Regulatory T cells, derived from naive CD4+ CD25- T cells by in vitro foxp3 gene transfer, can induce transplantation tolerance
Regulatory T cells, derived from naive CD4+ CD25- T cells by in vitro foxp3 gene transfer, can induce transplantation tolerance
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DOI：
10.1097/01.tp.0000159147.56408.9c
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发表时间：
2005-05-27
期刊：
影响因子：
6.2
通讯作者：
Dyson, J
中科院分区：
文献类型：
--
作者：
Chai, JG;Xue, SA;Dyson, J
背景资料。调节性T(Treg)细胞是通过将Foxp3基因转移到初始的CD4(+)25(-)T细胞中而在体外产生的，已被证明可以抑制炎症和自身免疫性疾病的发展，但它们是否能够防止同种异体移植排斥反应尚不清楚。本研究探讨了通过Foxp3基因转移从初始的CD4(+)T细胞产生的Treg细胞是否能诱导移植耐受。Hy特异的T细胞受体(TCR)转基因的CD4(+)25(-)T细胞被逆转录病毒转导Foxp3基因。用荧光激活细胞分选仪、T细胞增殖试验、酶联免疫吸附试验和细胞内细胞因子染色等方法检测转导细胞的表型、功能和细胞因子谱。通过过继转移和皮肤移植实验，观察转导Foxp3基因的HY特异性T细胞能否抑制同基因男性移植物的排斥反应。Foxp3逆转录病毒转导的CD4(+)25(-)T细胞表达一组与Treg活性密切相关的细胞表面和细胞内分子。这种Treg表型在体外培养过程中是稳定的，并有一些进一步的成熟。在体外，Foxp3转导的细胞是功能性无能和抑制性T细胞。体内过继转移转导Foxp3的HY特异性TCR转基因CD4(+)T细胞可保护男性皮肤移植物免受同基因女性的排斥反应。然而，将Foxp3基因逆转录病毒转导到非TCR转基因的CD4(+)25(-)T细胞中，对男性皮肤移植排斥反应没有影响。本研究首次证明了转导Foxp3基因的T细胞可以控制同种异体移植的排斥反应，提示T细胞Foxp3基因转移在临床移植中可能具有治疗价值。
Background. Regulatory T (Treg) cells, generated in vitro by Foxp3 gene transfer into naive CD4(+)25(-) T cells, have been shown to inhibit the development of inflammation and autoimmune disease, but it is not known whether they are able to prevent allograft rejection. This study investigated whether Treg cells generated from naive CD4(+) T cells by Foxp3 gene transfer could induce transplantation tolerance.Methods. HY-specific, T-cell receptor (TCR) -transgenic CD4(+)25(-) T cells were retrovirally transduced with the Foxp3 gene. The phenotype, function, and cytokine profiles of the transduced cells were examined in vitro by fluorescence-activated cell sorter, T-cell proliferation assays, enzyme-linked immunosorbent assay, and intracellular cytokine staining. Adoptive transfer and skin grafting experiments were conducted to assess whether Foxp3-transduced HY-specific T cells could prevent the rejection of syngeneic male grafts.Results. CD4(+)25(-) T cells retrovirally transduced with Foxp3 express a panel of cell surface and intracellular molecules closely associated with Treg activity. This Treg phenotype was stable during in vitro culture with some further maturation. In vitro, Foxp3-transduced cells were functionally anergic and suppressive T cells. In vivo adoptive transfer of Foxp3-transduced HY-specific TCR-transgenic CD4(+) T cells protected male skin grafts from rejection by syngeneic females. Retroviral transduction of the Foxp3 gene into non-TCR-transgenic CD4(+)25(-) T cells, however, had no influence on male skin graft rejection.Conclusion. This study provides the first evidence that Foxp3-transduced T cells can control the rejection of an allogeneic transplant and suggests that T-cell Foxp3 gene transfer may have therapeutic value in clinical transplantation.