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J immunol:CD200R信号调节肿瘤特异性T细胞免疫反应

2016-07-08 生物谷Bioon.com 生物谷Bioon.com

  2016年7月8日 讯 /生物谷BIOON/ --肿瘤相关的炎症与免疫反应是肿瘤微环境中调节肿瘤生长,发育以及恶化的关键因子。肿瘤相关的髓系细胞(TAMC)对其的血管生成、扩散以及T细胞反应等具有重要的影响。因此,找到调控TAMC的关键信号通路对于开发癌症的免疫疗法是十分有意义的。此前研究发现,CD200-CD200R的相互作用可能对于肿瘤的生长与恶化有一定的作用。 CD2

 

2016年7月8日 讯 /生物谷BIOON/ --肿瘤相关的炎症与免疫反应是肿瘤微环境中调节肿瘤生长,发育以及恶化的关键因子。肿瘤相关的髓系细胞(TAMC)对其的血管生成、扩散以及T细胞反应等具有重要的影响。因此,找到调控TAMC的关键信号通路对于开发癌症的免疫疗法是十分有意义的。此前研究发现,CD200-CD200R的相互作用可能对于肿瘤的生长与恶化有一定的作用。

CD200(OX-2)是IG超家族的一员,它含有两个胞外Ig结构域以及一个作用不明的胞内段基序。CD200在大量细胞表面均有表达,包括B细胞以及激活后的T细胞。CD200R,即CD200的受体,也是Ig超家族的一员,它主要表达于中性粒细胞,巨噬细胞以及杆状细胞。体外实验表明,CD200R的激活能够抑制髓系细胞的活性。与大多数Ig超家族成员不同,CD200R缺少ITIM结构域,但其拥有一个67aa的胞内段,其中含有三个酪氨酸残基。在被CD200R激活之后,第三个酪氨酸将会被磷酸化,之后将会引发胞内DOK-1与DOK-2的聚集与磷酸化。两者随后与RasGAP以及SHIP结合。在巨噬细胞与杆状细胞中,这一反应能够抑制ERK、JNK以及P38的磷酸化。小鼠试验表明,CD200R在巨噬细胞中的激活能够抑制自体免疫反应。这些结果说明CD200-CD200R信号参与抑制了髓系细胞的功能。
 
CD200在多种癌症细胞中也有表达,包括黑色素瘤。一般认为CD200具有促肿瘤化的效应。然而,这以结论是基于同种异体的模型试验得出的。此前研究利用同源的小鼠肿瘤模型,发现CD200可能能够抑制肿瘤的生长以及恶化。为了进一步研究CD200R信号在肿瘤发生中的作用,来自俄亥俄州立大学的Xue-Feng Bai课题组进行了深入研究,相关结果发表在最近一期的《Journal of Immunology》杂志上。
 
首先,作者将正常的B16黑色素瘤细胞与过表达CD200的B16细胞移植入B6小鼠体内,经过检测,发现过表达CD200能够明显抑制肿瘤的生长。之后,作者对不同的肿瘤组织进行分析,发现CD200过表达的肿瘤组织中含有更高水平的CD4与CD8 T细胞。进一步分析后,作者发现这部分浸润的CD4 T细胞主要成分为Treg细胞以及Th1细胞;另外,在CD200阳性的肿瘤中CD8 T细胞的比例也有明显升高。因此,CD200的表达的确能够影响肿瘤相关T细胞的反应。
 
进一步,为了证明CD200抑制肿瘤生长的效应是源于CD200R信号通路,作者构建了CD200R缺失突变的小鼠。通过肿瘤移植的试验,作者发现在CD200R缺失突变的小鼠中CD200阳性的肿瘤生长速率明显提高,而CD200阴性的肿瘤在两种小鼠中的生长速率基本一致。之后,作者发现在CD200R缺失突变体小鼠中,髓系细胞的增殖以及肿瘤的血管生成反应都明显增强。另外,CD200R的缺失也能够导致CD200阳性肿瘤组织中T细胞反应水平的下降。
 
综上,作者证明了CD200通过调节CD200R信号通路能够起到促进肿瘤特异性T细胞免疫反应的作用。

原始出处:
 
Jin-Qing Liu, Fatemeh Talebian, Lisha Wu, Zhihao Liu, Ming-Song Li, Laichu Wu, Jianmin Zhu, Joseph Markowitz, William E. Carson III, Sujit Basu and Xue-Feng Bai.
A Critical Role for CD200R Signaling in Limiting the Growth and Metastasis of CD200+ Melanoma.doi: 10.4049/jimmunol.1600052

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    2016-07-20 aliceclz
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