Multivalent Antigens for Promoting B and T Cell Activation

TLDR

Effective vaccines need antigens that robustly activate both B and T cells, yet identifying antigen features that enhance B‑T cell communication remains difficult with conventional antigens. The study aimed to use ring‑opening metathesis polymerization to create multivalent antigens bearing both B‑cell and T‑cell epitopes in order to investigate how antigen structure influences B‑cell and T‑cell activation and communication. The antigens were engineered with backbone substitution levels quantifiable by (19)F NMR and a T‑cell peptide that is released in B cells by cathepsin D, a feature essential for T‑cell activation. High‑valency polymeric antigens induced stronger B‑cell receptor internalization and T‑cell activation than low‑valency or protein antigens, indicating that such designs could guide the development of more effective vaccines.

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 (19)F 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.