Glucocorticoid-Induced TNF Receptor Family-Related Protein Ligand is Requisite for Optimal Functioning of Regulatory CD4(+) T Cells.
Glucocorticoid-Induced TNF Receptor Family-Related Protein Ligand is Requisite for Optimal Functioning of Regulatory CD4(+) T Cells.
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DOI：
10.3389/fimmu.2014.00035
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发表时间：
2014
影响因子：
7.3
通讯作者：
Terhorst C
中科院分区：
文献类型：
--
作者：
Liao G;O'Keeffe MS;Wang G;van Driel B;de Waal Malefyt R;Reinecker HC;Herzog RW;Terhorst C
糖皮质激素诱导的肿瘤坏死因子受体家族相关蛋白（TNFRSF18、CD357）在调节性 T 细胞 (Treg) 上组成型表达，并且在效应 T 细胞上可诱导。在本报告中，我们研究了糖皮质激素诱导的 TNF 受体家族相关蛋白配体 (GITR-L)（由抗原呈递细胞表达）对 Tregs 发育和扩增的作用。我们发现 GITR-L 对于胸腺中自然存在的 FoxP3+ Treg 细胞的发育是可有可无的。然而，注射树突状细胞（DC）诱导因子 Flt3 配体后，GITR-L−/− 小鼠中 Treg 的扩增受到损害。此外，来自 GITR-L−/− 小鼠肝脏的 DC 在体外诱导抗原特异性 Treg 细胞增殖的效率低于来自 WT 同窝小鼠的相同细胞。使用腺相关病毒 (AAV8-OVA) 将卵清蛋白基因转移到 GITR-L−/−FoxP3(GFP) 报告小鼠的肝细胞中后，肝脏和脾脏中抗原特异性 Treg 的数量减少。 Tregs 数量的减少导致卵清蛋白特异性 CD8+ T 效应细胞数量的增加。这是非常重要的，因为抗原特异性 CD8+ 细胞的增殖本身依赖于 GITR-L 的存在，如体外实验和过继转移至接受 AAV8-OVA 的 GITR-L−/−Rag−/− 和 Rag−/− 小鼠中所示。令人惊讶的是，给予 αCD3 显着减少了 GITR-L−/− 小鼠肝脏和脾脏中 FoxP3+ Treg 细胞的数量，但对 WT 小鼠没有影响。由于可溶性 Fc-GITR-L 部分拯救了 αCD3 诱导的 FoxP3+CD4+ Treg 细胞的 CD103+ 子集的体外耗竭，因此我们得出结论，抗原呈递细胞表达 GITR-L 对于最佳 Treg 介导的免疫反应调节（包括基因转移过程中的反应）是必要的。
Glucocorticoid-induced tumor necrosis factor receptor family-related protein (TNFRSF18, CD357) is constitutively expressed on regulatory T cells (Tregs) and is inducible on effector T cells. In this report, we examine the role of glucocorticoid-induced TNF receptor family-related protein ligand (GITR-L), which is expressed by antigen presenting cells, on the development and expansion of Tregs. We found that GITR-L is dispensable for the development of naturally occurring FoxP3+ Treg cells in the thymus. However, the expansion of Treg in GITR-L−/− mice is impaired after injection of the dendritic cells (DCs) inducing factor Flt3 ligand. Furthermore, DCs from the liver of GITR-L−/− mice were less efficient in inducing proliferation of antigen-specific Treg cells in vitro than the same cells from WT littermates. Upon gene transfer of ovalbumin into hepatocytes of GITR-L−/−FoxP3(GFP) reporter mice using adeno-associated virus (AAV8-OVA) the number of antigen-specific Treg in liver and spleen is reduced. The reduced number of Tregs resulted in an increase in the number of ovalbumin specific CD8+ T effector cells. This is highly significant because proliferation of antigen-specific CD8+ cells itself is dependent on the presence of GITR-L, as shown by in vitro experiments and by adoptive transfers into GITR-L−/−Rag−/− and Rag−/− mice that had received AAV8-OVA. Surprisingly, administering αCD3 significantly reduced the numbers of FoxP3+ Treg cells in the liver and spleen of GITR-L−/− but not WT mice. Because soluble Fc-GITR-L partially rescues αCD3 induced in vitro depletion of the CD103+ subset of FoxP3+CD4+ Treg cells, we conclude that expression of GITR-L by antigen presenting cells is requisite for optimal Treg-mediated regulation of immune responses including those in response during gene transfer.
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