Rabbit ATG but not horse ATG promotes expansion of functional CD4+CD25highFOXP3+ regulatory T cells in vitro
Rabbit ATG but not horse ATG promotes expansion of functional CD4+CD25highFOXP3+ regulatory T cells in vitro
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DOI：
10.1182/blood-2008-01-130146
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发表时间：
2008-04-01
期刊：
影响因子：
20.3
通讯作者：
Young, Neal S.
中科院分区：
文献类型：
--
作者：
Feng, Xingmin;Kajigaya, Sachiko;Young, Neal S.
调节性T细胞（Treg）在抑制免疫应答和维持耐受中起重要作用。兔抗胸腺细胞球蛋白（rATG）和马抗胸腺细胞球蛋白（hATG）被广泛用于治疗免疫介导的综合征，但它们对Treg的影响尚不清楚。我们在此显示，在体外培养正常人外周血单核细胞（PBMC）与低剂量rATG导致功能性Treg的显着扩增，通过将CD4（+）CD25（-）T细胞转化为CD4（+）CD25（+）T细胞。hATG没有扩增，而是减少了Treg。免疫印迹显示，暴露于rATG的CD4（+）CD25（-）和CD4（+）CD25（+）T细胞中FOXP3和NFAT 1的表达增加。与用hATG处理的PBMCs相比，用rATG处理的PBMCs在培养上清中显示出增加的白细胞介素-10。此外，rATG和hATG在刺激CD4（+）T细胞的潜力上显示出差异，如使用不同的活化标志物所检测的。基因芯片显示，rATG诱导的PBMC中的基因表达模式显着不同，与hATG处理或未处理的PBMC相比。我们的研究结果表明，rATG扩增Treg，可能是通过增强NFAT 1表达的转录调节，进而赋予CD4（+）CD25（-）T细胞FOXP3表达和调节活性。rATG的治疗作用可能不仅是因为淋巴细胞耗竭，还因为Treg细胞数量和功能增强。
Regulatory T cells (Treg) play important roles in suppressing immune responses and maintaining tolerance. Rabbit antithymocyte globulin (rATG) and horse ATG (hATG) are widely used in the treatment of immune-mediated syndromes, but their effects on Treg are unknown. We show here that in vitro culture of normal human peripheral blood mononuclear cells (PBMCs) with a low-dose rATG resulted in marked expansion of functional Treg by converting CD4(+)CD25(-) T cells to CD4(+)CD25(+) T cells. hATG did not expand but rather decreased Treg. Immunoblot showed increased expression of FOXP3 and NFAT1 in CD4(+)CD25(-) and CD4(+)CD25(+) T cells exposed to rATG. PBMCs treated with rATG displayed increased interleukin-10 in culture supernatants than those treated with hATG. Furthermore, rATG and hATG showed differences in their potential to stimulate CD4(+) T cells as examined using different activation markers. Microarray revealed that rATG induced markedly different gene-expression patterns in PBMCs, compared with hATG-treated or untreated PBMCs. Our findings indicate that rATG expanded Treg, probably through transcriptional regulation by enhanced NFAT1 expression, in turn conferring CD4(+)CD25(-) T cell FOXP3 expression and regulatory activity. The therapeutic effects of rATG may occur not only because of lymphocyte depletion but also enhanced Treg cell number and function.