Institut National de la Santé et de la Recherche Médicale, Unité 844, Hôpital St. Eloi, Université Montpellier I, France.
J Immunol. 2010 Jul 1;185(1):302-12. doi: 10.4049/jimmunol.0902007. Epub 2010 May 28.
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.
间充质干细胞（MSCs）通过抑制 T 细胞的激活和增殖来发挥免疫调节作用。由于 Th17 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 MSCs 上粘附分子的表达，从而促进 Th17 细胞与 MSCs 的粘附，并因此调节后者细胞的功能。IFN-γ和 TNF-α协同增强了 MSCs 对 CD54 的表达，使趋化因子配体 CCL20 能够诱导 Th17 细胞在体外与 MSCs 的粘附。MSCs 可防止幼稚 CD4+T 细胞在体外分化为 Th17 细胞，并抑制完全分化的 Th17 细胞产生 IL-17、IL-22、IFN-γ和 TNF-α；这部分是通过 PGE2 介导的，其在与 Th17 细胞的共培养中增强。此外，MSCs 诱导 IL-10 的产生，并在 FOXP3 基因座的启动子处对 Th17 细胞的 H3K4me3 进行三甲基化，而在 Th17 细胞中则抑制 RORC 基因相应区域的三甲基化。这些表观遗传变化与叉头框 P3 的诱导以及 Th17 细胞获得抑制体外激活的 CD4+T 细胞增殖反应的能力有关，当 MSCs 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，MSCs 通过 CCR6 介导 Th17 细胞的粘附，并通过诱导这些细胞中的 T 细胞调节表型来发挥抗炎作用。
