T细胞耗竭在aGVHD与GVL分离中的作用

急性移植物抗宿主病（aGVHD）和移植物抗白血病效应（GVL）可分离性较弱是目前制约异基因造血干细胞移植（allo-HSCT）疗效的瓶颈，主要原因之一是我们对T细胞在受者体内长期发育和转归情况了解较少。T细胞耗竭现象是近年免疫学领域的新发现，在调节T细胞长期发育和发挥效应中起重要作用。我们前期研究发现CD4+和CD8+ T细胞耗竭在aGVHD和GVL中发挥不同作用，提示靶向调节T细胞耗竭具有分离aGVHD和GVL的潜力。本项目拟运用条件性基因敲除小鼠，深入探索allo-HSCT中T细胞耗竭的发生规律，明确各T细胞亚群耗竭对aGVHD和GVL的影响，研究干预Klf4和Irf4表达靶向调节T细胞耗竭在分离aGVHD和GVL中的作用。如获成功，则有望解析调控T细胞在受者体内长期发育和转归的新机制，也可为allo-HSCT和异基因CAR-T等过继免疫治疗后aGVHD和GVL分离提供新思路和新靶标。

Donor T-cell mediates both acute graft-versus-host disease (GVHD) and graft-versus-leukemia/lymphoma (GVL) response after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Key to improve outcome of allo-HSCT is developing our understanding of the biological differences of aGVHD and GVL response, which unfortunately is poorly understood up to date. Dissecting aGVHD and GVL depends on a well understanding of long term development and maintenance of donor T cells. T-cell exhaustion is a terminal differentiation state of T-cell development, which plays an important role in regulating long term survival and effect of T cells. We recently found that blocking exhaustion of CD4-positive and CD8-positive T cells showed significant but different impact on pathogenesis of aGVHD and GVL response, which suggests targeting exhaustion of different T-cell subsets has a potential in separation of aGVHD and GVL response. Based on the role of exhausted T-cell and our previous findings, we interrogate how exhausted T cells develop from effector T cells following allo-HSCT. In this study, we plan to explore the role of exhaustion of different T-cell subsets in aGVHD and GVL. Selective regulation of exhaustion of different T-cell subsets would be achieved using conditional knockout mice. We plan to further study the impact of regulation of T-cell exhaustion on separation of aGVHD and GVL. Our study might uncover the mechanism governing long term development and maintenance of donor T cells, which would provide new strategy in dissecting aGVHD and GVL after adoptive transfer therapy such as allo-HSCT and allogeneic CAR-T treatment.