LILRB4 ITIMs mediate the T cell suppression and infiltration of acute myeloid leukemia cells
LILRB4 ITIMs mediate the T cell suppression and infiltration of acute myeloid leukemia cells
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LILRB4 ITIM 介导急性髓系白血病细胞的 T 细胞抑制和浸润。
DOI：
10.1038/s41423-019-0321-2
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发表时间：
2020-03-01
影响因子：
24.1
通讯作者：
Zhang, Cheng Cheng
中科院分区：
文献类型：
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作者：
Li, Zunling;Deng, Mi;Zhang, Cheng Cheng
我们最近证明，白细胞免疫球蛋白样受体4（LILRB 4）表达的单核细胞急性髓系白血病（AML）细胞介导的T细胞抑制和白血病细胞浸润通过其胞内域。LILRB 4的胞质结构域包含三个基于免疫受体酪氨酸的抑制基序（ITIM）; 360、412和442位的酪氨酸是磷酸化位点。在这里，我们分析了AML细胞中LILRB 4的ITIM如何介导其功能。我们的体外和体内数据显示，LILRB 4的Y-412和Y-442，而不是Y-360，是T细胞抑制所必需的，并且所有三种ITIM都是白血病细胞浸润所必需的。我们构建了含有LILRB 4胞外结构域和LILRB 1胞内结构域的嵌合蛋白，反之亦然。LILRB 4的胞内结构域介导T细胞抑制和AML细胞迁移，但LILRB 1不介导。因此，我们的研究确定了LILRB 4 ITIM在AML细胞中的独特信号传导作用。
We recently demonstrated that leukocyte Ig-like receptor 4 (LILRB4) expressed by monocytic acute myeloid leukemia (AML) cells mediates T-cell inhibition and leukemia cell infiltration via its intracellular domain. The cytoplasmic domain of LILRB4 contains three immunoreceptor tyrosine-based inhibitory motifs (ITIMs); the tyrosines at positions 360, 412, and 442 are phosphorylation sites. Here, we analyzed how the ITIMs of LILRB4 in AML cells mediate its function. Our in vitro and in vivo data show that Y-412 and Y-442, but not Y-360, of LILRB4 are required for T-cell inhibition, and all three ITIMs are needed for leukemia cell infiltration. We constructed chimeric proteins containing the extracellular domain of LILRB4 and the intracellular domain of LILRB1 and vice versa. The intracellular domain of LILRB4, but not that of LILRB1, mediates T-cell suppression and AML cell migration. Our studies thus defined the unique signaling roles of LILRB4 ITIMs in AML cells.