Kang Seung G, Wang Chuanwu, Matsumoto Satoshi, Kim Chang H
Department of Comparative Pathobiology, Laboratory of Immunology and Hematopoiesis, Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
Gastroenterology. 2009 Oct;137(4):1391-402.e1-6. doi: 10.1053/j.gastro.2009.06.063. Epub 2009 Jul 24.
BACKGROUND & AIMS: Retinoic acid plays a positive role in induction of FoxP3(+) regulatory T cells. Because retinoic acid is produced as a metabolite of vitamin A in the intestine and FoxP3(+) T cells regulate intestinal inflammation, we investigated the impact of vitamin A status on the regulatory T cells and inflammation in the intestine.
The SAMP1/YP model is a mouse model of Crohn's disease. We made vitamin A-deficient, vitamin A-excessive, and normal SAMP1/YP mice and assessed the intestinal inflammation. We also investigated the phenotype and function of FoxP3(+) T cells induced in different levels of vitamin A availability in regulation of intestinal inflammation in a T-cell-induced inflammation model in SCID mice.
The limited and excessive vitamin A conditions induced distinct FoxP3(+) T-cell subsets in vivo, and both ameliorated the intestinal inflammation in SAMP1/YP mice. The limited vitamin A condition greatly induced unusual CD103(+)CCR7(+) FoxP3(+) cells, while the high vitamin A condition induced CCR9(+)alpha4beta7(+) FoxP3(+) T cells in the intestine. Both FoxP3(+) T-cell populations, when transferred into mice with ongoing intestinal inflammation, were highly effective in reversing the inflammation. Blockade or lack of occupancy of RARalpha is a mechanism to induce highly suppressive CD103(+)CCR7(+) FoxP3(+) cells in both the thymus and periphery in limited vitamin A availability.
Our results identify novel pathways of inducing highly suppressive FoxP3(+) regulatory T cells that can effectively control intestinal inflammation. The results have significant ramifications in treating inflammatory bowel diseases.
维甲酸在诱导FoxP3(+)调节性T细胞方面发挥着积极作用。由于维甲酸是维生素A在肠道内的代谢产物，且FoxP3(+) T细胞可调节肠道炎症，因此我们研究了维生素A状态对肠道调节性T细胞及炎症的影响。
SAMP1/YP模型是一种克罗恩病小鼠模型。我们制备了维生素A缺乏、维生素A过量及正常的SAMP1/YP小鼠，并评估肠道炎症情况。我们还在SCID小鼠的T细胞诱导炎症模型中，研究了在不同维生素A水平下诱导产生的FoxP3(+) T细胞在调节肠道炎症中的表型和功能。
维生素A水平有限及过量的条件在体内诱导出不同的FoxP3(+) T细胞亚群，二者均改善了SAMP1/YP小鼠的肠道炎症。维生素A水平有限的条件极大地诱导出异常的CD103(+)CCR7(+) FoxP3(+)细胞，而高维生素A条件则在肠道中诱导出CCR9(+)α4β7(+) FoxP3(+) T细胞。当将这两种FoxP3(+) T细胞群体转移至患有持续性肠道炎症的小鼠体内时，二者在逆转炎症方面均非常有效。RARα的阻断或未被占据是在维生素A水平有限时，在胸腺和外周诱导产生高抑制性CD103(+)CCR7(+) FoxP3(+)细胞的一种机制。
我们的研究结果确定了诱导高抑制性FoxP3(+)调节性T细胞的新途径，这些细胞可有效控制肠道炎症。这些结果对治疗炎症性肠病具有重要意义。
