GITR engagement preferentially enhances proliferation of functionally competent CD4+CD25+FoxP3+ regulatory T cells
GITR engagement preferentially enhances proliferation of functionally competent CD4+CD25+FoxP3+ regulatory T cells
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DOI：
10.1093/intimm/dxq001
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发表时间：
2010-04-01
影响因子：
4.4
通讯作者：
Terhorst, Cox
中科院分区：
文献类型：
--
作者：
Liao, Gongxian;Nayak, Sushrusha;Terhorst, Cox
天然存在的调节性T细胞（Treg）表达高水平的糖皮质激素诱导的肿瘤坏死因子受体（GITR）。然而，GITR在Treg生物学中的作用的研究由于观察到在活化后效应CD 4（+）T（Ten）细胞也表达受体而变得复杂。在这里，我们剖析了GITR诱导的信号网络在FoxP 3（+）Treg的扩展和功能中的贡献。我们证明，高亲和力可溶性Fc-GITR-L二聚体与α CD 3缀合，特异性增强Treg的体外增殖，Treg保留其表型标志物（CD 25和FoxP 3）及其抑制功能，同时最小程度地影响Teff细胞。此外，Fc-GITR-L不损害Teff对抑制的敏感性，如通过使用GITR缺陷和GITR充足的CD 4（+）T细胞亚群的共培养物所判断的。值得注意的是，即使在不存在抗原刺激的情况下，通过用Fc-GITR-L注射FoxP 3-IRES-GFP小鼠，也可以在体内观察到Treg的这种扩增。为了测试这些发现在治疗上的功效，我们使用C3 H/HeJ血友病B易感小鼠模型。在该模型中使用肝靶向的人凝血因子IX（hF.IX）基因治疗已显示诱导肝毒性和随后的hF.IX表达失败。有趣的是，向接受肝脏靶向hF.IX基因治疗的血友病易感小鼠注射Fc-GITR-L增加了F.IX的表达并减少了抗凝因子。我们得出结论，GITR接合在体外和体内均增强Treg增殖，并且Fc-GITR-L可能是用于体内耐受诱导的有用工具。
Naturally occurring regulatory T cells (Treg) express high levels of glucocorticoid-induced tumour necrosis factor receptor (GITR). However, studies of the role of GITR in Treg biology has been complicated by the observation that upon activation effector CD4(+) T (Ten) cells also express the receptor. Here, we dissect the contribution of GITR-induced signaling networks in the expansion and function of FoxP3(+) Treg. We demonstrate that a high-affinity soluble Fc-GITR-L dimer, in conjugation with alpha CD3, specifically enhances in vitro proliferation of Treg, which retain their phenotypic markers (CD25 and FoxP3) and their suppressor function, while minimally affecting Teff cells. Furthermore, Fc-GITR-L does not impair Teff susceptibility to suppression, as judged by cocultures employing GITR-deficient and GITR-sufficient CD4(+) T-cell subsets. Notably, this expansion of Treg could also be seen in vivo, by injecting FoxP3-IRES-GFP mice with Fc-GITR-L even in the absence of antigenic stimulation. In order to test the efficacy of these findings therapeutically, we made use of a C3H/HeJ hemophilia B-prone mouse model. The use of liver-targeted human coagulation factor IX (hF.IX) gene therapy in this model has been shown to induce liver toxicity and the subsequent failure of hF.IX expression. Interestingly, injection of Fc-GITR-L into the hemophilia-prone mice that were undergoing liver-targeted hF.IX gene therapy increased the expression of F.IX and reduced the anticoagulation factors. We conclude that GITR engagement enhances Treg proliferation both in vitro and in vivo and that Fc-GITR-L may be a useful tool for in vivo tolerance induction.