AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice.
AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice.
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DOI：
10.1016/j.celrep.2016.09.082
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发表时间：
2016-10-25
期刊：
影响因子：
8.8
通讯作者：
Quintana FJ
中科院分区：
文献类型：
--
作者：
Goettel JA;Gandhi R;Kenison JE;Yeste A;Murugaiyan G;Sambanthamoorthy S;Griffith AE;Patel B;Shouval DS;Weiner HL;Snapper SB;Quintana FJ
基于广泛抑制炎症的炎症性肠病的现有疗法导致可变的临床益处和不希望的副作用。促进免疫耐受的潜在治疗方法是体内诱导调节性T细胞（TCLs）。在这里，我们报告了使用无毒激动剂2-（1′ H-吲哚-3 ′-羰基）-噻唑-4-羧酸甲酯（ITE）激活芳烃受体在体外诱导人T细胞活化，其通过CD 39和颗粒酶B介导的机制抑制效应T细胞。然后，我们开发了人源化鼠系统，其中人CD 4 + T细胞在暴露于2，4，6-三硝基苯磺酸后驱动结肠炎，并评估ITE作为潜在治疗剂。ITE给药改善了人源化小鼠的结肠炎，增加了CD 39、粒酶B和分泌IL-10的人调节性T细胞。这些结果建立了一个实验模型，以研究人体体内的CD 4 + T细胞反应，并确定无毒的AHR激动剂ITE作为促进肠道免疫耐受的潜在疗法。
Existing therapies for inflammatory bowel disease 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 IL-10-secreting human regulatory T cells. 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.
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