The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells.
The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells.
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DOI：
10.1016/j.immuni.2012.09.008
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发表时间：
2012-10-19
期刊：
影响因子：
32.4
通讯作者：
Lord GM
中科院分区：
文献类型：
--
作者：
Powell N;Walker AW;Stolarczyk E;Canavan JB;Gökmen MR;Marks E;Jackson I;Hashim A;Curtis MA;Jenner RG;Howard JK;Parkhill J;MacDonald TT;Lord GM
先天免疫系统中缺乏转录因子T-bet的小鼠会发生微生物群依赖性结肠炎。在这里，我们表明，白细胞介素-17 A（IL-17 A）产生IL-7 R α+先天淋巴细胞（ILC）是Tbx 21 −/− Rag 2 −/−溃疡性结肠炎（TRUC）小鼠疾病的有力促进者。由CD 103 − CD 11b+树突状细胞产生的TNF-α与IL-23协同作用，驱动ILC产生IL-17 A，这表明树突状细胞和ILC之间存在一个以前未被认识的细胞串扰层。我们已经确定幽门螺杆菌是TRUC小鼠中驱动过量TNF-α产生和促进结肠炎的关键疾病触发因素。重要的是，T-bet还抑制IL-7 R的表达，IL-7 R是参与控制肠ILC稳态的关键分子。IL-7 R信号传导在TRUC疾病中的重要性通过在IL-7 R阻断后肠ILC的显著减少和减弱的结肠炎而突出。总之，这些数据表明了T-bet调节粘膜树突状细胞、ILC和肠道微生物群之间复杂相互作用的机制。TRUC小鼠中的慢性结肠炎是由产生IL-17的先天性淋巴细胞介导的，TNF-α与IL-23协同诱导先天性IL-17的产生，幽门螺杆菌引发TRUC小鼠的肠道病理学，IL-7 R转录是肠道ILC稳态的关键检查点。
Mice lacking the transcription factor T-bet in the innate immune system develop microbiota-dependent colitis. Here, we show that interleukin-17A (IL-17A)-producing IL-7Rα+ innate lymphoid cells (ILCs) were potent promoters of disease in Tbx21−/−Rag2−/− ulcerative colitis (TRUC) mice. TNF-α produced by CD103−CD11b+ dendritic cells synergized with IL-23 to drive IL-17A production by ILCs, demonstrating a previously unrecognized layer of cellular crosstalk between dendritic cells and ILCs. We have identified Helicobacter typhlonius as a key disease trigger driving excess TNF-α production and promoting colitis in TRUC mice. Crucially, T-bet also suppressed the expression of IL-7R, a key molecule involved in controlling intestinal ILC homeostasis. The importance of IL-7R signaling in TRUC disease was highlighted by the dramatic reduction in intestinal ILCs and attenuated colitis following IL-7R blockade. Taken together, these data demonstrate the mechanism by which T-bet regulates the complex interplay between mucosal dendritic cells, ILCs, and the intestinal microbiota. ► Chronic colitis in TRUC mice was mediated by IL-17-producing innate lymphoid cells ► TNF-α synergized with IL-23 to induce innate IL-17 production ► Helicobacter typhlonius triggered intestinal pathology in TRUC mice ► T-bet regulated IL-7R transcription, a key checkpoint in intestinal ILC homeostasis
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影响因子：
14.9
作者：
Pruesse E;Quast C;Knittel K;Fuchs BM;Ludwig W;Peplies J;Glöckner FO
通讯作者：
Glöckner FO
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
14.9
作者：
Cole JR;Wang Q;Cardenas E;Fish J;Chai B;Farris RJ;Kulam-Syed-Mohideen AS;McGarrell DM;Marsh T;Garrity GM;Tiedje JM
通讯作者：
Tiedje JM
影响因子：
4.4
作者：
Schloss, Patrick D.;Westcott, Sarah L.;Weber, Carolyn F.
通讯作者：
Weber, Carolyn F.
DOI：
10.1073/pnas.0909357106
发表时间：
2009-10-20
影响因子：
11.1
作者：
Jenner, Richard G.;Townsend, Michael J.;Lord, Graham M.
通讯作者：
Lord, Graham M.