Tissue-derived hedgehog proteins modulate Th differentiation and disease.
Tissue-derived hedgehog proteins modulate Th differentiation and disease.
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DOI：
10.4049/jimmunol.1202541
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发表时间：
2013-03-15
期刊：
影响因子：
--
通讯作者：
Crompton T
中科院分区：
文献类型：
--
作者：
Furmanski AL;Saldana JI;Ono M;Sahni H;Paschalidis N;D'Acquisto F;Crompton T
对复杂的免疫介导疾病的全基因组关联研究表明，许多遗传因素，每一个都具有个体低风险，有助于整体疾病。因此，研究免疫反应如何通过组织环境进行微妙的修改是及时和重要的。在这里，我们探讨了组织衍生分子在影响T细胞功能方面的作用，由于其迁移性质，T细胞在其寿命期间与许多不同的微环境接触。Hedgehog（Hh）蛋白充当分泌的形态发生素，在实体组织中提供浓度依赖性位置和时间细胞命运特化。Hh信号是胚胎发生所必需的，并且在出生后组织更新和恶性肿瘤中是重要的。然而，Hh在动态的流体系统中的功能，如在哺乳动物免疫中，在很大程度上是未知的。在这里，我们表明，在T细胞的Hh依赖性转录促进Th2的转录程序和分化，加剧过敏性病理。有趣的是，在诱导过敏性疾病后，肺上皮细胞中的Sonic Hedgehog（Shh）表达增加，并且肺T细胞上调Hh靶基因表达，表明T细胞对体内局部分泌的Hh配体有应答。我们发现，IL 4，关键的Th2细胞因子，是一种新的转录靶细胞的Hh信号在T细胞，提供了一种机制的作用，Hh在Th细胞分化。我们认为，从发炎、重塑或恶性组织分泌的Hh可以调节局部T细胞功能。我们的数据提出了一个意想不到的和新的作用，组织来源的形态发生素在调节体液免疫反应，与过敏和肿瘤反应的影响，提示新的用途抗Hh治疗。
Genome-wide association studies into complex immune-mediated diseases have indicated that many genetic factors, each with individual low risk, contribute to overall disease. It is therefore timely and important to characterise how immune responses may be subtly modified by tissue context. Here we explore the role of tissue-derived molecules in influencing the function of T-cells, which, due to their migratory nature, come into contact with many different microenvironments through their lifespan. Hedgehog (Hh) proteins act as secreted morphogens, providing concentration-dependent positional and temporal cell-fate specification in solid tissues. Hh signalling is required for embryogenesis and is important in postnatal tissue renewal and in malignancy. However, the function of Hh in dynamic, fluid systems such as in mammalian immunity is largely unknown. Here we show that Hh-dependent transcription in T-cells promoted Th2 transcriptional programs and differentiation, exacerbating allergic pathology. Interestingly, expression of Sonic Hedgehog (Shh) increased in lung epithelial cells following the induction of allergic disease, and lung T-cells upregulated Hh-target gene expression, indicating that T-cells respond to locally-secreted Hh ligands in vivo. We show that Il4, the key Th2 cytokine, is a novel transcriptional target of Hh signals in T-cells, providing one mechanism for the role of Hh in Th differentiation. We propose that Hh, secreted from inflamed, remodelling or malignant tissue can modulate local T-cell function. Our data present an unexpected and novel role for tissue-derived morphogens in the regulation of fluid immune responses, with implications for allergy and tumour responses, suggesting new uses for anti-Hh therapeutics.
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