Mesenchymal Stem Cells Inhibit Human Th17 Cell Differentiation and Function and Induce a T Regulatory Cell Phenotype
Mesenchymal Stem Cells Inhibit Human Th17 Cell Differentiation and Function and Induce a T Regulatory Cell Phenotype
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DOI：
10.4049/jimmunol.0902007
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发表时间：
2010-07-01
影响因子：
4.4
通讯作者：
Yssel, Hans
中科院分区：
文献类型：
--
作者：
Ghannam, Soufiane;Pene, Jerome;Yssel, Hans
骨髓间充质干细胞（Mesenchymal stem cells，MSCs）通过抑制T细胞活化和增殖发挥免疫调节作用。由于Th 17细胞在炎症性疾病发病机制中的有害作用，我们研究了促炎细胞因子是否可以改变人MSC上粘附分子的表达，从而有助于增加Th 17细胞与MSC的粘附，并因此调节后者细胞的功能。IFN-γ和TNF-α协同增强MSC的CD 54表达，使得CCR 6趋化因子配体CCL 20能够诱导Th 17细胞与MSC的体外粘附。MSC阻止初始CD 4（+）T细胞体外分化为Th 17细胞，并抑制完全分化的Th 17细胞产生IL-17、IL-22、IFN-γ和TNF-α;这部分通过PGE介导（2），其产生在与Th 17细胞共培养中增强。此外，MSC诱导IL-10的产生和FOXP 3基因位点启动子处组蛋白H3 K4 me 3的三甲基化，而它抑制了Th 17细胞中RORC基因中相应区域的三甲基化。这些表观遗传变化与叉头盒p3的诱导和Th 17细胞抑制活化的CD 4（+）T细胞的体外增殖反应的能力的获得相关，当MSC与IFN-γ和TNF-α预孵育时，这种能力增强。这些结果表明，在炎症条件下，MSC通过CCR 6介导Th 17细胞的粘附，并通过在这些细胞中诱导T细胞调节表型发挥抗炎作用。免疫学杂志，2010，185：302-312。
Mesenchymal stem cells (MSCs) exert immunomodulatory properties via the inhibition of T cell activation and proliferation. Because of the deleterious role of Th17 cells in the pathogenesis of inflammatory disease, we investigated whether proinflammatory cytokines could modify the expression of adhesion molecules on human MSCs, thereby contributing to increased Th17 cell adhesion to MSCs and, as a consequence, modulating the function of the latter cells. IFN-gamma and TNF-alpha synergistically enhanced the expression of CD54 by MSCs, enabling the CCR6 chemokine ligand CCL20 to induce in vitro adhesion of Th17 cells to MSCs. MSCs prevented the in vitro differentiation of naive CD4(+) T cells into Th17 cells and inhibited the production of IL-17, IL-22, IFN-gamma, and TNF-alpha by fully differentiated Th17 cells; this was mediated, in part, via PGE(2), the production of which was enhanced in cocultures with Th17 cells. Moreover, MSCs induced the production of IL-10 and trimethylation of histone H3K4me3 at the promoter of the FOXP3 gene locus, whereas it suppressed trimethylation of the corresponding region in the RORC gene in Th17 cells. These epigenetic changes were associated with the induction of fork head box p3 and the acquisition by Th17 cells of the capacity to inhibit in vitro proliferative responses of activated CD4(+) T cells, which was enhanced when MSCs were preincubated with IFN-gamma and TNF-alpha. These results showed that, under inflammatory conditions, MSCs mediate the adhesion of Th17 cells via CCR6 and exert anti-inflammatory effects through the induction of a T cell regulatory phenotype in these cells. The Journal of Immunology, 2010, 185: 302-312.