Multivalent Antigens for Promoting B and T Cell Activation

Abstract

Efficacious vaccines require antigens that elicit productive immune system activation. Antigens that afford robust antibody production activate both B and T cells. Elucidating the antigen properties that enhance B–T cell communication is difficult with traditional antigens. We therefore used ring-opening metathesis polymerization to access chemically defined, multivalent antigens containing both B and T cell epitopes to explore how antigen structure impacts B cell and T cell activation and communication. The bifunctional antigens were designed so that the backbone substitution level of each antigenic epitope could be quantified using 19F NMR. The T cell peptide epitope was appended so that it could be liberated in B cells via the action of the endosomal protease cathepsin D, and this design feature was critical for T cell activation. Antigens with high BCR epitope valency induce greater BCR-mediated internalization and T cell activation than did low valency antigens, and these high-valency polymeric antigens were superior to protein antigens. We anticipate that these findings can guide the design of more effective vaccines.

Enolesters as chain end‐functionalizing agents for the living ring opening metathesis polymerization

“…Ethyl vinyl ether ( EVE ) has long been known to selectively terminate living ROMP polymers by transferring a methylene group onto the polymer chain end forming a so‐called Fischer‐carbene . Substituted vinyl ethers have therefore been employed to attach larger molecular fragments to the ends of polymer chains . A high cis ‐content in these vinyl ethers is, however, crucial to achieve rapid termination as the cis ‐vinyl ethers react significantly faster with the ruthenium alkylidene than the trans ‐vinyl ethers.…”

Designing Multivalent Ligands to Control Biological Interactions: From Vaccines and Cellular Effectors to Targeted Drug Delivery

“…T cell receptors (TCRs) recognize peptide‐MHCII complexes and this B‐T cell contact promotes B cell proliferation and differentiation. To understand how antigen features influence this B‐T cell communication, Bennett et al . synthesized bifunctional antigens consisting of polymeric scaffolds displaying a B cell epitope that triggers the BCR and a T cell peptide epitope which upon uptake is released from the polymer backbone and presented to T cells (Figure ).…”

“…Figure shows the engagement of B and T cells stained in red and green, respectively as a time lapse upon treatment with the multivalent bifunctional polymeric antigen array. The study emphasizes the attributes of polymeric scaffolds that are well suited for manipulating immune responses, such as the ease of antigen display and control over valency …”

“…The frames show an overlay of brightfield and fluorescence images and represent a single T cell signaling event. Figure adapted from with permission. Copyright 2015 American Chemical society.…”

Surface engineering for lymphocyte programming

“…This reaction was found to be correlated to the number of repeat units in the construct with an approximately 10-fold increase in B-Cell mediated T-Cell activation for a 6-fold increase in the number of repeating units [51]. …”