Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue Cancer Center, Bindley Bioscience Center, Purdue University, West Lafayette, IN, USA.
Eur J Immunol. 2012 Oct;42(10):2683-96. doi: 10.1002/eji.201142317. Epub 2012 Aug 6.
While induced FoxP3(+) T cells (iTreg cells) are promising cellular therapeutics to treat inflammatory diseases, a limitation in utilizing iTreg cells prepared in vitro is their low stability in inflammatory conditions. Progesterone (P4) is an immune regulatory nuclear hormone with a potent Treg induction activity. We reasoned that this function of progesterone would be utilized to generate iTreg cells with highly suppressive activity and improved stability in vivo. Here we generated iTreg cells with progesterone in vitro and found that progesterone generates iTreg cells that are highly stable in inflammatory conditions. Moreover, P4-induced iTreg cells highly express latency-associated peptide TGF-β1 and are efficient in regulating inflammation in multiple tissues, whereas control iTreg cells induced with TGF-β1 alone are less stable and ineffective in suppressing inflammation. The function of progesterone in inducing iTreg cells with improved regulatory activity is associated with the function of P4 in suppressing the mTOR pathway. Moreover, the function of progesterone in inducing FoxP3(+) T cells is decreased but not completely abolished on nuclear progesterone receptor-deficient T cells, suggesting that both nuclear and nonnuclear progesterone receptors are involved in mediating the function. We conclude that P4 can be utilized to generate iTreg cells with a high therapeutic potential in treatment of tissue inflammation.
虽然诱导 FoxP3(+)T 细胞（iTreg 细胞）是治疗炎症性疾病有前途的细胞治疗方法，但在利用体外制备的 iTreg 细胞时存在一个限制，即它们在炎症条件下的稳定性较低。孕酮（P4）是一种具有免疫调节活性的核激素，具有很强的 Treg 诱导活性。我们推断，孕酮的这种功能将被用于产生具有高度抑制活性和体内稳定性的 iTreg 细胞。在这里，我们在体外用孕酮生成 iTreg 细胞，发现孕酮生成的 iTreg 细胞在炎症条件下具有高度稳定性。此外，P4 诱导的 iTreg 细胞高表达潜伏相关肽 TGF-β1，并能有效地调节多种组织的炎症，而单独用 TGF-β1 诱导的对照 iTreg 细胞稳定性较差，抑制炎症的效果较差。孕酮在诱导具有改善调节活性的 iTreg 细胞中的作用与 P4 抑制 mTOR 途径的作用有关。此外，在核孕酮受体缺陷 T 细胞上，孕酮诱导 FoxP3(+)T 细胞的功能降低但并未完全消除，表明核孕酮受体和非核孕酮受体都参与介导该功能。我们得出结论，P4 可用于生成具有高治疗潜力的 iTreg 细胞，用于治疗组织炎症。
