Fazekasova Henrieta, Golshayan Dela, Read Joseph, Tsallios Aristotle, Tsang Julia Yuen-Shan, Dorling Anthony, George Andrew J T, Lechler Robert I, Lombardi Giovanna, Mirenda Vincenzo
Immunoregulation Laboratory, MRC Centre of Transplantation DIIID, King's College London, Guy's Campus, London, United Kingdom.
Transplantation. 2009 Jun 15;87(11):1617-28. doi: 10.1097/TP.0b013e3181a5504c.
The central function of dendritic cells (DC) in inducing and preventing immune responses makes them ideal therapeutic targets for the induction of immunologic tolerance. In a rat in vivo model, we showed that dexamethasone-treated DC (Dex-DC) induced indirect pathway-mediated regulation and that CD4+CD25+ T cells were involved in the observed effects. The aim of the present study was to investigate the mechanisms underlying the acquired immunoregulatory properties of Dex-DC in the rat and human experimental systems.
After treatment with dexamethasone (Dex), the immunogenicity of Dex-DC was analyzed in T-cell proliferation and two-step hyporesponsiveness induction assays. After carboxyfluorescein diacetate succinimidyl ester labeling, CD4+CD25+ regulatory T-cell expansion was analyzed by flow cytometry, and cytokine secretion was measured by ELISA.
In this study, we demonstrate in vitro that rat Dex-DC induced selective expansion of CD4+CD25+ regulatory T cells, which were responsible for alloantigen-specific hyporesponsiveness. The induction of regulatory T-cell division by rat Dex-DC was due to secretion of interleukin (IL)-2 by DC. Similarly, in human studies, monocyte-derived Dex-DC were also poorly immunogenic, were able to induce T-cell anergy in vitro, and expand a population of T cells with regulatory functions. This was accompanied by a change in the cytokine profile in DC and T cells in favor of IL-10.
These data suggest that Dex-DC induced tolerance by different mechanisms in the two systems studied. Both rat and human Dex-DC were able to induce and expand regulatory T cells, which occurred in an IL-2 dependent manner in the rat system.
树突状细胞（DC）在诱导和预防免疫反应中的核心功能使其成为诱导免疫耐受的理想治疗靶点。在大鼠体内模型中，我们发现地塞米松处理的DC（Dex-DC）可诱导间接途径介导的调节作用，且CD4+CD25+ T细胞参与了所观察到的效应。本研究的目的是探讨在大鼠和人类实验系统中，Dex-DC获得性免疫调节特性的潜在机制。
用地塞米松（Dex）处理后，在T细胞增殖和两步低反应性诱导试验中分析Dex-DC的免疫原性。用羧基荧光素二乙酸琥珀酰亚胺酯标记后，通过流式细胞术分析CD4+CD25+调节性T细胞的扩增情况，并用ELISA检测细胞因子分泌。
在本研究中，我们在体外证明大鼠Dex-DC可诱导CD4+CD25+调节性T细胞的选择性扩增，这些细胞负责同种异体抗原特异性低反应性。大鼠Dex-DC诱导调节性T细胞分裂是由于DC分泌白细胞介素（IL）-2。同样，在人类研究中，单核细胞来源的Dex-DC免疫原性也很差，能够在体外诱导T细胞无反应性，并扩增具有调节功能的T细胞群体。这伴随着DC和T细胞中细胞因子谱向有利于IL-10的方向变化。
这些数据表明，在两个研究系统中，Dex-DC通过不同机制诱导耐受。大鼠和人类的Dex-DC都能够诱导和扩增调节性T细胞，在大鼠系统中这是以IL-2依赖的方式发生的。
