Regulation of IgG antibody responses by epitope density and CD21-mediated costimulation

TLDR

Epitope density and organization are key determinants of B cell activation, yet distinguishing their effects from local antigen concentration is challenging because organized antigens are typically particulate while non‑organized ones are soluble, leading to potentially distinct interactions within lymphoid tissues. The study aimed to determine how antigen organization regulates B cell responses by immunizing mice with virus‑like particles bearing varying epitope densities. Using the same particulate virus‑like particle scaffold, the authors presented identical epitopes with differing degrees of organization to isolate the effect of organization from epitope density. IgM responses were independent of epitope density and CD21/CD35 status, whereas IgG production required higher epitope densities and was diminished when CD21/CD35 was absent, demonstrating that IgG but not IgM responses are governed by epitope density and B cell costimulatory thresholds.

Abstract

Epitope density and organization have been shown to be important factors for B cell activation in many animal model systems. However, it has been difficult to separate the role of antigen organization from the role of local antigen concentrations because highly organized antigens are usually particulate whereas non-organized antigens are more soluble. Hence, highly organized and non-organized antigens may interact with different cell types and in different locations within lymphoid organs. In order to assess the role of antigen organization in regulating B cell responses, we immunized mice with highly repetitive virus-like particles, which exhibit different epitope densities covalently attached to them. Therefore, the same particulate structure was used to present identical epitopes that differed in their degree of organization. Induction of epitope-specific IgM titers, reflecting early B cell activation, were unaffected by the degree of epitope density. Furthermore, the absence of Th cells or CD21/CD35 did not reduce the IgM response. In contrast, the degree of organization was a critical factor influencing the magnitude of the epitope-specific IgG response. Moreover, the threshold for IgG responses was shifted in the absence of CD21/CD35, resulting in the requirement for higher epitope densities to allow efficient IgG responses. Thus, IgG but not IgM responses are regulated by epitope density and B cell costimulatory thresholds.