Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells
Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells
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DOI：
10.1136/gut.2008.175166
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发表时间：
2009-11-01
期刊：
影响因子：
24.5
通讯作者：
Rescigno, M.
中科院分区：
文献类型：
--
作者：
Iliev, I. D.;Spadoni, I.;Rescigno, M.
目的：在小鼠中，表达CD103的肠道树突状细胞(DC)亚群驱动调节性T(T-reg)细胞的发育。此外，最近有研究表明，人类肠道上皮细胞(IECS)和DC之间的相互作用有助于通过诱导非炎症性DC来维持肠道免疫稳态。本研究旨在探讨IECS能否促进CD103(+)耐受树突状细胞的分化，并对人肠系膜淋巴结(MLN)来源的原代CD103(+)DCs的功能进行评价。方法：用Caco-2细胞培养上清或克罗恩病患者IECs培养上清液处理单核细胞来源的DC(MoDC)和循环中的CD1c(+)DC，分析其诱导T-reg细胞分化的能力。在某些情况下，转化生长因子β(TGFβ)、维甲酸(RA)或胸腺基质淋巴生成素(TSLP)在条件作用前被中和。结果：人IECS可促进耐受树突状细胞的分化，并能促进适应性Foxp3(+)T-reg细胞的发育。克罗恩病患者失去了这种控制，与原发IECS的耐受因子表达减少平行。经RA或IEC上清液诱导分化的MODC上调CD103的表达。从MLN中分离的人原代CD103(+)DC被赋予了促进T-reg细胞分化的能力。此DC亚群表达CCR7，可能代表固有层来源的迁移性群体。结论：在人类肠道中发现了一群具有耐受性的CD103(+)DC，该群体可能因IEC来源的因子而分化，并驱动T-reg细胞的发育。
Objective: In mice, a subpopulation of gut dendritic cells (DCs) expressing CD103 drives the development of regulatory T (T-reg) cells. Further, it was recently described that the cross-talk between human intestinal epithelial cells (IECs) and DCs helps in maintaining gut immune homeostasis via the induction of non-inflammatory DCs. In this study, an analysis was carried out to determine whether IECs could promote the differentiation of CD103(+) tolerogenic DCs, and the function of primary CD103(+) DCs isolated from human mesenteric lymph nodes (MLNs) was evaluated.Methods: Monocyte-derived DCs (MoDCs) and circulating CD1c(+) DCs were conditioned or not with supernatants from Caco-2 cells or IECs isolated from healthy donors or donors with Crohn's disease and analysed for their ability to induce T-reg cell differentiation. In some cases, transforming growth factor beta (TGF beta), retinoic acid (RA) or thymic stromal lymphopoietin (TSLP) were neutralised before conditioning. CD103(+) and CD103(-) DCs were sorted by fluorescence-activated cell sorting (FACS) from MLNs and used in T-reg cell differentiation experiments.Results: It was found that human IECs promoted the differentiation of tolerogenic DCs able to drive the development of adaptive Foxp3(+) T-reg cells. This control was lost in patients with Crohn's disease and paralleled a reduced expression of tolerogenic factors by primary IECs. MoDCs differentiated with RA or IEC supernatant upregulated the expression of CD103. Consistently, human primary CD103(+) DCs isolated from MLNs were endowed with the ability to drive T-reg cell differentiation. This subset of DCs expressed CCR7 and probably represents a lamina propria-derived migratory population.Conclusions: A population of tolerogenic CD103(+) DCs was identified in the human gut that probably differentiate in response to IEC-derived factors and drive T-reg cell development.