组蛋白乙酰化/去乙酰化表观调控效应型记忆CD8+T细胞及其防治GVHD的研究

Graft-versus-host disease (GVHD) is a major barrier for successful allogeneic hematopoietic stem cell transplantation. Allogeneic memory effector CD8+ T cells (TEM), which mediate host tissue injury, and dendritic cells, which initiate allogeneic T cell responses, play essential roles in the development of the disease. Epigenetic modification is known to be involved in the activation, differentiation and effector function of T cells. In the pilot study, we found for the first time that AR42, which is a specific histone deacetylase inhibitor, significantly decreased TEM and reduced GVHD in experimental mice. In addition, we found that treatment of dendritic cells with AR42 resulted in the generation of dendritic cells with enhanced suppressive effects on TEM. These findings suggest that modulation of TEM and dendritic cells by targeting histone acetylation and deactylation have beneficial effects on reducing GVHD. Building on these results, we propose to study the regulatory effects of histone acetylation and deactylation on differentiation, proliferation, homeostasis and effector function of TEM, dissect the relationships among histone acetylation and deactylation, Wnt signaling pathway, and activation of dendritic cells. Our study will provide new insights into the essential roles of histone acetylation and deactylation in the pathogenesis of GVHD and illuminate the underlying mechanisms. Results from these studies, if accomplished, will lead to new strategies to treat GVHD by epigenetic modulation of allogeneic T cell responses.

移植物抗宿主病（GVHD）已成为异体骨髓/造血干细胞移植的主要限制因素，而异体效应型记忆CD8+ T细胞（TEM）是造成GVHD损伤的关键因素。近年研究表明表观修饰是调控免疫细胞活化、分化及效应功能的重要形式。项目组预初实验首先发现新型组蛋白去乙酰化酶抑制剂AR42可抑制受者体内TEM细胞，并有效缓解GVHD，这一效应也可能与AR42 调抑树突状细胞（DC）作用有关，提示组蛋白乙酰化/去乙酰化表观修饰可调控TEM，并是防治GVHD的有效途径。在此基础上，拟进一步研究组蛋白乙酰化/去乙酰化表观修饰对TEM细胞分化、增殖、稳态维持及效应功能的调控，阐释其与Wnt/TCF-1信号通路和/或DC刺激信号等有关的细胞和分子机制。以此揭示表观调控在GVHD发生发展中的作用及机制，建立以组蛋白乙酰化/去乙酰化表观修饰调控TEM细胞为手段的GVHD防治新策略。

移植物抗宿主病（GVHD）已成为异体骨髓/造血干细胞移植的主要限制因素，而异体效应型记忆CD8+T细胞（TEM）是造成GVHD损伤的关键因素。近年研究表明表观修饰是调控免疫细胞活化、分化及效应功能的重要形式。我们的研究表明，新型组蛋白去乙酰化酶抑制剂AR42能够抑制异体反应性CD8+T细胞的活化、增殖、迁移及其效应功能，并诱导其凋亡，与此同时，可促进受者体内DC中IDO表达水平的上升，从而间接抑制异体反应性CD8+T细胞的效应功能，从而有效缓解GVHD。在此基础上，我们利用质谱及免疫共沉淀分析发现，Hsp90可与Ezh2直接结合并维持Ezh2的蛋白稳定性。进一步利用Hsp90的抑制剂AUY922并结合GVHD小鼠疾病模型，我们的研究表明，AUY922药物处理可有效抑制异体反应性T细胞的活化、增殖及其效应功能的发挥，并促进异体反应性T细胞的凋亡，缓解GVHD发生发展。同时，体内外研究证明，AUY922对T细胞的作用依赖于其对Ezh2蛋白表达的抑制。另外，体内AUY922防治处理并不影响移植后的移植物抗白血病效应（GVL）以及受者的免疫重建能力。我们的发现为表观遗传分子调控异体反应性CD8+T细胞拓展了新思路，为临床GVHD的治疗提供了新的策略与潜在靶点。