Post-natal paucity of regulatory T cells and control of NK cell activation in experimental biliary atresia.
Post-natal paucity of regulatory T cells and control of NK cell activation in experimental biliary atresia.
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DOI：
10.1016/j.jhep.2009.12.027
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发表时间：
2010-05
影响因子：
25.7
通讯作者：
Chougnet CA
中科院分区：
文献类型：
--
作者：
Miethke AG;Saxena V;Shivakumar P;Sabla GE;Simmons J;Chougnet CA
虽然最近的研究已经确定了T细胞和NK细胞在胆道闭锁（BA）的发病机制中的重要作用，但对胆管损伤的易感性仅限于新生儿期的机制尚不清楚。我们通过流式细胞术在两组新生小鼠中用恒河猴轮状病毒（RRV）在生命的第7天（无导管损伤）或第1天（导致BA）激发肝脏调节性T细胞（TCRs），在共培养试验中确定与效应细胞的功能相互作用，并检查过继转移CD 4+细胞对BA表型的影响。虽然第7天RRV感染在3天内使肝TCLs（Foxp 3 + CD 4 + CD 25+）增加10倍，但在第1天感染后的该时间点没有发生TCLs增加。在体外，TcR有效抑制肝脏树突状细胞对NK细胞的激活，并减少RRV感染后促炎细胞因子（包括TNFα和IL-15）的产生。在体内，在RRV接种之前过继转移CD 4+细胞导致存活率增加、体重增加改善、肝脏NK细胞群体减少和供体THBG在肝脏中的持续存在。1)在围产期RRV感染后早期，肝脏缺乏Treg 2; 2）Treg 2在体外抑制幼稚NK细胞的DC依赖性活化，并且含有Treg的CD 4+细胞在体内抑制肝脏NK细胞扩增。因此，出生后缺乏TdR可能是一个关键因素，允许肝DCs在新生儿胆管损伤开始期间在NK细胞活化中不受阻碍地发挥作用。
Although recent studies have identified important roles for T and NK cells in the pathogenesis of biliary atresia (BA), the mechanisms by which susceptibility to bile duct injury is restricted to the neonatal period are unknown. We characterised hepatic regulatory T cells (Tregs) by flow cytometry in two groups of neonatal mice challenged with rhesus rotavirus (RRV) at day 7 (no ductal injury) or day 1 of life (resulting in BA), determined the functional interaction with effector cells in co-culture assays, and examined the effect of adoptive transfer of CD4+ cells on the BA phenotype. While day 7 RRV infection increased hepatic Tregs (Foxp3+ CD4+ CD25+) by 10-fold within 3 days, no increase in Tregs occurred at this time point following infection on day 1. In vitro, Tregs effectively suppressed NK cell activation by hepatic dendritic cells and decreased the production of pro-inflammatory cytokines, including TNFα and IL-15, following RRV infection. In vivo, adoptive transfer of CD4+ cells prior to RRV inoculation led to increased survival, improved weight gain, decreased population of hepatic NK cells, and persistence of donor Tregs in the liver. 1) The liver is devoid of Tregs early after perinatal RRV infection; 2) Tregs suppress DC-dependent activation of naive NK cells in vitro, and Treg-containing CD4+ cells inhibit hepatic NK cell expansion in vivo. Thus, the postnatal absence of Tregs may be a key factor that allows hepatic DCs to act unopposed in NK cell activation during the initiation of neonatal bile duct injury.
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