Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells.
Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells.
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视黄酸和雷帕霉素的单一作用和联合作用可调节诱导性人类调节性 T 细胞的生成、活性和归巢潜力。
DOI：
10.1371/journal.pone.0182009
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Fierro JA
中科院分区：
文献类型：
--
作者：
Candia E;Reyes P;Covian C;Rodriguez F;Wainstein N;Morales J;Mosso C;Rosemblatt M;Fierro JA
CD4+CD25+FOXP3+调节性T细胞（Treg细胞）的过继转移已成功用于治疗移植物抗宿主病，并代表了治疗自身免疫性疾病和移植排斥的有前途的策略。本研究的目的是评估全反式视黄酸 (atRA) 和雷帕霉素 (RAPA) 对短期培养中诱导的人 Treg 细胞的数量、表型、归巢标记表达、DNA 甲基化和功能的影响。在 IL-2、TGF-β1、atRA 和 RAPA 的不同组合存在下，对初始 T 细胞进行多克隆刺激并培养五天。所得细胞的特征在于 FOXP3 的表达、激活、表面和归巢标记。还评估了保守非编码序列 2 的甲基化。通过体外抑制测定对不同培养条件进行功能比较。用 IL-2/TGFβ1 培养初始人类 T 细胞导致产生 54.2% 的 Treg 细胞 (CD4+CD25+FOXP3+)，而添加 100 nM atRA 则将 Treg 细胞的产量增加至 66% (p = 0.0088)。在任何这些环境中，添加 RAPA 都不会增加 Treg 细胞的数量。 atRA 存在下生成的 Treg 细胞的 β7 整合素表达增加，几乎达到生成的 Treg 细胞的 100%，而 RAPA 处理的细胞显示 CXCR4 表达增强。归巢分子的差异表达凸显了诱导具有不同器官特异性归巢特性的 Treg 细胞的可能性。 atRA 和 RAPA 对高度甲基化的 CNS2 位点均没有影响，这支持了以下报道：它们对 Treg 细胞谱系稳定性的贡献不是由该位点的甲基化变化介导的。在 RAPA 存在下产生的 Treg 细胞对效应细胞的增殖表现出最有效的抑制作用。
Adoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Treg cells) has been successfully utilized to treat graft versus host disease and represents a promising strategy for the treatment of autoimmune diseases and transplant rejection. The aim of this study was to evaluate the effects of all-trans retinoic acid (atRA) and rapamycin (RAPA) on the number, phenotype, homing markers expression, DNA methylation, and function of induced human Treg cells in short-term cultures. Naive T cells were polyclonally stimulated and cultured for five days in the presence of different combinations of IL-2, TGF-β1, atRA and RAPA. The resulting cells were characterized by the expression of FOXP3, activation, surface and homing markers. Methylation of the Conserved Non-coding Sequence 2 was also evaluated. Functional comparison of the different culture conditions was performed by suppression assays in vitro. Culturing naive human T cells with IL-2/TGFβ1 resulted in the generation of 54.2% of Treg cells (CD4+CD25+FOXP3+) whereas the addition of 100 nM atRA increased the yield of Treg cells to 66% (p = 0.0088). The addition of RAPA did not increase the number of Treg cells in any of these settings. Treg cells generated in the presence of atRA had an increased expression of the β7 integrin to nearly 100% of the generated Treg cells, while RAPA treated cells showed enhanced expression of CXCR4. The differential expression of homing molecules highlights the possibility of inducing Treg cells with differential organ-specific homing properties. Neither atRA nor RAPA had an effect on the highly methylated CNS2 sites, supporting reports that their contribution to the lineage stability of Treg cells is not mediated by methylation changes in this locus. Treg cells generated in the presence of RAPA show the most potent suppression effect on the proliferation of effector cells.
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影响因子：
24.5
作者：
Canavan JB;Scottà C;Vossenkämper A;Goldberg R;Elder MJ;Shoval I;Marks E;Stolarczyk E;Lo JW;Powell N;Fazekasova H;Irving PM;Sanderson JD;Howard JK;Yagel S;Afzali B;MacDonald TT;Hernandez-Fuentes MP;Shpigel NY;Lombardi G;Lord GM
通讯作者：
Lord GM
影响因子：
20.3
作者：
Duhen, Thomas;Duhen, Rebekka;Campbell, Daniel J.
通讯作者：
Campbell, Daniel J.
影响因子：
17.1
作者：
Bluestone JA;Buckner JH;Fitch M;Gitelman SE;Gupta S;Hellerstein MK;Herold KC;Lares A;Lee MR;Li K;Liu W;Long SA;Masiello LM;Nguyen V;Putnam AL;Rieck M;Sayre PH;Tang Q
通讯作者：
Tang Q
影响因子：
3.7
作者：
Evans-Marin HL;Cao AT;Yao S;Chen F;He C;Liu H;Wu W;Gonzalez MG;Dann SM;Cong Y
通讯作者：
Cong Y
影响因子：
9.8
作者：
Floess S;Freyer J;Siewert C;Baron U;Olek S;Polansky J;Schlawe K;Chang HD;Bopp T;Schmitt E;Klein-Hessling S;Serfling E;Hamann A;Huehn J
通讯作者：
Huehn J