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

作者：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

来源：Cell Reports, 2016, 17(5): 1318-1329.

DOI：10.1016/j.celrep.2016.09.082

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 nontoxic 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.

• 出版日期2016-10-25