Abstract：
Graft-versus-host disease (GVHD), manifesting as either acute (aGVHD) or chronic (cGVHD), presents significant life-threatening complications following allogeneic hematopoietic cell transplantation. Here, we investigated Friend virus leukemia integration 1 (Fli-1) in GVHD pathogenesis and validated Fli-1 as a therapeutic target. Using genetic approaches, we found that Fli-1 dynamically regulated different T cell subsets in allogeneic responses and pathogenicity in the development of aGVHD and cGVHD. Compared with homozygous Fli1-deficient or WT T cells, heterozygous Fli1-deficient T cells induced the mildest GVHD, as evidenced by the lowest Th1 and Th17 cell differentiation. Single-cell RNA-Seq analysis revealed that Fli-1 differentially regulated CD4+ and CD8+ T cell responses. Fli-1 promoted the transcription of Th1/Th17 pathways and T cell receptor-inducible (TCR-inducible) transcription factors in CD4+ T cells, while suppressing activation- and function-related gene pathways in CD8+ T cells. Importantly, a low dose of camptothecin, topotecan, or etoposide acted as a potent Fli-1 inhibitor and significantly attenuated GVHD severity, while preserving the graft-versus-leukemia (GVL) effect. This observation was extended to a xenograft model, in which GVHD was induced by human T cells. In conclusion, we provide evidence that Fli-1 plays a crucial role in alloreactive CD4+ T cell activation and differentiation and that targeting Fli-1 may be an attractive strategy for treating GVHD without compromising the GVL effect.
摘要：
移植物抗宿主病（GVHD），表现为急性（aGVHD）或慢性（cGVHD），在异基因造血细胞移植后出现严重危及生命的并发症。这里,我们研究了Friend病毒白血病整合1(Fli-1)在GVHD发病机制中的作用,并验证了Fli-1作为治疗靶点.使用遗传方法，我们发现Fli-1在aGVHD和cGVHD发展过程中动态调节不同T细胞亚群的异基因应答和致病性。与纯合Fli1缺陷型或WTT细胞相比，杂合子Fli1缺陷型T细胞诱导最温和的GVHD，如最低的Th1和Th17细胞分化所证明。单细胞RNA-Seq分析显示Fli-1差异调节CD4+和CD8+T细胞应答。Fli-1促进CD4+T细胞中Th1/Th17通路和T细胞受体诱导（TCR诱导）转录因子的转录,同时抑制CD8+T细胞中激活和功能相关的基因途径。重要的是,低剂量的喜树碱,托泊替康,或依托泊苷作为有效的Fli-1抑制剂，并显着减轻GVHD的严重程度，同时保留移植物抗白血病（GVL）作用。这一观察结果被扩展到异种移植模型，其中GVHD由人T细胞诱导。总之,我们提供的证据表明,Fli-1在同种反应性CD4+T细胞活化和分化中起关键作用,靶向Fli-1可能是治疗GVHD且不损害GVL效应的有吸引力的策略.
