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Antigen structure affects cellular routing through DC-SIGN.

Cassie M Jarvis1, Daniel B Zwick2, Joseph C Grim3

  • 1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.

Proceedings of the National Academy of Sciences of the United States of America
|July 5, 2019
PubMed
Summary
This summary is machine-generated.

Antigen size and structure dramatically influence how dendritic cell (DC) lectins, like DC-SIGN, internalize and traffic molecules. Particulate antigens, unlike smaller polymers, are directed to pockets that harbor HIV-1, impacting vaccine design and pathogen targeting.

Keywords:
C-type lectinHIVantigenendocytosispolymer

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Area of Science:

  • Immunology and Virology
  • Biomaterials and Nanotechnology

Background:

  • Dendritic cell (DC) lectins, such as DC-SIGN, are crucial for antigen recognition and uptake, but can be exploited by pathogens like HIV-1.
  • Antigen routing within DCs determines whether peptides are presented for immunity or if pathogens evade degradation, enabling infection.
  • HIV-1 engagement with DC-SIGN leads to trafficking to specific cellular pockets, facilitating T cell infection.

Purpose of the Study:

  • To investigate how the physical properties of antigens, specifically size and structure, affect their fate after internalization by C-type lectin receptors (CLRs).
  • To explore the potential for designing synthetic vaccines and targeting viral reservoirs based on antigen structure-dependent trafficking.

Main Methods:

  • Utilized ring-opening metathesis polymerization to synthesize glycopolymers displaying mannoside ligands for DC-SIGN, varying in length and size.
  • Assessed the rate and extent of glycopolymer internalization and their colocalization with early endosomes.
  • Induced polymer aggregation to create particulate antigens and observed their trafficking patterns upon DC-SIGN engagement.

Main Results:

  • Glycopolymer internalization rate and efficiency were dependent on polymer length; longer polymers were internalized more rapidly and extensively.
  • Both short and long glycopolymers trafficked to early endosomes, indicating similar initial routing.
  • Particulate antigens, formed by polymer aggregation, were uniquely diverted to invaginated pockets, similar to HIV-1 trafficking pathways.

Conclusions:

  • Antigen structure, particularly its physical form (particulate vs. polymeric), significantly dictates DC-SIGN-mediated uptake and intracellular trafficking.
  • These findings have implications for the rational design of synthetic vaccines that leverage specific antigen presentation pathways.
  • The results suggest novel strategies for targeting DC reservoirs harboring viral pathogens by manipulating antigen structure.