Human adipose-tissue derived mesenchymal stem cells induce functional de-novo regulatory T cells with methylated FOXP3 gene DNA
Human adipose-tissue derived mesenchymal stem cells induce functional de-novo regulatory T cells with methylated FOXP3 gene DNA
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DOI：
10.1111/cei.12120
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发表时间：
2013-08-01
影响因子：
4.6
通讯作者：
Baan, C. C.
中科院分区：
文献类型：
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作者：
Engela, A. U.;Hoogduijn, M. J.;Baan, C. C.
由于其免疫调节特性，间充质干细胞 (MSC) 成为治疗自身免疫性疾病、移植物抗宿主病和同种异体移植排斥的细胞疗法的有趣候选者。 MSC 抑制效应 T 细胞的增殖并诱导具有调节表型的 T 细胞。迄今为止，尚不清楚人MSC诱导的CD4（+）CD25（+）CD127（-）叉头盒P3（FoxP3）（+）T细胞是否具有功能以及它们是否源自效应T细胞或代表扩展的天然调节T细胞（nT（reg））。从肾供体获得的肾周脂肪组织来源的间充质干细胞（ASC）诱导来自同种异体刺激的CD25（-/dim）细胞的CD4（+）T细胞群中CD25（+）CD127（-）FoxP3（+）细胞的百分比增加2u 1倍。白细胞介素 (IL)-2 受体阻断阻止了这种诱导。 ASC 诱导的 T 细胞 (iT(reg)) 与 nT(reg) 一样有效地抑制效应细胞增殖。 iT(reg) 部分内的绝大多数细胞具有甲基化的 FOXP3 基因 T-reg 特异性去甲基化区域 (TSDR)，表明它们不是 nT(reg) 来源。总之，ASC 诱导效应 T 细胞产生 T-reg。这些iT(reg)具有与nT(reg)相当的免疫抑制能力。它们的诱导依赖于 IL-2 途径。 MSC 抑制免疫细胞增殖同时产生新生免疫抑制细胞的双重作用强调了它们作为细胞免疫治疗剂的潜力。
Due to their immunomodulatory properties, mesenchymal stem cells (MSC) are interesting candidates for cellular therapy for autoimmune disorders, graft-versus-host disease and allograft rejection. MSC inhibit the proliferation of effector T cells and induce T cells with a regulatory phenotype. So far it is unknown whether human MSC-induced CD4(+)CD25(+)CD127(-)forkhead box P3 (FoxP3)(+) T cells are functional and whether they originate from effector T cells or represent expanded natural regulatory T cells (nT(reg)). Perirenal adipose-tissue derived MSC (ASC) obtained from kidney donors induced a 2 u 1-fold increase in the percentage of CD25(+)CD127(-)FoxP3(+) cells within the CD4(+) T cell population from allostimulated CD25(-/dim) cells. Interleukin (IL)-2 receptor blocking prevented this induction. The ASC-induced T cells (iT(reg)) inhibited effector cell proliferation as effectively as nT(reg). The vast majority of cells within the iT(reg) fraction had a methylated FOXP3 gene T-reg-specific demethylated region (TSDR) indicating that they were not of nT(reg) origin. In conclusion, ASC induce T-reg from effector T cells. These iT(reg) have immunosuppressive capacities comparable to those of nT(reg). Their induction is IL-2 pathway-dependent. The dual effect of MSC of inhibiting immune cell proliferation while generating de-novo immunosuppressive cells emphasizes their potential as cellular immunotherapeutic agent.