Tumor Cell-Released TLR4 Ligands Stimulate Gr-1+CD11b+ F4/80+ Cells to Induce Apoptosis of Activated T Cells
Tumor Cell-Released TLR4 Ligands Stimulate Gr-1+CD11b+ F4/80+ Cells to Induce Apoptosis of Activated T Cells
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DOI：
10.4049/jimmunol.1000772
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发表时间：
2010-09-01
影响因子：
4.4
通讯作者：
Feng, Zuo-Hua
中科院分区：
文献类型：
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作者：
Liu, Yan-Yan;Sun, Ling-Cong;Feng, Zuo-Hua
GR-1(+)CD11b(+)F4/80(+)细胞在肿瘤发生发展中起重要作用，对肿瘤免疫治疗有负面影响。到目前为止，经典的和交替的巨噬细胞激活刺激对其免疫抑制表型的调节机制还不是很清楚。在这项研究中，我们发现来自坏死性肿瘤细胞的分子(NTC-ms)刺激Gr-1(+)CD11b(+)F4/80(+)细胞诱导激活的T细胞凋亡，而不是未刺激的T细胞。NTC-ms通过TLR4信号通路诱导Gr-1(+)CD11b(+)F4/80(+)细胞中精氨酸酶I和IL-10的表达水平高于NO合成酶2和IL-12的表达水平。IL-10可增强NTC-ms刺激的Gr-1(+)CD11b(+)F4/80(+)细胞的诱导凋亡能力。只有当Gr-1(+)CD11b(+)F4/80(+)细胞对干扰素-γ的反应不减弱时，干扰素-γ才能降低Gr-1(+)CD11b(+)F4/80(+)细胞的诱导凋亡能力。然而，肿瘤可以减弱Gr-1(+)CD11b(+)F4/80(+)细胞表达IL-12的能力，部分原因是Gr-1(+)CD11b(+)F4/80(+)细胞和肿瘤来源的NTC-ms中存在活性的STAT3。在这种情况下，干扰素-γ不能有效降低Gr-1(+)CD11b(+)F4/80(+)细胞的诱导凋亡能力。4-1BBL/可溶性程序性死亡-1联合肿瘤免疫治疗可显著降低但不能完全消除Gr-1(+)CD11b(+)F4/80(+)细胞在局部微环境中的诱导凋亡能力。阻断TLR4信号通路可进一步降低Gr-1(+)CD11b(+)F4/80(+)细胞的诱导凋亡能力，增强4-1BBL/可溶性程序性死亡-1对肿瘤生长的抑制作用。这些发现表明不同的信号通路与Gr-1(+)CD11b(+)F4/80(+)细胞的诱导凋亡能力有关，并强调了阻断TLR4信号通路以防止Gr-1(+)CD11b(+)F4/80(+)细胞诱导T细胞凋亡的重要性。《免疫学杂志》，2010,185：2773-2782。
Gr-1(+)CD11b(+)F4/80(+) cells play important roles in tumor development and have a negative effect on tumor immunotherapy. So far, the mechanisms underlying the regulation of their immunosuppressive phenotype by classical and alternative macrophage activation stimuli are not well elucidated. In this study, we found that molecules from necrotic tumor cells (NTC-Ms) stimulated Gr-1(+)CD11b(+)F4/80(+) cells to induce apoptosis of activated T cells but not nonstimulated T cells. The apoptosis-inducing capacity was determined by higher expression levels of arginase I and IL-10 relative to those of NO synthase 2 and IL-12 in Gr-1(+)CD11b(+) F4/80(+) cells, which were induced by NTC-Ms through TLR4 signaling. The apoptosis-inducing capacity of NTC-Ms-stimulated Gr-1(+)CD11b(+)F4/80(+) cells could be enhanced by IL-10. IFN-gamma may reduce the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells only if their response to IFN-gamma was not attenuated. However, the potential of Gr-1(+)CD11b(+)F4/80(+) cells to express IL-12 in response to IFN-gamma could be attenuated by tumor, partially due to the existence of active STAT3 in Gr-1(+)CD11b(+)F4/80(+) cells and NTC-Ms from tumor. In this situation, IFN-gamma could not effectively reduce the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells. Tumor immunotherapy with 4-1BBL/soluble programmed death-1 may significantly reduce, but not abolish the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells in local microenvironment. Blockade of TLR4 signaling could further reduce the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells and enhance the suppressive effect of 4-1BBL/soluble form of programmed death-1 on tumor growth. These findings indicate the relationship of distinct signaling pathways with apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells and emphasize the importance of blocking TLR4 signaling to prevent the induction of T cell apoptosis by Gr-1(+)CD11b(+)F4/80(+) cells. The Journal of Immunology, 2010, 185: 2773-2782.