MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice
MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice
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DOI：
10.1182/blood-2015-02-627356
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发表时间：
2015-09-10
期刊：
影响因子：
20.3
通讯作者：
Yu, Xue-Zhong
中科院分区：
文献类型：
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作者：
Wu, Yongxia;Heinrichs, Jessica;Yu, Xue-Zhong
microRNA（miRs）在协调免疫应答的许多方面发挥重要作用。miR-17-92簇编码6个miR，包括17、18 a、19 a、20 a、19 b-1和92-1，是这些miR中表征最好的。miR-17-92簇已被证明可调节多种免疫应答，包括感染、肿瘤和自身免疫，但该簇在T细胞对同种异体抗原应答中的作用尚未被探索。通过使用主要组织相容性复合体（MHC）匹配，不匹配，和单倍体相合的小鼠异基因骨髓移植（allo-BMT）模型，我们证明了供体T细胞上的miR-17-92的表达是诱导移植物抗宿主病（GVHD），但移植物抗白血病（GVL）的效果是必要的。miR-17-92在促进CD 4 T细胞活化、增殖、存活和Th 1分化中起主要作用，同时抑制Th 2和iTreg分化。或者，miR-17-92可以促进CD 8 T细胞向GVHD靶器官的迁移，但对CD 8 T细胞增殖、存活或细胞溶解功能的影响最小，这可能有助于由缺乏miR-17-92的T细胞介导的保留的GVL效应。此外，我们评估了一种翻译方法，发现系统性给药Eschomir阻断miR-17或miR-19 b在这种光泽显着抑制同种异体反应性T细胞扩增和干扰素-γ（IFN-γ）的生产，并延长受GVHD折磨的受者的生存期，同时保留GVL效应。总之，目前的工作提供了强有力的理论基础，并证明了靶向miR-17-92用于控制GVHD同时在allo-BMT后保留GVL活性的可行性。
MicroRNAs (miRs) play important roles in orchestrating many aspects of the immune response. The miR-17-92 cluster, which encodes 6miRs including 17, 18a, 19a, 20a, 19b-1, and 92-1, is among the best characterized of these miRs. The miR-17-92 cluster has been shown to regulate a variety of immune responses including infection, tumor, and autoimmunity, but the role of this cluster in T-cell response to alloantigens has not been previously explored. By using major histocompatibility complex (MHC)-matched, -mismatched, and haploidentical murine models of allogeneic bone marrow transplantation (allo-BMT), we demonstrate that the expression of miR-17-92 on donor T cells is essential for the induction of graft-versus-host disease (GVHD), but dispensable for the graft-versus-leukemia (GVL) effect. The miR-17-92 plays a major role in promoting CD4 T-cell activation, proliferation, survival, and Th1 differentiation, while inhibiting Th2 and iTreg differentiation. Alternatively, miR-17-92 may promote migration of CD8 T cells to GVHD target organs, but has minimal impact on CD8 T-cell proliferation, survival, or cytolytic function, which could contribute to the preserved GVL effect mediated by T cells deficient for miR-17-92. Furthermore, we evaluated a translational approach and found that systemic administration of antagomir to blockmiR-17 ormiR-19b in this luster significantly inhibited alloreactive T-cell expansion and interferon-gamma (IFN gamma) production, and prolonged the survival in recipients afflicted with GVHD while preserving the GVL effect. Taken together, the current work provides a strong rationale and demonstrates the feasibility to target miR-17-92 for the control of GVHD while preserving GVL activity after allo-BMT.