Blimp-1-Mediated Pathway Promotes Type I IFN Production in Plasmacytoid Dendritic Cells by Targeting to Interleukin-1 Receptor-Associated Kinase M.

Yi-An Ko,Kuo-I Lin,Jian-Jong Liang,Chin-Hsiu Liu,Yueh-Hsuan Chan,Yi-Ling Lin,Yi-Ping Hsueh,Tsung-Hsien Chuang

doi:10.3389/fimmu.2018.01828

Abstract

Plasmacytoid dendritic cells (pDCs) are a specialized subset of DCs capable of rapidly producing copious amounts of type I IFN (IFN-I) in response to viral infections. The mechanism regulating rapid production of IFN-I after pDCs are exposed to viral nucleic acids remains elusive. Here, we show that the transcription factor Blimp-1 is promptly induced in pDCs after exposure to TLR7 and TLR9 ligands via a unique Ras-related C3 botulinum toxin substrate (Rac)-mediated pathway. Deletion of the Prdm1 gene encoding Blimp-1 impaired production of IFN-I, but not other cytokines, upon viral infection or treatment with CpG DNA in pDCs. Accordingly, mice lacking Blimp-1 in DCs failed to produce IFN-I after CpG stimulation and did not mount proper antiviral responses following flavivirus infection. The development of pDCs in bone marrow as well as the induction of several activation markers, such as CD86, CD69, and MHCII, by CpG stimulation was generally not affected by the absence of Blimp-1. Mechanistically, we found that Blimp-1 controls the activation of IKKα and IRF7 by directly suppressing interleukin-1 receptor-associated kinase 3 (Irak3), a negative regulator of TLR signaling, in pDCs. Together, we identify a Blimp-1-dependent pathway that rapidly facilitates IFN-I production by relieving interleukin-1 receptor-associated kinase M, encoded by Irak3, in pDCs.

Highlights

Plasmacytoid dendritic cells are a distinctive subset of DCs with low abundance and a short lifespan [1]
Compared with the Plasmacytoid dendritic cells (pDCs) treated with medium alone, Blimp-1 expression in pDCs was upregulated after treatment with CpG-A or influenza virus (H1N1) infection (Figures 1A,B), which induced high IFN-I production (Figure 1C)
Similar to human pDCs, a rapid induction of Blimp-1 in mouse splenic pDCs was detected 3 h after intravenous injection of DOTAP/CpG-A, as compared with the DOTAP injected group (Figure 1D). This rapid induction of Blimp-1 was observed after exposure of Flt3-ligand-cultured bone marrow (BM)-derived pDCs (FLpDCs) to the CpG-A as compared with the medium treated FLpDCs (Figure 1E)

Summary

Introduction

Plasmacytoid dendritic cells (pDCs) are a distinctive subset of DCs with low abundance and a short lifespan [1]. They produce copious amounts of type I IFN (IFN-I) by utilizing highly expressed TLR7 and TLR9 to sense pathogen-derived single-stranded RNA and unmethylated DNA, respectively [2,3,4]. Besides IFN-I, pDCs secret proinflammatory cytokines to combat early phase infection, including IL-6, IL-12, and TNF-α. Aberrant pDC-derived IFN-I production is associated with the activation and expansion of auto-reactive T and B cells in autoimmune diseases [6]. Despite the importance of pDCs in the antiviral response and autoimmunity, the underlying regulatory pathways that contribute to the rapid large-scale production of IFN-I remain elusive

Methods

Results

Conclusion