Liver Is Able to Activate Naive CD8+ T Cells with Dysfunctional Anti-Viral Activity in the Murine System
Liver Is Able to Activate Naive CD8+ T Cells with Dysfunctional Anti-Viral Activity in the Murine System
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DOI：
10.1371/journal.pone.0007619
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发表时间：
2009-10-30
期刊：
影响因子：
3.7
通讯作者：
Hahn, Young S.
中科院分区：
文献类型：
--
作者：
Lukens, John R.;Dolina, Joseph S.;Hahn, Young S.
由于持续暴露于细菌成分和非致病性食物抗原，肝脏具有明显的致耐受性。在肝脏环境中产生有效免疫应答所需的中枢免疫介质尚未完全阐明。在这篇报道中，我们证明了在腺病毒感染过程中，当次级淋巴组织中的T细胞被激活时，肝脏确实可以支持效应CD 8（+）T细胞。相反，当病毒抗原主要通过静脉内（IV）腺病毒感染递送至肝脏时，肝内CD 8（+）T细胞产生炎性细胞因子和裂解靶细胞的能力显著受损。此外，在IV腺病毒感染期间产生的肝内CD 8（+）T细胞表达升高水平的PD-1。值得注意的是，较低剂量的腺病毒感染不能挽救肝内CD 8（+）T细胞应答的受损效应功能。相反，肝内抗原识别限制了在CD 8（+）T细胞应答的引发和效应阶段产生有效的抗病毒应答，并解释了在IV腺病毒感染期间观察到的功能失调的CD 8 + T细胞应答。这些结果还暗示，操纵抗原递送将有助于设计针对持续性病毒感染的改进的疫苗接种策略。
The liver possesses distinct tolerogenic properties because of continuous exposure to bacterial constituents and nonpathogenic food antigen. The central immune mediators required for the generation of effective immune responses in the liver environment have not been fully elucidated. In this report, we demonstrate that the liver can indeed support effector CD8(+) T cells during adenovirus infection when the T cells are primed in secondary lymphoid tissues. In contrast, when viral antigen is delivered predominantly to the liver via intravenous (IV) adenovirus infection, intrahepatic CD8(+) T cells are significantly impaired in their ability to produce inflammatory cytokines and lyse target cells. Additionally, intrahepatic CD8(+) T cells generated during IV adenovirus infection express elevated levels of PD-1. Notably, lower doses of adenovirus infection do not rescue the impaired effector function of intrahepatic CD8(+) T cell responses. Instead, intrahepatic antigen recognition limits the generation of potent anti-viral responses at both priming and effector stages of the CD8(+) T cell response and accounts for the dysfunctional CD8+ T cell response observed during IV adenovirus infection. These results also implicate that manipulation of antigen delivery will facilitate the design of improved vaccination strategies to persistent viral infection.