Mesenchymal stromal cells induce regulatory T cells via epigenetic conversion of human conventional CD4 T cells in vitro,STEM CELLS

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Mesenchymal stromal cells induce regulatory T cells via epigenetic conversion of human conventional CD4 T cells in vitro
STEM CELLS ( IF 4.0 ) Pub Date : 2020-04-30 , DOI: 10.1002/stem.3185
Rita I Azevedo ₁ , Ekaterina Minskaia ₁ , Ana Fernandes-Platzgummer ₂ , Ana I S Vieira ₁ , Cláudia L da Silva ₂ , Joaquim M S Cabral ₂ , João F Lacerda ₁

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Regulatory T cells (Treg) play a critical role in immune tolerance. The scarcity of Treg therapy clinical trials in humans has been largely due to the difficulty in obtaining sufficient Treg numbers. We performed a preclinical investigation on the potential of mesenchymal stromal cells (MSCs) to expand Treg in vitro to support future clinical trials. Human peripheral blood mononuclear cells from healthy donors were cocultured with allogeneic bone marrow‐derived MSCs expanded under xenogeneic‐free conditions. Our data show an increase in the counts and frequency of CD4+ CD25high Foxp3+ CD127low Treg cells (4‐ and 6‐fold, respectively) after a 14‐day coculture. However, natural Treg do not proliferate in coculture with MSCs. When purified conventional CD4 T cells (Tcon) are cocultured with MSCs, only cells that acquire a Treg‐like phenotype proliferate. These MSC‐induced Treg‐like cells also resemble Treg functionally, since they suppress autologous Tcon proliferation. Importantly, the DNA methylation profile of MSC‐induced Treg‐like cells more closely resembles that of natural Treg than of Tcon, indicating that this population is stable. The expression of PD‐1 is higher in Treg‐like cells than in Tcon, whereas the frequency of PDL‐1 increases in MSCs after coculture. TGF‐β levels are also significantly increased MSC cocultures. Overall, our data suggest that Treg enrichment by MSCs results from Tcon conversion into Treg‐like cells, rather than to expansion of natural Treg, possibly through mechanisms involving TGF‐β and/or PD‐1/PDL‐1 expression. This MSC‐induced Treg population closely resembles natural Treg in terms of phenotype, suppressive ability, and methylation profile.

中文翻译：

间充质基质细胞通过体外人类常规 CD4 T 细胞的表观遗传转化诱导调节性 T 细胞

调节性 T 细胞 (Treg) 在免疫耐受中起关键作用。人类 Treg 治疗临床试验的稀缺主要是由于难以获得足够的 Treg 数量。我们对间充质基质细胞 (MSC) 在体外扩增 Treg 以支持未来临床试验的潜力进行了临床前研究。来自健康供体的人外周血单核细胞与在无异种条件下扩增的同种异体骨髓来源的 MSC 共培养。我们的数据显示，共培养 14 天后，CD4+ CD25high Foxp3+ CD127low Treg 细胞的数量和频率增加（分别为 4 倍和 6 倍）。然而，天然 Treg 在与 MSC 共培养时不会增殖。当纯化的常规 CD4 T 细胞 (Tcon) 与 MSC 共培养时，只有获得 Treg 样表型的细胞才会增殖。这些 MSC 诱导的 Treg 样细胞在功能上也类似于 Treg，因为它们抑制自体 Tcon 增殖。重要的是，MSC 诱导的 Treg 样细胞的 DNA 甲基化谱比 Tcon 更类似于天然 Treg，表明该群体是稳定的。PD-1 在 Treg 样细胞中的表达高于 Tcon，而共培养后 MSCs 中 PDL-1 的表达频率增加。TGF-β 水平也显着增加 MSC 共培养物。总的来说，我们的数据表明，MSCs 富集 Treg 是由于 Tcon 转化为 Treg 样细胞，而不是天然 Treg 的扩增，可能是通过涉及 TGF-β 和/或 PD-1/PDL-1 表达的机制。这种 MSC 诱导的 Treg 群体在表型方面与天然 Treg 非常相似，

更新日期：2020-04-30

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