Department of Biological Sciences and the Research Center for Women's Disease, Sookmyung Women's University, Seoul, Republic of Korea.
Department of Life Science & Technology, PaiChai University, Daejeon, Republic of Korea; and.
J Leukoc Biol. 2016 Dec;100(6):1273-1284. doi: 10.1189/jlb.1A0215-068RR. Epub 2016 Sep 6.
Myeloid-derived suppressor cells (MDSCs) are immature cells that do not differentiate into mature myeloid cells. Two major populations of PMN-MDSCs (Ly6GLy6CGr1CD11b) and MO-MDSCs (Ly6GLy6CGr-1CD11b) have an immune suppressive function. Interferon regulatory factor 4 (IRF4) has a role in the negative regulation of TLR signaling and is associated with lymphoid cell development. However, the roles of IRF4 in myeloid cell differentiation are unclear. In this study, we found that IRF4 expression was remarkably suppressed during the development of MDSCs in the tumor microenvironment. Both the mRNA and protein levels of IRF4 in MDSCs were gradually reduced, depending on the development of tumors in the 4T1 model. siRNA-mediated knockdown of IRF4 in bone marrow cells promoted the differentiation of PMN-MDSCs. Similarly, IRF4 inhibition in bone marrow cells using simvastatin, which has been known to inhibit IRF4 expression, increased PMN-MDSC numbers. In contrast, IRF4 overexpression in bone marrow cells inhibited the total numbers of MDSCs, especially PMN-MDSCs. Notably, treatment with IL-4, an upstream regulator of IRF4, induced IRF4 expression in the bone marrow cells, and consequently, IL-4-induced IRF4 expression resulted in a decrease in PMN-MDSC numbers. Finally, we confirmed that IRF4 expression in MDSCs can modulate their activity to inhibit T cell proliferation through IL-10 production and ROS generation, and myeloid-specific deletion of IRF4 leads to the increase of MDSC differentiation. Our present findings indicate that IRF4 reduction induced by tumor formation can increase the number of MDSCs, and increases in the IRF4 expression in MDSCs may infringe on the immune-suppressive function of MDSCs.
髓源性抑制细胞（MDSCs）是未分化为成熟髓系细胞的不成熟细胞。PMN-MDSCs（Ly6GLy6CGr1CD11b）和 MO-MDSCs（Ly6GLy6CGr-1CD11b）这两种主要的 PMN-MDSC 群体具有免疫抑制功能。干扰素调节因子 4（IRF4）在 TLR 信号的负调控中起作用，并与淋巴样细胞发育有关。然而，IRF4 在髓系细胞分化中的作用尚不清楚。在这项研究中，我们发现在肿瘤微环境中 MDSC 的发育过程中，IRF4 的表达明显受到抑制。在 4T1 模型中，随着肿瘤的发展，MDSC 中的 IRF4mRNA 和蛋白水平逐渐降低。用 siRNA 介导的骨髓细胞中 IRF4 的敲低促进了 PMN-MDSC 的分化。同样，用辛伐他汀抑制骨髓细胞中的 IRF4（已知辛伐他汀可抑制 IRF4 的表达）也增加了 PMN-MDSC 的数量。相比之下，骨髓细胞中 IRF4 的过表达抑制了 MDSC 的总数，尤其是 PMN-MDSC。值得注意的是，IL-4（IRF4 的上游调节剂）处理可诱导骨髓细胞中 IRF4 的表达，并且，IL-4 诱导的 IRF4 表达导致 PMN-MDSC 数量减少。最后，我们证实 MDSC 中的 IRF4 表达可以通过产生 IL-10 和 ROS 来调节其抑制 T 细胞增殖的活性，并且骨髓细胞特异性缺失 IRF4 会导致 MDSC 分化增加。我们的研究结果表明，肿瘤形成诱导的 IRF4 减少可以增加 MDSC 的数量，并且 MDSC 中 IRF4 的表达增加可能会损害 MDSC 的免疫抑制功能。
