Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

Ugolini, Matteo; Gerhard, Jenny; Burkert, Sanne; Jensen, Kristoffer Jarlov; Georg, Philipp; Ebner, Friederike; Volkers, Sarah M.; Thada, Shruthi; Dietert, Kristina; Bauer, Laura L.; Schäfer, Alexander; Helbig, Elisa T; Opitz, Bastian; Kurth, Florian; Sur, Saubashya; Dittrich, Nickel; Gaddam, Sumanlatha; Conrad, Melanie L.; Benn, Christine Stabell; Blohm, Ulrike; Gruber, Achim D.; Hutloff, Andreas; Hartmann, Susanne; Boekschoten, Mark V.; Müller, Michael; Jungersen, Gregers; Schumann, Ralf R.; Suttorp, Norbert; Sander, Leif E.

doi:10.1038/s41590-018-0068-4

Cited by 132 publications

(182 citation statements)

References 84 publications

(107 reference statements)

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“…Others show that IL‐1β, produced by monocytes downstream of TLR signalling and inflammasome activation, induces differentiation of T follicular helper cells, which augment antibody production . Moreover, Ugolini et al . demonstrate that TLR8 engagement represents a mechanism via which CD14 + CD16 + monocytes selectively detect viable as opposed to dead microorganisms, and signal this via producing IL‐1β, which activates T follicular helper cells.…”

Section: Discussionmentioning

confidence: 99%

“…Others show that IL-1b, produced by monocytes downstream of TLR signalling and inflammasome activation, induces differentiation of T follicular helper cells, which augment antibody production. 37 Moreover, Ugolini et al 38 demonstrate that TLR8 engagement represents a mechanism via which CD14 + CD16 + monocytes selectively detect viable as opposed to dead microorganisms, and signal this via producing IL-1b, which activates T follicular helper cells. Similarly, Kwissa et al 21 found that CD14 + CD16 + monocytes, which are induced by dengue virus infection, and by R848 but not CpG, enhance B-cell differentiation, providing another possible explanation for the differential role of monocytes in R848-versus CpG-stimulated B-cell differentiation.…”

Section: Monocytesmentioning

confidence: 99%

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Distinguishing naive‐ from memory‐derived human B cells during acute responses

et al. 2019

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Objectives A fundamental question in influenza research is whether antibody titre decline upon successive exposure to variant strains is consequent to recall of cross‐reactive memory B cells that competitively inhibit naive B‐cell responses. In connection, it is not clear whether naive and memory B cells remain phenotypically distinct acutely after activation such that they may be distinguished ex vivo. Methods Here, we first compared the capacity of anti‐Ig and Toll‐like‐receptor (TLR) 7/8 and TLR9 agonists (R848 and CpG) to augment human B‐cell differentiation induced by IL‐21 and sCD40L. The conditions that induced optimal differentiation were then used to compare the post‐activation phenotype of sort‐purified naive and memory B‐cell subsets by FACS and antibody‐secreting cell (ASC) ELISPOT. Results Sort‐purified naive and memory B cells underwent robust plasmablast and ASC formation when stimulated with R848, but not CpG, and co‐cultured with monocytes. This coincided with increased IL‐1β and IL‐6 production when B cells were co‐cultured with monocytes and stimulated with R848, but not CpG. Naive B cells underwent equivalent ASC generation, but exhibited less class‐switch and modulation of CD27, CD38 and CD20 expression than memory B cells after stimulation with R848 and monocytes for 6 days. Conclusion Stimulation with R848, IL‐21 and sCD40L in the presence of monocytes induces robust differentiation and ASC generation from both naive and memory B‐cells. However, naive and memory B cells retain key phenotypic differences after activation that may facilitate ex vivo discrimination and better characterisation of acute responses to variant antigens.

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Section: Discussionmentioning

confidence: 99%

Section: Monocytesmentioning

confidence: 99%

Distinguishing naive‐ from memory‐derived human B cells during acute responses

et al. 2019

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“…TLRs 7 and 8 are implicated in the recognition of naturally derived uridineerich ssRNAs of influenza and HIV [36]. In addition TLR7 and TLR8 recognize bacterial RNA [51,64]. Furthermore, TLR7 and 8 are expressed in human plasmacytoid DCs (pDCs), in T and B cells, monocytes and macrophages [65,66].…”

Section: Adjuvant Strategiesmentioning

confidence: 99%

“…Recently, Zhang et al identified, for the first time, human TLR8 small antagonist molecules with a novel inhibition mechanism [304]. SAR studies on the pyrazolo[1,5-a]pyrimidine series led to identification of the compound: CU-CPT8m (64), which proved to be the most active with an IC50 of 67 nM and a strong ability to inhibit the production of pro-inflammatory cytokines (Fig. 34).…”

Section: Bicycles Analoguesmentioning

confidence: 99%

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

Patinote

Karroum

Moarbess

et al. 2020

European Journal of Medicinal Chemistry

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a b s t r a c tThe discovery of the TLRs family and more precisely its functions opened a variety of gates to modulate immunological host responses. TLRs 7/8 are located in the endosomal compartment and activate a specific signaling pathway in a MyD88-dependant manner. According to their involvement into various autoimmune, inflammatory and malignant diseases, researchers have designed diverse TLRs 7/8 ligands able to boost or block the inherent signal transduction. These modulators are often small synthetic compounds and most act as agonists and to a much lesser extent as antagonists. Some of them have reached preclinical and clinical trials, and only one has been approved by the FDA and EMA, imiquimod. The key to the success of these modulators probably lies in their combination with other therapies as recently demonstrated. We gather in this review more than 360 scientific publications, reviews and patents, relating the extensive work carried out by researchers on the design of TLRs 7/8 modulators, which are classified firstly by their biological activities (agonist or antagonist) and then by their chemical structures, which total syntheses are not discussed here. This review also reports about 90 clinical cases, thereby showing the biological interest of these modulators in multiple pathologies.

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“…Unlike TLR7, TLR8 activation mainly results in the production of inflammatory cytokines due to the types of cells in which it is expressed. A recent study demonstrated that recognition of live bacteria by TLR8 induced human monocytes to produce large amounts of IL-12, which drives a follicular helper T-cell response in naive human CD4 + T cells [85]. …”

Section: Antiviral Immunity Mediated By Rna Sensorsmentioning

confidence: 99%

Extracellular RNA Sensing by Pattern Recognition Receptors

et al. 2018

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RNA works as a genome and messenger in RNA viruses, and it sends messages in most of the creatures of the Earth, including viruses, bacteria, fungi, plants, and animals. The human innate immune system has evolved to detect single- and double-stranded RNA molecules from microbes by pattern recognition receptors and induce defense reactions against infections such as the production of type I interferons and inflammatory cytokines. To avoid cytokine toxicity causing chronic inflammation or autoimmunity by sensing self-RNA, the activation of RNA sensors is strictly regulated. All of the Toll-like receptors that recognize RNA are localized to endosomes/lysosomes, which require internalization of RNA for sensing through an endocytic pathway. RIG-I-like receptors sense RNA in cytosol. These receptors are expressed in a cell type-specific fashion, enabling sensing of RNA for a wide range of microbial invasions. At the same time, both endosomal and cytoplasmic receptors have strategies to respond only to RNA of pathogenic microorganisms or dying cells. RNA are potential vaccine adjuvants for immune enhancement against cancer and provide a benefit for vaccinations. Understanding the detailed molecular mechanisms of the RNA-sensing system will help us to broaden the clinical utility of RNA adjuvants for patients with incurable diseases.

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Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

Cited by 132 publications

References 84 publications

Distinguishing naive‐ from memory‐derived human B cells during acute responses

Distinguishing naive‐ from memory‐derived human B cells during acute responses

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

Extracellular RNA Sensing by Pattern Recognition Receptors

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