SMAD4 TGF-β-independent function preconditions naive CD8+ T cells to prevent severe chronic intestinal inflammation.
SMAD4 TGF-β-independent function preconditions naive CD8+ T cells to prevent severe chronic intestinal inflammation.
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DOI：
10.1172/jci151020
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发表时间：
2022-04-15
影响因子：
15.9
通讯作者：
Soudja, Saidi M'Homa
中科院分区：
文献类型：
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作者：
Igalouzene, Ramdane;Hernandez-Vargas, Hector;Benech, Nicolas;Guyennon, Alexandre;Bauche, David;Barrachina, Celia;Dubois, Emeric;Marie, Julien C.;Soudja, Saidi M'Homa
SMAD 4是TGF-β信号转导的介导因子，在T细胞中起重要作用，以预防炎症性肠病（IBD）。然而，这种控制的确切机制仍然难以捉摸。使用遗传和表观遗传方法，我们揭示了SMAD 4阻止幼稚CD 8 + T细胞成为肠道致病性的意想不到的机制。在TGF-β受体参与之前，SMAD 4抑制幼稚CD 8 + T细胞中TGF-β标签的表观遗传、转录和功能景观。在机制上，在TGF-β信号传导之前，SMAD 4结合几种TGF-β靶基因的启动子和增强子，并通过调节组蛋白脱乙酰化，抑制它们的表达。因此，无论TGF-β信号如何，SMAD 4限制TGF-β负反馈环基因（如Smad 7和Ski）的表达，并可能使CD 8 + T细胞适应TGF-β的免疫调节作用。此外，SMAD 4消融通过增强初始CD 8 + T细胞对IL-7的应答而赋予初始CD 8 + T细胞上级存活能力，以及通过促进编码整合素CD 103的Itgae的表达而赋予初始CD 8 + T细胞增强的保留在肠上皮内的能力。累积、上皮保留和逃避TGF-β控制引起肠道中慢性微生物群驱动的CD 8 + T细胞活化。因此，以TGF-β非依赖性方式，SMAD 4印记了预先调节幼稚CD 8 + T细胞命运的程序，从而预防IBD。
SMAD4, a mediator of TGF-β signaling, plays an important role in T cells to prevent inflammatory bowel disease (IBD). However, the precise mechanisms underlying this control remain elusive. Using both genetic and epigenetic approaches, we revealed an unexpected mechanism by which SMAD4 prevents naive CD8+ T cells from becoming pathogenic for the gut. Prior to the engagement of the TGF-β receptor, SMAD4 restrains the epigenetic, transcriptional, and functional landscape of the TGF-β signature in naive CD8+ T cells. Mechanistically, prior to TGF-β signaling, SMAD4 binds to promoters and enhancers of several TGF-β target genes, and by regulating histone deacetylation, suppresses their expression. Consequently, regardless of a TGF-β signal, SMAD4 limits the expression of TGF-β negative feedback loop genes, such as Smad7 and Ski, and likely conditions CD8+ T cells for the immunoregulatory effects of TGF-β. In addition, SMAD4 ablation conferred naive CD8+ T cells with both a superior survival capacity, by enhancing their response to IL-7, as well as an enhanced capacity to be retained within the intestinal epithelium, by promoting the expression of Itgae, which encodes the integrin CD103. Accumulation, epithelial retention, and escape from TGF-β control elicited chronic microbiota-driven CD8+ T cell activation in the gut. Hence, in a TGF-β–independent manner, SMAD4 imprints a program that preconditions naive CD8+ T cell fate, preventing IBD.