Cyclooxygenase-2 in mucosal DC mediates induction of regulatory T cells in the intestine through suppression of IL-4
Cyclooxygenase-2 in mucosal DC mediates induction of regulatory T cells in the intestine through suppression of IL-4
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DOI：
10.1038/mi.2009.2
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发表时间：
2009-05-01
影响因子：
8
通讯作者：
Samsom, J. N.
中科院分区：
文献类型：
--
作者：
Broere, F.;du Pre, M. F.;Samsom, J. N.
口服摄入蛋白质通过诱导肠系膜淋巴结（MLN）中的调节性T细胞（Tr细胞）导致耐受。在此，我们发现，在MLN中，体内抑制环氧化酶-2（考克斯-2）可抑制口服耐受，并与产生白细胞介素（IL）-4的T细胞分化增强和Foxp 3（+）Tr细胞分化减少有关。结果，这些分化的粘膜T细胞的功能抑制能力丧失。IL-4与耐受性丧失有因果关系，因为在考克斯-2抑制期间用抗IL-4抗体治疗小鼠恢复了耐受性。MLN中的树突状细胞（DC）差异表达考克斯-2，还原实验表明，选择性抑制这些细胞中的酶可抑制Foxp 3（+）Tr-细胞的体外分化。重要的是，MLN-DC中考克斯-2的抑制引起T细胞的加塔-3表达增加和IL-4释放增加，这与受损的Tr-细胞分化直接相关。这些数据提供了重要的见解，在肠道中从头TR细胞诱导和耐受的驱动机制。
Oral intake of protein leads to tolerance through the induction of regulatory T cells (Tr cells) in mesenteric lymph nodes (MLNs). Here we show that the inhibition of cyclooxygenase-2 (COX-2) in vivo suppressed oral tolerance and was associated with enhanced differentiation of interleukin (IL)-4-producing T cells and reduced Foxp3(+) Tr-cell differentiation in MLN. As a result, the functional suppressive capacity of these differentiated mucosal T cells was lost. IL-4 was causally related to loss of tolerance as treatment of mice with anti-IL-4 antibodies during COX-2 inhibition restored tolerance. Dendritic cells (DCs) in the MLN differentially expressed COX-2 and reductionist experiments revealed that selective inhibition of the enzyme in these cells inhibited Foxp3(+) Tr-cell differentiation in vitro. Importantly, the inhibition of COX-2 in MLN-DC caused increased GATA-3 expression and enhanced IL-4 release by T cells, which was directly related to impaired Tr-cell differentiation. These data provide crucial insights into the mechanisms driving de novo Tr-cell induction and tolerance in the intestine.