Proenkephalin+ regulatory T cells expanded by ultraviolet B exposure maintain skin homeostasis with a healing function
Proenkephalin+ regulatory T cells expanded by ultraviolet B exposure maintain skin homeostasis with a healing function
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DOI：
10.1073/pnas.2000372117
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发表时间：
2020-08
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通讯作者：
H. Shime;M. Odanaka;M. Tsuiji;T. Matoba;M. Imai;Y. Yasumizu;R. Uraki;K. Minohara;Maiko Watanabe;A. Bonito;H. Fukuyama;N. Ohkura;S. Sakaguchi;A. Morita;S. Yamazaki
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作者：
H. Shime;M. Odanaka;M. Tsuiji;T. Matoba;M. Imai;Y. Yasumizu;R. Uraki;K. Minohara;Maiko Watanabe;A. Bonito;H. Fukuyama;N. Ohkura;S. Sakaguchi;A. Morita;S. Yamazaki
调节性T细胞（Regulatory T, Treg）表达CD25和Foxp3，约占外周血CD4+ T细胞的5% ~ 10%，通过抑制各种免疫应答维持免疫自身耐受。在这里，我们发现皮肤Treg细胞通过UVB暴露扩增具有独特的TCR库和愈合功能。UVB-expanded skin Treg （UVB-skin Treg）细胞表达内源性阿片前体proenkephalin （PENK）和表皮生长因子受体配体amphiregulin （AREG）。在皮肤外植体实验中，treg衍生的PENK和AREG促进了角质细胞的生长。此外，uvb扩增的皮肤Treg细胞在体内促进伤口愈合中发挥了关键作用。我们的研究结果为开发使用PENK+ uvb皮肤Treg细胞的治疗提供了新的启示。调节性T （Treg）细胞表达CD25（白细胞介素-2受体α链）和Foxp3转录因子，维持免疫自身耐受并抑制各种免疫反应。在这里，我们报告皮肤Treg细胞在紫外线B （UVB）照射下扩增的特征。我们发现，具有愈合功能的皮肤Treg细胞在UVB照射下通过内源性阿片前体proenkephalin （PENK）的表达而扩增。UVB暴露后，皮肤Treg细胞扩增出独特的TCR库。此外，它们高度表达了一组独特的基因，这些基因富含“参与炎症反应的伤口愈合”和“神经肽信号通路”，正如Penk的高表达所表明的那样。我们发现，不仅在uvb扩增皮肤Treg （UVB-skin Treg）细胞中检测到PENK蛋白水平的表达，而且在体外皮肤外植试验中，来自Treg细胞的PENK衍生的神经肽蛋氨酸脑啡肽（Met-ENK）促进了表皮角质形成细胞的生长。值得注意的是，在体内伤口愈合试验中，uvb皮肤Treg细胞也促进了伤口愈合。此外，uvb皮肤Treg细胞产生双调节蛋白（AREG），在Treg介导的组织修复中起关键作用。PENK+ uvb -皮肤Treg细胞的独特功能鉴定为维持皮肤稳态提供了一种机制。
Significance Regulatory T (Treg) cells, expressing CD25 and Foxp3, constitute about 5 to 10% of peripheral CD4+ T cells and maintain immunological self-tolerance through the suppression of various immune responses. Here we found that skin Treg cells expanded by UVB exposure possess a unique TCR repertoire and a healing function. UVB-expanded skin Treg (UVB-skin Treg) cells expressed proenkephalin (PENK), an endogenous opioid precursor, and amphiregulin (AREG), the epidermal growth factor receptor ligand. The Treg-derived PENK and AREG promoted keratinocyte outgrowth in a skin explant assay. Moreover, UVB-expanded skin Treg cells played a key role in promoting wound healing in vivo. Our results provide a new implication in developing a therapy using PENK+UVB-skin Treg cells. Regulatory T (Treg) cells, expressing CD25 (interleukin-2 receptor α chain) and Foxp3 transcription factor, maintain immunological self-tolerance and suppress various immune responses. Here we report a feature of skin Treg cells expanded by ultraviolet B (UVB) exposure. We found that skin Treg cells possessing a healing function are expanded by UVB exposure with the expression of an endogenous opioid precursor, proenkephalin (PENK). Upon UVB exposure, skin Treg cells were expanded with a unique TCR repertoire. Also, they highly expressed a distinctive set of genes enriched in “wound healing involved in inflammatory responses” and the “neuropeptide signaling pathway,” as indicated by the high expression of Penk. We found that not only was PENK expression at the protein level detected in the UVB-expanded skin Treg (UVB-skin Treg) cells, but that a PENK-derived neuropeptide, methionine enkephalin (Met-ENK), from Treg cells promoted the outgrowth of epidermal keratinocytes in an ex vivo skin explant assay. Notably, UVB-skin Treg cells also promoted wound healing in an in vivo wound closure assay. In addition, UVB-skin Treg cells produced amphiregulin (AREG), which plays a key role in Treg-mediated tissue repair. Identification of a unique function of PENK+ UVB-skin Treg cells provides a mechanism for maintaining skin homeostasis.