Factors in B cell competition and immunodominance

Abstract

The majority of all vaccines work by inducing protective antibody responses. The mechanisms by which the B cells responsible for producing protective antibodies are elicited to respond are not well understood. Interclonal B cell competition to complex antigens, particularly in germinal centers, has emerged as an important hurdle in designing effective vaccines. This review will focus on recent advances in understanding the roles of B cell precursor frequency, B cell receptor affinity for antigen, antigen avidity, and other factors that can substantially alter the outcomes of B cell responses to complex antigens. Understanding the interdependence of these fundamental factors that affect B cell responses can inform current vaccine design efforts for pathogens with complex proteins as candidate immunogens such as HIV, influenza, and coronaviruses.

Keywords: HIV; complex antigens; germinal center; immunodominance; immunoglobulin; vaccine.

Figure 1:. Interdependence of precursor frequency, antigen affinity, and avidity in B cell outcomes.

Models of B cell priming dynamics across ranges of precursor frequency, antigen affinity, and antigen avidity. (A) Model of B cell priming outcomes when precursor frequency is high or low. When antigen-specific B cells are frequent (1 in 10³ B cells) many B cells can easily be recruited to GCs across a wide affinity and avidity range. However, when precursor frequency is low, high affinity multimeric immunogens may be required to prime B cells to successfully compete in GCs. (B) Model of B cell priming dynamics across a range of high to low affinities. (C) Model of B cell priming dynamics across a range of theoretical avidities. A 60mer antigen primed B cells to GCs under conditions when a monomeric antigen did not. (D) Graphical models of interdependence of all 3 parameters on successful priming of B cells.

Figure 2:. Estimated specificities of B cells in a representative GC.

A model diagraming potential composition of a representative GC response over time. See main text for details.

Figure 3:. Immunodominance factors involved in development of protective B cell responses.

Precursor frequency, BCR affinity, and antigen avidity are interdependent variables in determining B cell success in GCs following immunization. Additional parameters such as method of immunization, T cell helper epitopes, and adjuvant properties can also be important factors influencing outcomes of immunodominance.