Autocrine activation of canonical BMP signaling regulates PD-L1 and PD-L2 expression in human dendritic cells
Autocrine activation of canonical BMP signaling regulates PD-L1 and PD-L2 expression in human dendritic cells
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DOI：
10.1002/eji.201343693
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发表时间：
2014-04-01
影响因子：
5.4
通讯作者：
Varas, Alberto
中科院分区：
文献类型：
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作者：
Martinez, Victor G.;Hidalgo, Laura;Varas, Alberto
骨形态发生蛋白(BMPs)是一种多功能的生长因子，调节包括免疫系统在内的多种系统的分化和增殖。以前，我们描述了BMP信号通路在人类单核细胞来源的树突状细胞(MoDC)中具有功能，发现MoDC既表达信号转导所需的特定受体，也表达Smad蛋白。在这项研究中，我们提供了人类MoDC产生BMP-4的证据，并且这种产生在成熟过程中增加，BMP信号转导也是如此。当DC在BMP途径抑制剂存在的情况下成熟时，成熟标志物PD-L1和PD-L2的表达减少，而细胞因子的产生不受影响。因此，这些成熟的DC表现出增强的刺激T细胞和NK细胞的能力。最终，BMP信号在成熟过程中的抑制导致IRF-1的表达减少，IRF-1是一种正向调节PD-L1和PD-L2表达的转录因子。本研究表明，BMP信号通路可能通过IRF-1转录因子调控人MoDC成熟过程中PD-L1和PD-L2的表达，并指出BMP信号通路的调控可显著提高MoDC免疫治疗的免疫原性。
Bone morphogenetic proteins (BMPs) are multifunctional growth factors regulating differentiation and proliferation in numerous systems including the immune system. Previously, we described that the BMP signaling pathway is functional in human monocyte-derived dendritic cells (MoDCs), which were found to express both the specific receptors and the Smad proteins required for signal transduction. In this study, we provide evidence that human MoDCs produce BMP-4 and that this production is increased over the maturation process as is BMP signal transduction. When DCs are matured in the presence of an inhibitor of the BMP pathway, the expression of the maturation markers PD-L1 and PD-L2 is reduced, while cytokine production is not affected. As a result, these mature DCs present an augmented ability to stimulate both T cells and NK cells. Eventually, the inhibition of BMP signaling during maturation causes a reduced expression of IRF-1, a transcription factor that positively regulates the expression of PD-L1 and PD-L2. The present study indicates that the BMP signaling pathway regulates PD-L1 and PD-L2 expression in human MoDCs during the maturation process, probably through the IRF-1 transcription factor, and also points out that the manipulation of BMP signaling might considerably improve the immunogenicity of MoDCs used in immunotherapy.