IL-21 regulates experimental colitis by modulating the balance between Treg and Th17 cells

被引:141
|
作者
Fantini, Massimo C.
Rizzo, Agelamaria
Final, Daniele
Caruso, Roberta
Becker, Christoph
Neurath, Markus F.
MacDonald, Thomas T.
Pallone, Francesco
Monteleone, Giovanni
机构
[1] Univ Roma Tor Vergata, Dept Internal Med, Div Gastroenterol, I-00133 Rome, Italy
[2] Johannes Gutenberg Univ Mainz, Lab Mucosal Immunol, D-6500 Mainz, Germany
[3] Barts & London Queen Marys Sch Med & Dent, Inst Cell & Mol Sci, London, England
关键词
colitis; foxp3; IL-21; TGF-beta; T-reg cells;
D O I
10.1002/eji.200737766
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Regulatory T (T-reg) cells play a key role in the maintenance of the immune system homeostasis. T-reg cells can be generated in the periphery under control of TGF-beta, a cytokine involved in the negative control of the immune system. However, TGF-beta cooperates with IL-6 in the generation of Th17 cells, a novel class of effector cells involved in numerous inflammatory diseases, including colitis. Therefore, TGF-beta emerges as a mediator of both anti-inflammatory and pro-inflammatory processes, depending on the local cytokine milieu. Here we demonstrate that IL-21, a type-1 cytokine produced by T cells and involved in the pathogenesis of immune-mediated diseases, prevents the TGF-beta-dependent expression of FoxP3, the master regulator of T-reg cell commitment, and the induction of suppressive capacity in naive CD4(+) T cells, while promoting the differentiation of Th17 cells. In vivo, CD4(+) naive T cells activated in the presence of TGF-beta and IL-21 failed to suppress colitis while inducing an inflammatory response characterized by high levels of IL-17 and ROR gamma t, the transcription factor expressed by Th17 cells. Therefore, IL-21 emerges as a key modulator of TGF-beta signaling, leading to the reciprocal differentiation of Treg and Th17 cells.
引用
收藏
页码:3155 / 3163
页数:9
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