Interferon regulatory factor 4 (IRF4) controls myeloid-derived suppressor cell (MDSC) differentiation and function
Interferon regulatory factor 4 (IRF4) controls myeloid-derived suppressor cell (MDSC) differentiation and function
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DOI：
10.1189/jlb.1a0215-068rr
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发表时间：
2016-12-01
影响因子：
5.5
通讯作者：
Lim, Jong-Seok
中科院分区：
文献类型：
--
作者：
Nam, Sorim;Kang, Kyeongah;Lim, Jong-Seok
骨髓源性抑制细胞 (MDSC) 是不成熟的细胞，不会分化为成熟的骨髓细胞。 PMN-MDSC 的两个主要群体（Ly6G（高）Ly6C（低）Gr1（高）CD11b（+））和 MO-MDSC（Ly6G（-）Ly6C（高）Gr-1（int）CD11b（+））具有免疫抑制功能。干扰素调节因子 4 (IRF4) 在 TLR 信号传导的负调节中发挥作用，并与淋巴细胞发育相关。然而，IRF4 在骨髓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的表达被显着抑制。 MDSC中IRF4的mRNA和蛋白水平逐渐降低，具体取决于4T1模型中肿瘤的发展。骨髓细胞中 siRNA 介导的 IRF4 敲低促进了 PMN-MDSC 的分化。同样，使用辛伐他汀（已知可抑制 IRF4 表达）在骨髓细胞中抑制 IRF4，会增加 PMN-MDSC 数量。相反，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，用 IRF4 上游调节因子 IL-4 处理，诱导骨髓细胞中 IRF4 表达，因此，IL-4 诱导的 IRF4 表达导致 PMN-MDSC 数量减少。最后，我们证实MDSC中IRF4的表达可以调节其活性，通过IL-10的产生和ROS的产生来抑制T细胞增殖，并且IRF4的骨髓特异性缺失导致MDSC分化的增加。我们目前的研究结果表明，肿瘤形成引起的IRF4减少可以增加MDSC的数量，并且MDSC中IRF4表达的增加可能会损害MDSC的免疫抑制功能。
Myeloid-derived suppressor cells (MDSCs) are immature cells that do not differentiate into mature myeloid cells. Two major populations of PMN-MDSCs (Ly6G(high)Ly6C(low)Gr1(high)CD11b(+)) andMO-MDSCs (Ly6G(-)Ly6C(high)Gr-1(int)CD11b(+)) 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.