Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis
Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis
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DOI：
10.1152/ajpgi.00286.2007
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发表时间：
2008-01-01
影响因子：
4.5
通讯作者：
Watanabe, M.
中科院分区：
文献类型：
--
作者：
Ito, Y.;Kanai, T.;Watanabe, M.
最近的研究表明，NKG2D是自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、活化的CD8(+)T细胞和γDelta T细胞上的一种激活的共刺激受体，对炎症、转化和感染等细胞应激反应做出反应。在这里，我们发现过继转移CD4(+)CD45RB(High)T细胞引起的结肠炎SCID小鼠的肠道炎症的特征是CD4(+)NKG2D(+)T细胞显著增加，以及固有层CD11c(+)树突状细胞结构性表达NKG2D配体，如H60、MULT-1和RAE-1。此外，在将CD4(+)CD45Rb(高)T细胞转移到SCID小鼠体内后，使用非耗竭和中和的抗NKG2D单抗可显著抑制结肠炎的消退性疾病，消除白细胞的渗透，并减少固有层CD4(+)T细胞产生干扰素-γ。这些发现表明NKG2D信号通路在CD4(+)T细胞介导的疾病进展中起关键作用，并为炎症性肠病提供了一个新的治疗靶点。
It has been recently demonstrated that NKG2D is an activating costimulatory receptor on natural killer (NK) cells, natural killer T (NKT) cells, activated CD8(+) T cells, and gamma delta T cells, which respond to cellular stress, such as inflammation, transformation, and infection. Here we show that intestinal inflammation in colitic SCID mice induced by adoptive transfer of CD4(+) CD45RB(high) T cells is characterized by significant increase of CD4(+)NKG2D(+) T cells and constitutive expression of NKG2D ligands, such as H60, Mult-1, and Rae-1, by lamina propria CD11c(+) dendritic cells. Furthermore, treatment with nondepleting and neutralizing anti-NKG2D MAb after transfer of CD4(+)CD45RB(high) T cells into SCID mice significantly suppressed wasting disease with colitis, abrogated leukocyte infiltration, and reduced production of IFN-gamma by lamina propria CD4(+) T cells. These findings demonstrate that NKG2D signaling pathway is critically involved in CD4(+) T cell-mediated disease progression and suggest a new therapeutic target for inflammatory bowel diseases.