Stroopinsky Dina, Avivi Irit, Rowe Jacob M, Avigan David, Katz Tamar
Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
Eur J Immunol. 2009 Oct;39(10):2703-15. doi: 10.1002/eji.200839097.
Human induced CD4(+)CD25(+) T cells have been shown to express FOXP3, similar to naturally occurring Treg cells (nTreg). However, the suppressive capacity of these cells is still under debate. The current study was designed to investigate functional characteristics of CD25(+)FOXP3(+) derived from CD25(-) T cells. Stimulation of CD25(-) PBMC with allogeneic PBMC resulted in production of CD4(+)CD25(high) T cells. This process was more rapid and prominent when highly mature DC were used for stimulation. The resultant CD4(+)CD25(high) population concurrently exhibited regulatory markers FOXP3, CTLA-4, GITR, and inflammatory cytokines IL-2 and IFN-gamma. These human-induced FOXP3(+)IFN-gamma(+) T cells were shown, for the first time, to markedly inhibit alloreactive T-cell expansion, similar to nTreg. However, in contrast to nTreg, the induced CD4(+)CD25(+)FOXP3(+) cells did not suppress proliferation against a third party donor stimulus or CMV. This suggested that the cell population possessed a more selective suppressive capacity targeted against the original stimulus only. The induced human CD4(+)CD25(+)FOXP3(+) subset derived from CD25(-) T cells, while expressing inflammatory cytokines, exhibits a suppressive cell contact-dependent effect, restricted against T cells responding to the original stimulus. Such unique properties suggest that these cells are potentially ideal for the use as post-transplant GVH disease prophylaxis.
已证明人类诱导的CD4(+)CD25(+) T细胞表达FOXP3，类似于天然存在的调节性T细胞（nTreg）。然而，这些细胞的抑制能力仍存在争议。本研究旨在调查从CD25(-) T细胞衍生的CD25(+)FOXP3(+)细胞的功能特性。用异体PBMC刺激CD25(-) PBMC可产生CD4(+)CD25(高) T细胞。当使用高度成熟的树突状细胞（DC）进行刺激时，这一过程更快且更显著。产生的CD4(+)CD25(高)群体同时表现出调节性标志物FOXP3、细胞毒性T淋巴细胞相关抗原4（CTLA-4）、糖皮质激素诱导的肿瘤坏死因子受体（GITR）以及炎性细胞因子白细胞介素-2（IL-2）和干扰素-γ（IFN-γ）。首次证明这些人类诱导的FOXP3(+)IFN-γ(+) T细胞与nTreg相似，能显著抑制同种异体反应性T细胞增殖。然而，与nTreg不同的是，诱导产生的CD4(+)CD25(+)FOXP3(+)细胞不能抑制针对第三方供体刺激或巨细胞病毒（CMV）的增殖。这表明该细胞群体仅对原始刺激具有更具选择性的抑制能力。从CD25(-) T细胞衍生的诱导性人类CD4(+)CD25(+)FOXP3(+)亚群在表达炎性细胞因子的同时，表现出依赖细胞接触的抑制作用，仅针对对原始刺激产生反应的T细胞有抑制作用。这些独特特性表明，这些细胞可能是移植后移植物抗宿主病（GVH）预防的理想选择。
