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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Cell reports (Cambridge) Jg. 17; H. 5; S. 1318 - 1329
Hauptverfasser: 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.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 25.10.2016
Elsevier
Schlagworte:
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
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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.
Bibliographie: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