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Antigen structure affects cellular routing through DC-SIGN

Author(s)
Jarvis, Cassie M.; Zwick, Daniel B.; Grim, Joseph C.; Alam, Mohammad Murshid; Prost, Lynne R.; Gardiner, Jaye C.; Park, Soyeong; Zimdars, Laraine L.; Sherer, Nathan M.; Kiessling, Laura L; ... Show more Show less
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Abstract
Dendritic cell (DC) lectins mediate the recognition, uptake, and processing of antigens, but they can also be coopted by pathogens for infection. These distinct activities depend upon the routing of antigens within the cell. Antigens directed to endosomal compartments are degraded, and the peptides are presented on major histocompatibility complex class II molecules, thereby promoting immunity. Alternatively, HIV-1 can avoid degradation, as virus engagement with C-type lectin receptors (CLRs), such as DC-SIGN (DC-specific ICAM-3–grabbing nonintegrin) results in trafficking to surface-accessible invaginated pockets. This process appears to enable infection of T cells in trans. We sought to explore whether antigen fate upon CLR-mediated internalization was affected by antigen physical properties. To this end, we employed the ring-opening metathesis polymerization to generate glycopolymers that each display multiple copies of mannoside ligand for DC-SIGN, yet differ in length and size. The rate and extent of glycopolymer internalization depended upon polymer structure—longer polymers were internalized more rapidly and more efficiently than were shorter polymers. The trafficking, however, did not differ, and both short and longer polymers colocalized with transferrin-labeled early endosomes. To explore how DC-SIGN directs larger particles, such as pathogens, we induced aggregation of the polymers to access particulate antigens. Strikingly, these particulate antigens were diverted to the invaginated pockets that harbor HIV-1. Thus, antigen structure has a dramatic effect on DC-SIGN–mediated uptake and trafficking. These findings have consequences for the design of synthetic vaccines. Additionally, the results suggest strategies for targeting DC reservoirs that harbor viral pathogens.
Date issued
2019-07
URI
https://hdl.handle.net/1721.1/123339
Department
Massachusetts Institute of Technology. Department of Chemistry
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
National Academy of Sciences
Citation
Jarvis, Cassie M. et al. "Antigen structure affects cellular routing through DC-SIGN." Proceedings of National Academy Sciences 116, 30 (July 2019): 14862-14867 © 2019 National Academy of Sciences
Version: Final published version
ISSN
0027-8424
1091-6490

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