Abstract
DC-SIGN, a C-type lectin mainly expressed by DCs, mediates antigen uptake and can induce specific immune responses, depending on the ligand involved. Owing to these properties, DC-SIGN is an attracting target for approaches aimed at tailoring the immune response towards specific immunologic outcomes. A multivalent DC-SIGN ligand (Polyman26), containing at its core a fluorescent “rod-like” spacer and able to inhibit DC-SIGN mediated HIV infection in nanomolar concentration, has been recently developed by our group. We investigated the internalization pattern and the ability of Polyman26 to elicit innate immune responses. Results obtained by confocal microscopy indicate that Polyman26 is internalized by DCs via receptor- mediated endocytosis and is then routed to endolysosomal compartments, thus being presented together with MHC class II molecules, with important implications for the development of vaccines. Moreover, Polyman26 up-regulated the production of β-chemokines and pro-inflammatory cytokines (including IL-1β, IL-6, IL-12, and TNFα) as well as the expression of TLR9 and CD40L. These results indicate that glycomimetic DC-SIGN ligands should be further investigated and suggest that these compounds could be used to differentially stimulate immune responses.
Highlights
Immunomodulatory strategies are currently used in the attempt to prevent and treat a range of pathologies, including viral and bacterial infection, autoimmune disorders, and cancer; these strategies, are still in a pioneering stage and need to be much better defined
Multivalent dendrimers bearing glycomimetic DC-SIGN ligands performed as efficient inhibitors of DC-SIGN-mediated HIV infection of cellular and cervical explant models by competing with the ability of the virus to bind to the receptor[18,19,20]
Binds to DC-SIGN-wt and ΔRep, but not to the ΔCRD mutant. These results indicate that the lack of Carbohydrate Recognition Domain (CRD) prevents the interaction between Polyman[26] and DC-SIGN, demonstrating that this highly mannosylated dendrimer selectively binds to the carbohydrate recognition domain of the protein (Fig. 2)
Summary
Immunomodulatory strategies are currently used in the attempt to prevent and treat a range of pathologies, including viral and bacterial infection, autoimmune disorders, and cancer; these strategies, are still in a pioneering stage and need to be much better defined. Multivalent dendrimers bearing glycomimetic DC-SIGN ligands performed as efficient inhibitors of DC-SIGN-mediated HIV infection of cellular and cervical explant models by competing with the ability of the virus to bind to the receptor[18,19,20] One of the these molecules (Polyman19) could induce the expression of β-chemokines, cytokines, and co-stimulatory molecules involved in activating DCs, in modulating adaptive immunity, and in counteracting HIV infection[21]. We developed a novel type of glycodendrimers that include a linear rigid spacer (“rod-like” spacer) at their core[22] This structure allows to control the size of the dendrimers and tune it to fit the distance between adjacent binding sites on a DC-SIGN tetramer, reaching unprecedented affinity for constructs of similar valency. Thanks to the natural fluorescence of the rod-like spacer, the internalization pathway and the endocytic routing of the dendrimer to specific sub-cellular organelles were investigated
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
