Interferon regulatory factor 4 (IRF4) controls myeloid-derived suppressor cell (MDSC) differentiation and function

Abstract

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.

Ebola virus secreted glycoprotein decreases the anti-viral immunity of macrophages in early inflammatory responses

“…However, if sGP is given during the polarization of M1 macrophages then the production of IL-10 is significantly decreased. This could possibly be due to the activity of some sGP-mediated activation of a regulatory adaptor protein such as interferon regulatory factor-4 (IRF4), which has a profound inhibitory effect on proinflammatory cytokine production [29], but a milder inhibitory effect on IL-10 production [30,31]. The fact that sGP only interferes with the IL-10 production if given during the polarization step could be due to a role of a regulatory protein such as IRF-4 in the differentiation process of hematopoietic stem cells [31].…”

“…This could possibly be due to the activity of some sGP-mediated activation of a regulatory adaptor protein such as interferon regulatory factor-4 (IRF4), which has a profound inhibitory effect on proinflammatory cytokine production [29], but a milder inhibitory effect on IL-10 production [30,31]. The fact that sGP only interferes with the IL-10 production if given during the polarization step could be due to a role of a regulatory protein such as IRF-4 in the differentiation process of hematopoietic stem cells [31]. IRF-4 has been previously shown to be a target of viral processes to suppress the immune response and promote viral pathogenesis [32,33].…”

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

“…Since MDSCs are one of the key immunosuppressive cells involved in maintaining the tumor microenvironment in each skin cancers, abrogation of the suppressive function of MDSCs delays tumor growth in skin cancers. For example, Nam et al reported the significance of IFN regulatory factor (IRF)4 for the functional differentiation of MDSCs by myeloid-specific deletion of IRF4 to abrogate the inhibitory effects of MDSCs in suppressing T-cell proliferation [69]. More recently, Pan et al reported that increased expression of ten-eleven translocation-2 (tet2) on tumor-infiltrating myeloid cells maintained the suppressive function of immature myeloid cells through IL-1R/MyD88 pathways in melanoma patients [70].…”

Allo-priming as a universal anti-viral vaccine: protecting elderly from current COVID-19 and any future unknown viral outbreak

“…MDSCs are potent inducers of immunosenescence [119], sepsis-acquired immunodeficiency [120] as well as cancer metastasis and progression [121]. MDSC are positively correlated with IL-6 and negatively correlated with IFN-ϒ [122,123].…”