Identification of stem cell transcriptional programs normally expressed in embryonic and neural stem cells in alloreactive CD8+ T cells mediating graft-versus-host disease.
Identification of stem cell transcriptional programs normally expressed in embryonic and neural stem cells in alloreactive CD8+ T cells mediating graft-versus-host disease.
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DOI：
10.1016/j.bbmt.2010.01.012
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发表时间：
2010-06
影响因子：
4.3
通讯作者：
Zhang, Yi
中科院分区：
文献类型：
--
作者：
Kato, Koji;Cui, Shuaiying;Kuick, Rork;Mineishi, Shin;Hexner, Elizabeth;Ferrara, James L. M.;Emerson, Stephen G.;Zhang, Yi
移植物抗宿主病 (GVHD) 是同种异体造血干细胞移植后危及生命的并发症，其标志是持续同种异体效应 T 细胞 (TE) 介导的宿主组织细胞病变。然而，GVHD 期间调节同种异体反应性 TE 持续性的机制仍然很大程度上未知。使用小鼠 GVHD 模型，我们证明当过继转移到受辐射的次生同源受体小鼠中时，同种异体反应性 CD8+ TE 在体内迅速减少。相比之下，尽管同种异体反应性CD8+ TE在长期暴露于同种异体抗原时经历大量细胞凋亡，但它们在二次同种异体受体体内增殖、持续存在并引起严重的GVHD。因此，同种异体反应性 CD8+ TE 的持续增殖（由同种异体抗原刺激而不是稳态因子介导）对于维持其持久性至关重要。基因表达谱分析表明，虽然同种异体反应性 CD8+ TE 增加了与细胞死亡相关的基因的表达，但它们激活了一组通常在胚胎和神经干细胞中表达的干细胞基因。大多数干细胞基因与细胞周期调控、DNA 复制、染色质修饰和转录有关。其中一个基因 Ezh2 编码染色质修饰酶，在 CD8+ TE 中大量表达。沉默 Ezh2 显着降低同种抗原激活的 CD8+ T 细胞的增殖。因此，这些研究结果表明，一组干细胞基因可以在维持终末分化同种异体反应性 CD8+ TE 中发挥重要作用，并且可能是控制 GVHD 的治疗靶点。
A hallmark of graft-versus-host-disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is the cytopathic injury of host tissues mediated by persistent alloreactive effector T cells (TE). However, the mechanisms that regulate the persistence of alloreactive TE during GVHD remain largely unknown. Using mouse GVHD models, we demonstrate that alloreactive CD8+ TE rapidly diminished in vivo when adoptively transferred into irradiated secondary congenic recipient mice. In contrast, although alloreactive CD8+ TE underwent massive apoptosis upon chronic exposure to alloantigens, they proliferated in vivo in secondary allogeneic recipients, persisted and caused severe GVHD. Thus, the continuous proliferation of alloreactive CD8+ TE, which is mediated by alloantigenic stimuli rather than homeostatic factors, is critical to maintaining their persistence. Gene expression profile analysis revealed that while alloreactive CD8+ TE increased the expression of genes associated with cell death, they activated a group of stem cell genes normally expressed in embryonic and neural stem cells. Most of these stem cell genes are associated with cell cycle regulation, DNA replication, chromatin modification and transcription. One of these genes, Ezh2, which encodes a chromatin modifying enzyme, was abundantly expressed in CD8+ TE. Silencing Ezh2 significantly reduced the proliferation of alloantigen-activated CD8+ T cells. Thus, these findings identify that a group of stem cell genes could play important roles in sustaining terminally differentiated alloreactive CD8+ TE and may be therapeutic targets for controlling GVHD.
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影响因子：
64.5
作者：
Kaech, SM;Hemby, S;Ahmed, R
通讯作者：
Ahmed, R
DOI：
10.1084/jem.20081633
发表时间：
2009-02-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Haniffa M;Ginhoux F;Wang XN;Bigley V;Abel M;Dimmick I;Bullock S;Grisotto M;Booth T;Taub P;Hilkens C;Merad M;Collin M
通讯作者：
Collin M
影响因子：
21.3
作者：
Hansen, Klaus H.;Bracken, Adrian P.;Helin, Kristian
通讯作者：
Helin, Kristian
影响因子：
64.8
作者：
Belkaid, Y;Piccirillo, CA;Sacks, DL
通讯作者：
Sacks, DL
影响因子：
4.8
作者：
Board, PG;Coggan, M;Pandit, J
通讯作者：
Pandit, J