Regulatory T cells control the CD8 adaptive immune response at the time of ductal obstruction in experimental biliary atresia.
Regulatory T cells control the CD8 adaptive immune response at the time of ductal obstruction in experimental biliary atresia.
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DOI：
10.1002/hep.25662
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发表时间：
2012-07
期刊：
影响因子：
13.5
通讯作者：
Miethke, Alexander G.
中科院分区：
文献类型：
--
作者：
Lages, Celine S.;Simmons, Julia;Chougnet, Claire A.;Miethke, Alexander G.
CD8 T 淋巴细胞是人和恒河猴轮状病毒 (RRV) 诱导的实验性胆道闭锁 (BA) 胆管细胞损伤的效应细胞。在这里，我们假设新生儿 CD25+CD4+ 调节性 T 细胞 (Treg) 缺陷导致 BA 中肝 T 淋巴细胞的异常激活。我们发现，与没有过继转移的年龄匹配的感染对照相比，在接种 RRV 之前，过继转移总 CD4 细胞，但不减少 CD25 耗尽的 CD4 细胞，可减少感染后 7 天 (dpi) 的 CD8 细胞扩增、血浆胆红素水平、导管炎症和胆管上皮损伤。在寻找机制的过程中，我们发现，在与感染 RRV 的肝树突状细胞 (DC) 共培养时，经多克隆刺激后，幼稚 CD8 细胞体外产生的 IFNγ 增强，但与未感染小鼠的 DC 共培养则不然，这与 CD11b+ 骨髓 (m)DC 比例增加以及共刺激分子 CD86 上调相关。 RRV 引发的 DC。此外，DC依赖性T淋巴细胞活化被抗CD86抗体以剂量依赖性方式阻断。重要的是，在体外，mDC 上的 CD86 表达被 Tregs 下调，并且含有 Treg 的 CD4 细胞的过继转移在 7dpi 时降低了肝 mDC 上 CD86 的表达。相反，在对实验性 BA 具有抗性的小鼠中，RRV 接种后 12dpi 时，CD25+ 细胞耗竭加剧了胆管损伤，因为与未耗竭的感染对照相比，血浆胆红素水平升高了 20 倍以上。 Treg 缺失小鼠对肝胆损伤的易感性增加与肝 CD8 扩张和肝 DC 刺激能力增强有关。 BA 中驱动胆道梗阻的肝 T 淋巴细胞的激活由 mDC 通过 CD86 依赖性共刺激进行调节，并且容易受到 Tregs 的抑制。
CD8 T-lymphocytes are effector cells of cholangiocyte injury in human and in rhesus rotavirus (RRV) induced experimental biliary atresia (BA). Here, we hypothesize that neonatal deficiency in CD25+CD4+ regulatory T cells (Tregs) leads to aberrant activation of hepatic T-lymphocytes in BA. We found that adoptive transfer of total CD4 cells, but not of CD25-depleted CD4 cells, prior to RRV inoculation reduced expansion of CD8 cells, plasma bilirubin levels, ductal inflammation and bile duct epithelial injury at 7 days postinfection (dpi) compared with age-matched infected controls without adoptive transfer. Searching for mechanisms, we found that in vitro production of IFNγ by naïve CD8 cells upon polyclonal stimulation was enhanced in co-culture with hepatic dendritic cells (DC)s from RRV infected, but not with DCs from non-infected mice which was correlated with an increased proportion of CD11b+ myeloid (m)DCs and up-regulation of the costimulatory molecule CD86 on RRV-primed DCs. Furthermore, DC-dependent T-lymphocyte activation was blocked by anti-CD86 antibody in dose dependent fashion. Importantly, expression of CD86 on mDCs was down-regulated by Tregs in vitro, and adoptive transfer of Treg-containing CD4 cells decreased expression of CD86 on hepatic mDCs at 7dpi. On the contrary, in mice resistant to experimental BA, CD25+ cell depletion aggravated bile duct injury at 12dpi after RRV inoculation, as plasma bilirubin levels were elevated by >20fold compared with non-depleted infected controls. Increased susceptibility to hepatobiliary injury in Treg-depleted mice was linked to hepatic CD8 expansion and enhanced stimulatory capacity of hepatic DCs. Activation of hepatic T-lymphocytes driving biliary obstruction in BA is regulated by mDCs via CD86-dependent costimulation and is susceptible to inhibition by Tregs.
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影响因子：
17.1
作者：
Saxena V;Shivakumar P;Sabla G;Mourya R;Chougnet C;Bezerra JA
通讯作者：
Bezerra JA
影响因子：
29.4
作者：
Shivakumar, Pranavkumar;Sabla, Gregg;Bezerra, Jorge A.
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Bezerra, Jorge A.
影响因子：
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Regnault, A;Lankar, D;Lacabanne, V;Rodriguez, A;Thery, C;Rescigno, M;Saito, T;Verbeek, S;Bonnerot, C;Ricciardi-Castagnoli, P;Amigorena, S
通讯作者：
Amigorena, S
影响因子：
25.7
作者：
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通讯作者：
Chougnet CA
影响因子：
4.4
作者：
Haribhai, Dipica;Lin, Wen;Chatila, Talal A.
通讯作者：
Chatila, Talal A.