What are the primary limitations in B cell affinity maturation? How much affinity maturation can we drive with vaccination? A role for antibody feedback

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  • RMIT University


We discuss the impact of antibody feedback on affinity maturation of B cells. Competition from epitope-specific antibody produced earlier during the immune response leads to immune complex formation, which is essential for transport and deposition of antigen onto follicular dendritic cells (FDC). It also reduces the concentration of free epitope into the μM to nM range, which is essential for B cell receptors (BCR) to sense affinity dependent changes in binding capacity. Antibody feedback may also induce epitope spreading, leading to a broader selection of epitopes recognized by newly emerging B cell clones. This may be exploitable, providing ways to manipulate epitope usage induced by vaccination. Antibody mediated protection from disease is a great success, and public vaccination programs have led to herd immunity against a large number of diseases. Still, we do not understand well how affinity maturation is regulated, and how to translate this into good vaccine design. This has shown in recent discussions on how to induce efficiently neutralizing antibody against antigens with temporal variation such as influenza or HIV. We need to find ways not only to target non-variable epitopes that hide behind a screen of decoy epitopes which may vary over time [1-3], but also to induce highest affinity antibodies that can efficiently neutralize their targets. Affinity maturation of antibodies happens in germinal centers (GCs). They are the main source of affinity matured memory B cells and plasma cells. Understanding the regulation of the evolution of B cell clones within these structures is key to understand how to manipulate affinity maturation of B cell clones, their dominant specificities and how we might design vaccines that induce high affinity antibody to specific antigens or epitopes. B cells in GCs expand and undergo immunoglobulin VDJ gene hypermutation. These mutations produce variants with altered BCR affinities that are positively selected or die due to neglect. This cycle typically is repeated many times. Reproduction, variation, and selection are the hallmarks of Darwinian evolution. Key to a directional evolution (in this case towards higher affinity) is a driver of directional selection. How selection is regulated in the GC has been subject to intense study over recent years. Signals from T follicular helper (Tfh) cells are the master regulators of GC responses, directing recirculation of GC B cells into the GC dark zone where proliferation and further hypermutation happen [4, 5]. Signals from Tfh cells possibly also triggering differentiation of GC B cells into affinity matured plasma cells or memory B cells. The efficacy of Tfh signaling to B cells is dependent on whether GC B cells are able to present sufficient antigenic peptide to the T cells. This has been demonstrated in vitro [6], and more recently in a series of studies in vivo [4, 7]. The importance of T cell derived signals is also seen in T cell independent GCs, that cannot be sustained for more than a few days [8], and was predicted in theoretical studies [9]


Original languageEnglish
Article numbera028795
JournalCold Spring Harbor Perspectives in Biology
Issue number5
Early online date19 Jun 2017
Publication statusPublished - 1 May 2018