Regulatory NK1.1-CD4+NKG2D+ subset induced by NKG2DL+ cells promotes tumor evasion in mice
Regulatory NK1.1-CD4+NKG2D+ subset induced by NKG2DL+ cells promotes tumor evasion in mice
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NKG2DL 细胞诱导的调节性 NK1.1→CD4 NKG2D 子集促进小鼠肿瘤逃避
DOI：
10.1007/s00262-018-2172-6
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发表时间：
2018-07-01
影响因子：
5.8
通讯作者：
Gong，Weijuan
中科院分区：
文献类型：
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作者：
Lin，Zhijie;Han，Sen;Gong，Weijuan
调节性T细胞在自身耐受和肿瘤逃避中起关键作用。具有调节活性的CD 4 + NKG 2D+细胞存在于NKG 2DL+肿瘤和幼年型系统性红斑狼疮患者中。我们先前表明，在pCD 86-Rae-1ε转基因小鼠中存在产生TGF-β的CD 4 + NKG 2D +T细胞。在此，我们对pCD 86-Rae-1ε转基因小鼠和MC 38荷瘤小鼠模型进行了离体和体内研究，结果表明NK1.1− CD 4 + NKG 2D +T细胞在pCD 86-Rae-1ε转基因小鼠中具有调节活性。此外，在移植NKG 2DL+肿瘤细胞的小鼠中诱导了该T细胞亚群，产生TGF-β和FasL，并分泌少量IFN-γ。该T细胞亚群下调效应T细胞和树突状细胞的功能，其被抗TGF-β抗体消除。在体内，NK1.1− CD 4 + NKG 2D +T细胞的过继转移促进了小鼠中TGF-β依赖性肿瘤的生长。我们进一步发现，NK1.1− CD 4 + NKG 2D +T细胞的离体诱导依赖于抗CD 3和NKG 2DL刺激。此外，调节性NK1.1− CD 4 + NKG 2D +T细胞不表达Foxp 3或CD 25，表达中等水平的T-bet。Western印迹显示，在MC 38荷瘤小鼠和pCD 86-Rae-1ε转基因小鼠的NK 1.1 − CD 4 + NKG 2D +T细胞中，STAT 3信号被激活。总之，我们描述了一种调节性NK1.1− CD 4 + NKG 2D + T细胞群，该细胞群不同于其他调节性T细胞，并且在pCD 86-Rae-1ε转基因小鼠和MC 38荷瘤小鼠中异常升高。
Regulatory T cells play critical roles in self-tolerance and tumor evasion. CD4+NKG2D+cells with regulatory activity are present in patients with NKG2DL+tumors and juvenile systemic lupus erythematosus. We previously showed that TGF-β-producing CD4+NKG2D+T cells are present in pCD86-Rae-1ε transgenic mice. Here, we performed both ex vivo and in vivo studies on pCD86-Rae-1ε transgenic mice and an MC38 tumor-bearing mouse model and show that NK1.1−CD4+NKG2D+T cells have regulatory activity in pCD86-Rae-1ε transgenic mice. Furthermore, this T-cell subset was induced in mice transplanted with NKG2DL+tumor cells and produced TGF-β and FasL, and secreted low amounts of IFN-γ. This T-cell subset downregulated the function of effector T cells and dendritic cells, which were abolished by anti-TGF-β antibody. In vivo, adoptive transfer of NK1.1−CD4+NKG2D+T cells promoted TGF-β-dependent tumor growth in mice. We further found that ex vivo induction of NK1.1−CD4+NKG2D+T cells was dependent on both anti-CD3 and NKG2DL stimulation. Furthermore, regulatory NK1.1−CD4+NKG2D+T cells did not express Foxp3 or CD25 and expressed intermediate levels of T-bet. Western-blotting showed that STAT3 signaling was activated in NK1.1−CD4+NKG2D+T cells of MC38 tumor-bearing and pCD86-Rae-1ε transgenic mice. In conclusion, we describe a regulatory NK1.1−CD4+NKG2D+T-cell population, different from other regulatory T cells and abnormally elevated in pCD86-Rae-1ε transgenic and MC38 tumor-bearing mice.