line přístup:	Získat plný text
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Shrnutí:	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. [Display omitted] •Non-toxic AHR agonist ITE induces human regulatory T cells in vitro•ITE-mediated in vitro suppression is dependent on CD39 and Granzyme B•Human CD4 T cells drive TNBS-induced colitis in humanized mice•ITE protects against TNBS-induced colitis in humanized mice Therapeutic approaches aimed at expanding regulatory T cells in the gut to promote immune tolerance in patients with inflammatory bowel disease (IBD) are of clinical significance. Goettel et al. establish a humanized murine model of IBD driven by human T cells and find that activation of AHR by the non-toxic agonist ITE can prevent experimental colitis.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Co-first author Lead contact
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2016.09.082