The TLR7/8 ligand resiquimod targets monocyte-derived dendritic cell differentiation via TLR8 and augments functional dendritic cell generation

Hackstein, Holger; Knoche, Angela; Nockher, Angelika; Poeling, Jochen; Kubin, Thomas; Jurk, Marion; Vollmer, Jörg; Bein, Gregor

doi:10.1016/j.cellimm.2011.08.008

Cited by 43 publications

(33 citation statements)

References 46 publications

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“…42 This is an important finding because CD14 facilitates TLR2-dependent signaling by bacterial lipoproteins. 43,44,45 Upregulation of TLR2 and TLR8 also has been associated with enhanced clearance of human papillomavirus infection.…”

Section: Tlr Cross-talkmentioning

confidence: 92%

TLR8: the forgotten relative revindicated

et al. 2012

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The endosomal Toll-like receptors (TLRs) TLR3, TLR7, TLR8 and TLR9 are important in sensing foreign nucleic acids encountered by phagocytes. Because TLR8 was initially thought to be non-functional in mice, less is known about TLR8 than the genetically and functionally related TLR7. Originally associated with the recognition of single-stranded RNA of viral origin, there is now evidence that human TLR8 is also able to sense bacterial RNA released within phagosomal vacuoles, inducing the production of both nuclear factor (NF)-κB-dependent cytokines and type I interferons (IFNs), such as IFN-β. The functions of TLR8 extend beyond the recognition of foreign pathogens and include cross-talk with other endosomal TLRs, a process that may also have a role in the generation of autoimmunity.

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Section: Tlr Cross-talkmentioning

confidence: 92%

TLR8: the forgotten relative revindicated

et al. 2012

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“…Negative controls consisted of responder cells cultured with OVA in the absence of stimulator cells and responder cells cultured with stimulator cells in the absence of ovalbumin. Proliferation was quantitated by measurement of CFSE-dilution in responder cells by flow cytometry as described [33]. Positive bone-marrow-derived control DC pulsed with OVA induced naive CD4+ responder proliferation rates of >80%.…”

Section: Methodsmentioning

confidence: 99%

Modulation of respiratory dendritic cells during Klebsiella pneumonia infection

et al. 2013

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BackgroundKlebsiella pneumoniae is a leading cause of severe hospital-acquired respiratory tract infections and death but little is known regarding the modulation of respiratory dendritic cell (DC) subsets. Plasmacytoid DC (pDC) are specialized type 1 interferon producing cells and considered to be classical mediators of antiviral immunity.MethodBy using multiparameter flow cytometry analysis we have analysed the modulation of respiratory DC subsets after intratracheal Klebsiella pneumonia infection.ResultsData indicate that pDCs and MoDC were markedly elevated in the post acute pneumonia phase when compared to mock-infected controls. Analysis of draining mediastinal lymph nodes revealed a rapid increase of activated CD103+ DC, CD11b+ DC and MoDC within 48 h post infection. Lung pDC identification during bacterial pneumonia was confirmed by extended phenotyping for 120G8, mPDCA-1 and Siglec-H expression and by demonstration of high Interferon-alpha producing capacity after cell sorting. Cytokine expression analysis of ex vivo-sorted respiratory DC subpopulations from infected animals revealed elevated Interferon-alpha in pDC, elevated IFN-gamma, IL-4 and IL-13 in CD103+ DC and IL-19 and IL-12p35 in CD11b+ DC subsets in comparison to CD11c+ MHC-class IIlow cells indicating distinct functional roles. Antigen-specific naive CD4+ T cell stimulatory capacity of purified respiratory DC subsets was analysed in a model system with purified ovalbumin T cell receptor transgenic naive CD4+ responder T cells and respiratory DC subsets, pulsed with ovalbumin and matured with Klebsiella pneumoniae lysate. CD103+ DC and CD11b+ DC subsets represented the most potent naive CD4+ T helper cell activators.ConclusionThese results provide novel insight into the activation of respiratory DC subsets during Klebsiella pneumonia infection. The detection of increased respiratory pDC numbers in bacterial pneumonia may indicate possible novel pDC functions with respect to lung repair and regeneration.

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“…Several innate immune agonists have been shown to activate DC maturation in vitro, characterized by upregulation of MHC II and the costimulatory molecules CD80 and CD86 (35)(36)(37)(38). There are limited studies that show migratory DCs, which display a highly mature phenotype, can further mature in response to inflammatory stimuli (39).…”

Section: Discussionmentioning

confidence: 99%

Incorporation of CpG into a Liposomal Vaccine Formulation Increases the Maturation of Antigen-Loaded Dendritic Cells and Monocytes To Improve Local and Systemic Immunity

Neeland

Elhay²,

Nathanielsz³

et al. 2014

The Journal of Immunology

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Liposomal vaccine formulations incorporating stimulants that target innate immune receptors have been shown to significantly increase vaccine immunity. Following vaccination, innate cell populations respond to immune stimuli, phagocytose and process Ag, and migrate from the injection site, via the afferent lymphatic vessels, into the local lymph node. In this study, the signals received in the periphery promote and sculpt the adaptive immune response. Effector lymphocytes then leave the lymph node via the efferent lymphatic vessel to perform their systemic function. We have directly cannulated the ovine lymphatic vessels to detail the in vivo innate and adaptive immune responses occurring in the local draining lymphatic network following vaccination with a liposome-based delivery system incorporating CpG. We show that CpG induces the rapid recruitment of neutrophils, enhances dendritic cell–associated Ag transport, and influences the maturation of innate cells entering the afferent lymph. This translated into an extended period of lymph node shutdown, the induction of IFN-γ–positive T cells, and enhanced production of Ag-specific Abs. Taken together, the results of this study quantify the real-time in vivo kinetics of the immune response in a large animal model after vaccination of a dose comparable to that administered to humans. This study details enhancement of numerous immune mechanisms that provide an explanation for the immunogenic function of CpG when employed as an adjuvant within vaccines.

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The TLR7/8 ligand resiquimod targets monocyte-derived dendritic cell differentiation via TLR8 and augments functional dendritic cell generation

Cited by 43 publications

References 46 publications

TLR8: the forgotten relative revindicated

TLR8: the forgotten relative revindicated

Modulation of respiratory dendritic cells during Klebsiella pneumonia infection

Incorporation of CpG into a Liposomal Vaccine Formulation Increases the Maturation of Antigen-Loaded Dendritic Cells and Monocytes To Improve Local and Systemic Immunity

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