Paracrine inhibition of GM-CSF signaling by human cytomegalovirus in monocytes differentiating to dendritic cells
Paracrine inhibition of GM-CSF signaling by human cytomegalovirus in monocytes differentiating to dendritic cells
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DOI：
10.1182/blood-2011-02-337956
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发表时间：
2011-12-22
期刊：
影响因子：
20.3
通讯作者：
Davrinche, Christian
中科院分区：
文献类型：
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作者：
Carlier, Jerome;Martin, Helene;Davrinche, Christian
原发性 HCMV 感染或病毒重新激活可能会导致免疫系统缺陷的宿主患上严重疾病。该病毒可以通过靶向树突状细胞（DC）功能来干扰先天免疫和适应性免疫。单核细胞是体内 DC 的前体 (MoDC)，是 HCMV 的主要目标；它们还可能含有潜伏病毒。由受感染的单核细胞 (CMV-MoDC) 产生的 DC 具有改变的表型和功能缺陷。我们已经证明CMV-MoDCs不会响应脂多糖刺激而分泌IL-12，不能摄取死细胞，不能诱导T(H)1分化或初始同种异体CD4(+) T细胞的增殖。我们发现整个 CMV-MoDC 群体中的 GM-CSF 信号传导受到损害，尽管只有一半的细胞被有效感染，并且 IL-6 分泌和细胞因子信号传导 3 诱导的抑制因子导致了这种旁观者效应。我们还表明，从病毒血症患者的单核细胞离体衍生的 MoDC 具有与 CMV-MoDC 相同的改变表型，包括 STAT5 磷酸化降低，表明 GM-CSF 信号传导存在缺陷。因此，我们描述了 HCMV 诱导的免疫抑制的新机制，表明感染如何扰乱 GM-CSF 依赖的生理过程，并提出了基于 GM-CSF 的治疗方法。 (血液.2011;118(26):6783-6792)
A primary HCMV infection or virus reactivation may cause severe disease in hosts with a deficient immune system. The virus can disturb both innate and adaptive immunity by targeting dendritic cell (DC) functions. Monocytes, the precursors of DCs in vivo (MoDCs), are the primary targets of HCMV; they can also harbor latent virus. The DCs generated from infected monocytes (CMV-MoDCs) have an altered phenotype and functional defects. We have shown that CMV-MoDCs do not secrete IL-12 in response to lipopolysaccharide stimulation, cannot ingest dead cells, induce T(H)1 differentiation, or the proliferation of naive allogeneic CD4(+) T cells. We found that the GM-CSF signaling in an entire population of CMV-MoDCs was impaired, although only half of the cells were productively infected, and that IL-6 secretion and suppressors of cytokine signaling 3 induction contributed to this bystander effect. We also showed that MoDCs derived ex vivo from monocytes of viremic patients had the same altered phenotype as CMV-MoDCs, including decreased STAT5 phosphorylation, indicating defective GM-CSF signaling. We have thus described a new mechanism of HCMV-induced immunosupression, indicated how infection may disturb both GM-CSF-dependent physiologic processes and proposed GM-CSF-based therapeutic approaches. (Blood.2011;118(26):6783-6792)