An essential role for IFN-γ in regulation of alloreactive CD8 T cells following allogeneic hematopoietic cell transplantation
An essential role for IFN-γ in regulation of alloreactive CD8 T cells following allogeneic hematopoietic cell transplantation
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DOI：
10.1016/j.bbmt.2006.09.014
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发表时间：
2007-01-01
影响因子：
4.3
通讯作者：
Yang, Yong-Guang
中科院分区：
文献类型：
--
作者：
Asavaroengchai, Wannee;Wang, Hui;Yang, Yong-Guang
我们之前发现，与来自野生型（WT）供者的CD8 T细胞相比，来自ifn - γ基因敲除（GKO）供者的CD8 T细胞在完全mhc错配的菌株组合中诱导更严重的致死性GVHD。在本研究中，我们研究了ifn - γ在亲本-> F1 （B6 -> B6D2F1）异体HCT （alloo -HCT）模型中抑制GVHD的机制。在这个亲本-> F1单倍型错配的同种异体hct模型中，ifn - γ对GVHD具有很强的保护作用。接受GKO B6 cd4缺失脾细胞的辐照B6D2F1小鼠发生致死性GVHD，伴有严重的肺和肝损伤，而接受VVT B6供体类似细胞群的小鼠则长期存活。供体CD8细胞在供体细胞不能产生ifn - γ的异体受体中表现出快速激活、加速细胞分裂和减少/延迟激活诱导的细胞死亡。因此，GKO受体的活化/效应（即CD25（+）、CD62L（-）和CD44（高））供体CD8 T细胞的数量明显超过了WT受体。这些数据表明，ifn - γ通过抑制细胞分裂和促进细胞死亡负性调节CD8 T细胞反应，并提示阻断ifn - γ可增加同种异体hct患者GVHD的严重程度。(C) 2007年美国血液和骨髓移植学会。
We previously found that CD8 T cells from IFN-gamma gene knockout (GKO) donors induce more severe lethal GVHD compared with CD8 T cells from wild-type (WT) donors in fully MHC-mismatched strain combinations. In this study, we investigated the mechanisms by which IFN-gamma inhibits GVHD in a parent -> F1 (B6 -> B6D2F1) allogeneic HCT (allo-HCT) model. IFN-gamma was strongly protective against GVHD in this parent -> F1 haplotype-mismatched allo-HCT model. Irradiated B6D2F1 mice that received GKO B6 CD4-depleted splenocytes developed lethal GVHD with severe lung and liver injury, whereas those receiving a similar cell population from VVT B6 donors survived long term. Donor CD8 cells showed rapid activation, accelerated cell division, and reduced/delayed activation-induced cell death in allogeneic recipients in which donor cells were incapable of producing IFN-gamma. In consequence, the numbers of activated/effector (ie, CD25(+), CD62L(-), and CD44(high)) donor CD8 T cells in the recipients of GKO allo-HCT significantly exceeded those in mice receiving WT allo-HCT. These data show that IFN-gamma negatively regulates the CD8 T cell response by inhibiting cell division and promoting cell death and suggest that blockade of IFN-gamma could augment the severity of GVHD in patients undergoing allo-HCT. (C) 2007 American Society for Blood and Marrow Transplantation.