SOCS1 and SOCS3 Target IRF7 Degradation To Suppress TLR7-Mediated Type I IFN Production of Human Plasmacytoid Dendritic Cells.

Type I IFN production of plasmacytoid dendritic cells (pDCs) triggered by TLR-signaling is an essential part of antiviral responses and autoimmune reactions. Although it was well-documented that members of the cytokine signaling (SOCS) family regulate TLR-signaling, the mechanism of how SOCS proteins regulate TLR7-mediated type I IFN production has not been elucidated yet. In this article, we show that TLR7 activation in human pDCs induced the expression of SOCS1 and SOCS3. SOCS1 and SOCS3 strongly suppressed TLR7-mediated type I IFN production. Furthermore, we demonstrated that SOCS1- and SOCS3-bound IFN regulatory factor 7, a pivotal transcription factor of the TLR7 pathway, through the SH2 domain to promote its proteasomal degradation by lysine 48-linked polyubiquitination. Together, our results demonstrate that SOCS1/3-mediated degradation of IFN regulatory factor 7 directly regulates TLR7 signaling and type I IFN production in pDCs. This mechanism might be targeted by therapeutic approaches to either enhance type I IFN production in antiviral treatment or decrease type I IFN production in the treatment of autoimmune diseases.

Human plasmacytoid dendritic cells support Th17 cell effector function in response to TLR7 ligation.

Signals involved in the commitment of Th17 differentiation are of substantial interest for our understanding of antimicrobial defense mechanisms and autoimmune disorders. Various ways in which myeloid dendritic cells modulate Th17 differentiation have been identified. However, although plasmacytoid dendritic cells (PDCs) are regarded as important players in antiviral/antimicrobial host defense and autoimmune diseases, a putative modulatory role of PDCs in Th17 differentiation has not yet been elucidated in detail. We demonstrated that PDCs are capable of promoting Th17 differentiation in response to TLR7 stimulation. Further, both the differentiation of Th17 cells from naive T cells and the amplification of Th17 effector functions of memory T cells are promoted by PDCs after TLR7 activation. Our data are of strong clinical relevance because TLR7 activation in PDCs might represent one of the missing links between innate and adaptive immune mechanisms and contribute to the amplification of Th17-driven autoimmune disorders as well as viral host defense.

Toll-like receptor 7 agonists and skin.

Toll-like receptor (TLR) 7 is an intracellular TLR that is expressed on membranes of endosomes and recognizes nucleosides and nucleotides from intracellular pathogens. Synthetic agonists of TLR7 comprise guanine nucleoside analogues, stabilized immune modulatory RNA, as well as imidoazoquinoline-based compounds. Activation of pattern recognition receptors such as TLR with appropriate agonists induces a sophisticated defense machinery of the innate immune system. Targeting TLR pathways represents a cleverly devised and promising therapeutic strategy. At present, imiquimod is the most frequently used TLR7 ligand in clinical practice and has been approved for the treatment of external genital warts and (pre-) cancerous skin lesions such as actinic keratoses and superficial basal cell carcinoma. Upon topical application, this TLR7 agonist induces increased production of interferon-alpha, interleukin-12, tumor necrosis factor-alpha and a Th1 prone immune response. Imiquimod enforces the recruitment of myeloid and plasmacytoid dendritic cell subtypes and cytotoxic T cells, and increases the capacity of antigen-presenting cells to induce reactive T cells. Based on its multifaceted functions including proapoptotic, antifibrotic, antiangiogenic and antiaging effects, several reports about the efficacy of imiquimod as a treatment of various other skin diseases exist. This review summarizes the current knowledge about the immunological mechanisms induced by the TLR7 agonist imiquimod as well as established clinical therapies and putative applications of TLR7 agonists in the near future.

Inhibitory oligodeoxynucleotides downregulate herpes simplex virus-induced plasmacytoid dendritic cell type I interferon production and modulate cell function.

Recognition of nucleic acids by TLR9 expressed by human plasmacytoid dendritic cells (PDC) plays a key role in the defense against viral infections. Upon microbial pathogen stimulation, PDC secrete large amounts of type I interferon and arbitrate thereby both innate and adaptive immune mechanisms. Unmethylated CpG motifs, which are an integral part of bacterial or viral DNA, are used in vitro and in vivo to activate the TLR9 pathway, whereas inhibitory oligodeoxynucleotide (iODN) are capable of depressing TLR9 signaling. In this study we demonstrate that TTAGGG motifs containing iODN efficiently block the TLR9 signaling in terms of herpes simplex virus (HSV)-induced type I interferon production by PDC. However, iODN, as well as control ODN, still promote PDC maturation with upregulated expression of costimulatory molecules, major histocompatibility complex molecules, and other signs for PDC maturation. Furthermore, iODN and control ODN incubated PDC demonstrate increased T-cell stimulatory functions. Coculture experiments with autologous T cells indicate that iODN-treated PDC induce more CD4(+)CD25(+)Foxp3(+) T regulatory cells from naive CD4(+) T cells and preincubation of HSV-stimulated PDC with iODN upregulated T cells' IFN-gamma production. These data indicate that iODN, while blocking type I interferon production by PDC, modify PDC activation and maturation as well as T-cell priming and stimulation. Knowledge about the different functions of iODN on PDC elucidated might be crucial for immunotherapeutic strategies in which iODN motifs are used to prevent the interaction of CpG-DNA with TLR9 to calm down specific immunological responses, because our data indicate that iODN might not only have inhibitory functions but also be effective activators of immune cells.