Foxo1/IL-7R/GIMAP4轴调控常驻记忆性T细胞长期存活参与银屑病复发及机制研究

The recurrence is the difficulty of psoriasis treatment. The results from us and other research groups show that Tissue-Resident Memory T cells (TRM) are involved in the recurrence of psoriasis. The characteristic long-survival of TRM in the psoriatic lesions is vital for the recurrence, but the molecular mechanism is unknown. It has been demonstrated that Foxo1, IL-7R and GIMAP4 are related to the conditions of stress, metabolism, and immunity. Foxo1, IL-7R and GIMAP4 are involved in the regulation of T cell survival. And they are changed with the outcomes of psoriasis according to the recent analysis of RNA-Seq. We found that knock-out of GIMAP4 could cause the defect of T cell survival. Our other results suggest that IL-7R is the downstream of Foxo1, and it can up-regulate GIMAP4 expression and maintain the survival. We propose that the axis of Foxo1/IL-7R/GIMAP4 regulates the survival of TRM in the microenvironment of psoriatic lesions, based on the previous studies. We plan to further analyze the important roles of TRM in the recurrence of psoriasis on the levels of psoriatic lesional immune cells, cell lines, and animal modes. Next, we want to demonstrate the involvements of Foxo1, IL-7R, and GIMAP4 in the recurrence of psoriasis and the survival of TRM in psoriatic lesions. Last, we want to analyze and illuminate the mechanism of Foxo1/IL-7R/GIMAP4 axis in the survival of TRM in psoriatic lesion microenvironment. Our study will help to find new intervention target for the recurrence of psoriasis, and to establish the regulatory mechanism of TRM in autoimmune disorders.

银屑病复发是治疗难点。我们和其他组的研究表明，皮损常驻记忆性T细胞（Tissue-Resident Memory T cells, TRM）长期存活参与银屑病复发，但其长期存活的机制不清。Foxo1、IL-7R和GIMAP4与应激、代谢和免疫相关，均参与T细胞生存调控，且RNA-Seq基因表达谱显示它们在银屑病转归中显著改变。我们前期发现，GIMAP4敲除后T细胞生存显著降低，同时结果提示IL-7R是Foxo1下游分子，可上调GIMAP4，维持TRM存活。结合前期基础，我们提出Foxo1/IL-7R/GIMAP4轴调控银屑病皮损TRM长期存活的分子机制。拟在TRM、细胞系和动物模型水平，进一步明确TRM长期存活参与银屑病复发，并分析Foxo1、IL-7R和GIMAP4与复发的密切关系，证实并明确该轴对TRM长期存活的调控和分子机制，为防治银屑病复发提供靶点，为阐明TRM调控机制奠定基础。

银屑病的复发是临床治疗难点之一。我们和其他组的研究表明，皮损常驻记忆性T细胞（Tissue-Resident Memory T cells, TRM）的长期存活参与银屑病的复发，但其长期存活的机制尚不完全清楚。PI3K-Akt-FOXO1、γ链细胞因子（IL-7和IL-15）等均与应激、代谢和免疫相关，参与T细胞生存调控，且前期RNA芯片基因表达谱显示它们在银屑病转归中显著改变。结合前期基础，我们提出银屑病皮损微环境中γ链细胞因子调控银屑病皮损TRM长期存活的分子机制。拟在TRM、细胞系和动物模型水平，进一步明确恢复期皮损TRM长期存活及致病功能的维持，并分析Foxo1、IL-7/IL-15、Akt各亚型和GIMAP4与TRM存活的密切关系，证实并明确对TRM长期存活的调控轴和分子机制。我们发现CD8+CD69+ TRM细胞在银屑病恢复期皮损中仍大量存在，且具有分泌IL-17A等细胞因子的能力。皮损角质形成细胞和成纤维细胞激活后分泌的γ链细胞因子可通过磷酸化Akt3亚型-FOXO1，进而调控CD69和GIMAP4的表达，从而实现对TRM细胞长期存活的调控。研究结果可为有效防治银屑病的复发提供新靶点，为阐明TRM调控机制奠定基础。