Interferon regulatory factor 4 (IRF4) controls myeloid-derived suppressor cell (MDSC) differentiation and function.
Myeloid-derived suppressor cells (MDSCs) are immature cells that do not differentiate into mature myeloid cells. Two major populations of PMN-MDSCs (Ly6GhighLy6ClowGr1highCD11b+) and MO-MDSCs (Ly6G-Ly6ChighGr-1intCD11b+) 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.
Department of Biological Sciences and the Research Center for Women's Disease, Sookmyung Women's University, Seoul, Republic of Korea.
Sorim
S
Nam
Department of Biological Sciences and the Research Center for Women's Disease, Sookmyung Women's University, Seoul, Republic of Korea.
Kyeongah
K
Kang
Department of Biological Sciences and the Research Center for Women's Disease, Sookmyung Women's University, Seoul, Republic of Korea.
Jae Seon
JS
Cha
Department of Life Science & Technology, PaiChai University, Daejeon, Republic of Korea; and.
Jung Woo
JW
Kim
Genome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Hee Gu
HG
Lee
Department of Biological Sciences and the Research Center for Women's Disease, Sookmyung Women's University, Seoul, Republic of Korea.
Yonghwan
Y
Kim
Department of Biological Sciences and the Research Center for Women's Disease, Sookmyung Women's University, Seoul, Republic of Korea.
Young
Y
Yang
Department of Biological Sciences and the Research Center for Women's Disease, Sookmyung Women's University, Seoul, Republic of Korea.
Myeong-Sok
MS
Lee
Department of Biological Sciences and the Research Center for Women's Disease, Sookmyung Women's University, Seoul, Republic of Korea; jslim@sookmyung.ac.kr.
Jong-Seok
JS
Lim
D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D008325:Mammary Neoplasms, Experimental / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072737:Myeloid-Derived Suppressor Cells / Q000502:physiology*; D038042:Myelopoiesis; D009569:Nitric Oxide / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species; D019821:Simvastatin / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology; D000099218:Interferon Regulatory Factor-4
D050835:Interferon Regulatory Factors; D016753:Interleukin-10; D009569:Nitric Oxide; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D019821:Simvastatin; D000099218:Interferon Regulatory Factor-4; C556062:IL10 protein, mouse
T cell proliferation; myeloid cell; tumor cell-conditioned medium