CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease
CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease
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DOI：
10.1182/blood-2012-06-435735
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发表时间：
2013-08-01
期刊：
影响因子：
20.3
通讯作者：
Serody, Jonathan S.
中科院分区：
文献类型：
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作者：
Coghill, James M.;Fowler, Kenneth A.;Serody, Jonathan S.
供体调节性T细胞（T-CTL）的输注已被用于预防小鼠中的急性移植物抗宿主病（GVHD），并在1期临床试验中显示出希望。以前的工作表明，早期T-reg迁移到淋巴组织是重要的GVHD预防。然而，目前尚不清楚T-BMPs如何以及在何处纵向影响GVHD。为了更好地了解它们的作用机制，我们在小鼠干细胞移植模型中研究了2种T-reg相关趋化因子受体。CC趋化因子受体（CCR）4在移植环境中检测供体T-reg功能。然而，由于细胞死亡增加，供体T-cell缺乏CCR 8（CCR 8（-/-）），其预防致死性GVHD的能力严重受损。CCR 8刺激本身不能拯救T-lymphocyte免于凋亡。相反，CCR 8通过促进与树突状细胞的关键相互作用来增强T-reg的存活。在体内，供体骨髓来源的CD 11 c（+）抗原呈递细胞（APC）对促进移植后供体T-reg的维持很重要。相反，宿主CD 11 c（+）APC似乎不适合供体T-T细胞的早期激活和扩增。总的来说，我们的数据表明，持续的供体T-reg的存在是至关重要的，他们的有益特性，他们的生存取决于CCR 8和供体，而不是宿主CD 11 c（+）APC。
The infusion of donor regulatory T cells (T-regs) has been used to prevent acute graft-versus-host disease (GVHD) in mice and has shown promise in phase 1 clinical trials. Previous work suggested that early T-reg migration into lymphoid tissue was important for GVHD prevention. However, it is unclear how and where T-regs function longitudinally to affect GVHD. To better understand their mechanism of action, we studied 2 T-reg-associated chemokine receptors in murine stem cell transplant models. CC chemokine receptor (CCR) 4 was dispensable for donor T-reg function in the transplant setting. Donor T-regs lacking CCR8 (CCR8(-/-)), however, were severely impaired in their ability to prevent lethal GVHD because of increased cell death. By itself, CCR8 stimulation was unable to rescue T-regs from apoptosis. Instead, CCR8 potentiated T-reg survival by promoting critical interactions with dendritic cells. In vivo, donor bone marrow-derived CD11c(+) antigen-presenting cells (APCs) were important for promoting donor T-reg maintenance after transplant. In contrast, host CD11c(+) APCs appeared to be dispensable for early activation and expansion of donor T-regs. Collectively, our data indicate that a sustained donor T-reg presence is critical for their beneficial properties, and that their survival depends on CCR8 and donor but not host CD11c(+) APCs.