pDC Activation by TLR7/8 Ligand CL097 Compared to TLR7 Ligand IMQ or TLR9 Ligand CpG

Abstract

Plasmacytoid dendritic cells (pDCs) express high levels of the toll-like receptors (TLRs) TLR7 and TLR9. In response to TLR7 and TLR9 ligands, pDCs are primary producers of type I interferons. Our previous study demonstrated that pDCs activated by the TLR7 ligand imiquimod (IMQ) and the TLR9 ligand CpG A can kill breast cancer cells in vitro and inhibit tumor growth in vivo. Moreover, we observed a distinctive morphological, phenotypic change in pDCs after activation by IMQ and CpG A. However, the effect of other TLR7 and TLR9 ligands on pDCs remains less understood. In this study, we treat pDCs with the TLR7 ligand IMQ, TLR7/8 ligands (CL097 and CL075), and three TLR9 ligands (different types of CpGs). The size of pDCs increased significantly after activation by TLR7, or TLR7/8 ligands. TLR7, TLR7/8, and TLR9 ligands similarly modulated cytokine release, as well as protein expression of pDC markers, costimulatory molecules, and cytotoxic molecules. Interestingly, TLR7/8 ligands, especially CL097, induced stronger responses. These results are relevant to the further study of the role and mechanism of pDC-induced antitumor effects and may aid in the development of a new strategy for future tumor immunotherapy.

Application of imiquimod-induced murine psoriasis model in evaluating interleukin-17A antagonist

“…For psoriasis research, there are several categories of experimental animal models, among which the “direct induction” type is most feasible for industrial drug development and screening [ 13 , 14 ]. Imiquimod (IMQ) is a ligand for Toll-like receptors 7/8 which activates macrophages, monocytes and dendritic cells, by directly administrating on mice skin, it induces significant psoriasis-like skin damage [ 15 , 16 ], and this model has been well-studied and widely used in fundamental research [ 17 ]. However, there are differences existing in both mechanism and clinical feature between IMQ-induced psoriasis in mice and human psoriasis [ 18 ], meanwhile in consideration of its acute and severe characters in disease progression, the usage of IMQ model is restricted in preclinical drug development.…”

TLR9-Activating CpG-B ODN but Not TLR7 Agonists Triggers Antibody Formation to Factor IX in Muscle Gene Transfer

“…A recent study on in vitro stimulation of pDCs, by several TLR7 and TLR9 agonists, found that TLR7/8 agonists generally activated pDCs much more strongly than TLR7-specific agonists. 66 In response to different ligands, pDCs produced extremely different levels of cytokines, despite similar levels of activation markers. 66 For example, TLR7/8 agonists produced more than twice as much IFN-a compared with TLR7-specific or TLR9 agonists (CpG-A and CpG-C ODNs), but IFN-a production was absent for other TLR9 agonists (CpG-B ODNs).…”

“…66 In response to different ligands, pDCs produced extremely different levels of cytokines, despite similar levels of activation markers. 66 For example, TLR7/8 agonists produced more than twice as much IFN-a compared with TLR7-specific or TLR9 agonists (CpG-A and CpG-C ODNs), but IFN-a production was absent for other TLR9 agonists (CpG-B ODNs). 66 Furthermore, in contrast to the enhancement of antibody formation seen here and in previous studies when CpG-B ODNs are coadministered with muscle gene transfer, CpG-A and CpG-C ODNs fail to induce antibodies.…”

The transcription factor reservoir and chromatin landscape in activated plasmacytoid dendritic cells

“…As we and others have shown, pDCs are now known for their capacity to produce unmatched amounts of type I IFN in response to stimulation of their toll like receptors (TLRs) (Ali et al, 2019;Asselin-Paturel et al, 2001;Bauer et al, 2016;Gilliet et al, 2008;Reizis, 2019). In contrast to other dendritic cell (DC) subsets, pDCs express only a limited repertoire of TLRs, namely predominantly TLR7 and TLR9 (Hornung et al, 2002), which recognize guanosine-and uridine-rich ssRNA and DNA containing CpG motifs (Diebold et al, 2004;Ishii and Akira, 2006;Wu et al, 2019). After TLR7 and TLR9 activation, in addition to type I IFN production, pDCs acquire the ability to prime T cell responses (Salio et al, 2004).…”