SHIP Regulates the Reciprocal Development of T Regulatory and Th17 Cells
SHIP Regulates the Reciprocal Development of T Regulatory and Th17 Cells
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DOI：
10.4049/jimmunol.0803749
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发表时间：
2009-07-15
影响因子：
4.4
通讯作者：
Levings, Megan K.
中科院分区：
文献类型：
--
作者：
Locke, Natasha R.;Patterson, Scott J.;Levings, Megan K.
维持CD 4（+）Th和调节性T细胞（T细胞）亚群之间的适当平衡对于维持免疫稳态和预防自身免疫至关重要。通过对TGF-β的共同需求，外周诱导的TcR的发展与Th 17细胞的发展密切相关，所产生的谱系取决于促炎细胞因子如IL-6的存在。目前，对控制Th 17细胞与Tcl 3细胞发育的分子信号通路知之甚少。TGF-β介导的Foxp 3表达诱导和TGF 3的抑制活性需要PI 3 K途径活性降低。为了研究PI 3 K通路的负调节剂如何影响Treg发育，我们研究了调节PI 3 K活性的脂质磷酸酶SHIP是否也在Treg的发育和功能中发挥作用。SHIP缺陷型TcR在体外和结肠炎T细胞转移模型中保持抑制能力。令人惊讶的是，SHIP缺陷型Th细胞比野生型Th细胞显著更不能够引起结肠炎，这是由于在体外和体内Th 17细胞分化中的严重缺陷。SHIP缺陷型T细胞不能发育成Th 17细胞，伴随着IL-6刺激的STAT 3磷酸化降低，以及在TGF-β和视黄酸的影响下分化成Treg细胞的能力增加。这些数据表明，SHIP是必不可少的正常的Th 17细胞的发展，这种脂质磷酸酶起着关键的作用，在相互调节的T细胞和Th 17细胞。免疫学杂志，2009，183：975-983.
Maintaining an appropriate balance between subsets of CD4(+) Th and T regulatory cells (Tregs) is critical to maintain immune homeostasis and prevent autoimmunity. Through a common requirement for TGF-beta, the development of peripherally induced Tregs is intimately linked to that of Th17 cells, with the resulting lineages depending on the presence of proinflammatory cytokines such as IL-6. Currently very little is known about the molecular signaling pathways that control the development of Tregs vs Th17 cells. Reduced activity of the PI3K pathway is required for TGF-beta-mediated induction of Foxp3 expression and the suppressive activity of Tregs. To investigate how negative regulators of the PI3K pathway impact Treg development, we investigated whether SHIP, a lipid phosphatase that regulates PI3K activity, also plays a role in the development and function of Tregs. SHIP-deficient Tregs maintained suppressive capacity in vitro and in a T cell transfer model of colitis. Surprisingly, SHIP-deficient Th cells were significantly less able to cause colitis than were wild-type Th cells due to a profound deficiency in Th17 cell differentiation, both in vitro and in vivo. The inability of SHIP-deficient T cells to develop into Th17 cells was accompanied by decreased IL-6-stimulated phosphorylation of STAT3 and an increased capacity to differentiate into Treg cells under the influence of TGF-beta and retinoic acid. These data indicate that SHIP is essential for normal Th17 cell development and that this lipid phosphatase plays a key role in the reciprocal regulation of Tregs and Th17 cells. The Journal of Immunology, 2009, 183: 975-983.