Interferon regulatory factor 4 (IRF4) controls myeloid‐derived suppressor cell (MDSC) differentiation and function. Issue 6 (6th September 2016)

• Record Type: Journal Article
• Authors: Nam, Sorim; Kang, Kyeongah; Cha, Jae Seon; Kim, Jung Woo; Lee, Hee Gu; Kim, Yonghwan; Yang, Young; Lee, Myeong‐Sok; Lim, Jong‐Seok
• Is Part Of: Journal of leukocyte biology. Volume 100:Issue 6(2016)
• Page Start: 1273
• Page End: 1284
• Publication Date: 2016-09-06
• Subjects: myeloid cell -- tumor cell‐conditioned medium -- T cell proliferation; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.1A0215-068RR
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : IRF4 reduction induced by tumor formation can increase the number of MDSCs, where an increase in IRF4 expression may infringe immune suppressive function. Abstract : 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 + ) and MO‐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.