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皮内の制御性Ｔ細胞による皮膚免疫応答制御機構の解明

阐明皮内调节性T细胞控制皮肤免疫反应的机制

基本信息

批准号：
18F18096
负责人：
椛島健治
金额：
$ 1.47万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for JSPS Fellows
财政年份：
2018
资助国家：
日本
起止时间：
2018-04-25 至 2020-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18F18096/
关键词：
メラノサイト白斑神経 Regulatory T Cell Two photon microscopy Contact Hypersensitivity Dermal dendritic cell iSALT Regulatory T cell Skin inflammation Contact hypersensitivity 三次リンパ組織

项目摘要

The purpose of this research is to further understand regulatory T cell (Tregs) function in the skin during steady state and inflammatory conditions. Briefly, Treg behavior was visualized via a two-photon microscope in the ear skin of a live mouse using various Treg-specific fluorescent reporter mice during the contact hypersensitivity skin inflammatory response. Treg colocalization and interactions with dermal dendritic cells (DCs) was investigated via immunohistochemistry, and the combination of Treg and DC reporter mice.The Treg-Cre recombinase mouse (Foxp3-Cre) was also crossed with a R26-LSL-Gi-DREADD mouse to enable chemical inactivation of chemokine signaling to inhibit Treg migration in the skin. However issues with stochastic activity in the Foxp3-Cre mouse rendered the newly generated mouse unreliable as Gi-DREADD insertion was no longer Treg specific.While studying the relationship between sensory nerves and the immune system, we made a novel observation that chemical denervation with resiniferatoxin (RTX) induced hair loss in mice. Subsequent regrown hair in these bald areas were permenantly pigmented, suggesting a dysfunction in melanocyte stem cells of the affected hair follicles. As Tregs are known to reside around the hair follicle and support hair follicle cycling, we depleted Tregs prior to and during RTX-administration. Surprisingly, Treg-depleted mice had delayed hair regrowth, but regrown hair was still depigmented. This suggests that while Tregs may be important for hair follicle stem cells, they do not affect melanocyte stem cells in the follicle.

本研究的目的是进一步了解在稳态和炎症条件下皮肤中的调节性T细胞（TCFs）功能。简而言之，在接触性超敏反应皮肤炎症反应期间，使用各种Treg特异性荧光报告小鼠，通过双光子显微镜在活小鼠的耳皮肤中观察Treg行为。通过免疫组织化学以及Treg和DC报告小鼠的组合研究Treg与真皮树突状细胞（DCs）的共定位和相互作用。Treg-Cre重组酶小鼠（Foxp 3-Cre）还与R26-LSL-Gi-DREADD小鼠杂交以使得能够化学灭活趋化因子信号传导以抑制Treg在皮肤中的迁移。然而，Foxp 3-Cre小鼠中的随机活动问题使得新产生的小鼠不可靠，因为Gi-DREADD插入不再是Treg特异性的。在研究感觉神经和免疫系统之间的关系时，我们进行了一项新的观察，即用树脂毒素（RTX）化学去神经诱导小鼠脱发。随后在这些秃区再生的毛发是永久性色素沉着的，表明受影响毛囊的黑素细胞干细胞功能障碍。由于已知TdR存在于毛囊周围并支持毛囊循环，因此我们在RTX施用之前和期间耗尽TdR。令人惊讶的是，Treg耗尽的小鼠延迟了毛发再生，但再生的毛发仍然脱色。这表明，虽然TdR可能对毛囊干细胞很重要，但它们不会影响毛囊中的黑素细胞干细胞。