KLF2对T细胞迁移的双向调控在GVHD与GVL分离中的作用及机制

如何有效分离移植物抗宿主病（GVHD）与移植物抗白血病（GVL）效应是异基因造血干细胞移植亟需解决的难题。传统上抑制T细胞功能的方法极易损伤GVL效应。根据GVHD和GVL靶器官不同，促使供者T细胞在淋巴血液循环，减少其向GVHD靶器官浸润，可能是两者分离的有效策略。CXCR3是促T细胞迁移到GVHD多个靶器官最早表达的趋化因子受体，CCR7是T细胞归巢实现GVL的关键受体。虽然异基因造血干细胞移植中已有CXCR3和CCR7的相关研究，但靶向两者调控T细胞的合理分布却未见报道。我们前期发现KLF2可上调CCR7而下调CXCR3，减轻GVHD严重程度。本项目拟利用基因或药物干预手段调控供者T细胞KLF2表达，明确KLF2对小鼠移植后GVHD和GVL分离的作用及对T细胞迁移的影响，探索KLF2与CXCR3、CCR7作用位点及机制。如期完成将为实现GVHD和GVL的分离提供新的理论依据。

How to effectively separate graft-versus-host disease (GVHD) and graft-versus-Leukemia (GVL) effects after allogeneic haematopoietic stem cell transplantation is a major challenge. The traditional ways to inhibit functions of T cells are easy to damage GVL effect. Based on the different target organs of GVHD and GVL, increase of donor T cells in lymphatic or hematologic systems as well as decrease of T cells in GVHD target organs might be a effective strategy to separate them. CXCR3 as the earliest expressed chemokine receptor induces T cell trafficking to several GVHD target organs, while CCR7 contributed to GVL effect leads to T cell homing. Although studies have shown the role of CXCR3 and CCR7 in allogeneic haematopoietic stem cell transplantation, there is no report about combined regulation of them to make T cell physiological distribution. In our previous study, we found that KLF2 could up-regulate CCR7 level whereas down-regulate the expression of CXCR3, and GVHD severity were reduced. In the present study, we plan to modify KLF2 levels of donor T cells by genetic and drug strategies, and clear the role of KLF2 in the separation of GVHD and GVL in transplanted mouse model. Furthermore, the regulatory effect of KLF2 on T cell migration, the interaction region and mechanism of KLF2 and CXCR3 or CCR7 will be explored. If succeed, it will provide precious information and new strategies to separate GVHD and GVL.