Antibody modulation of B cell responses-Incorporating positive and negative feedback

Abstract

Antibodies are powerful modulators of ongoing and future B cell responses. While the concept of antibody feedback has been appreciated for over a century, the topic has seen a surge in interest due to the evidence that the broadening of antibody responses to SARS-CoV-2 after a third mRNA vaccination is a consequence of antibody feedback. Moreover, the discovery that slow antigen delivery can lead to more robust humoral immunity has put a spotlight on the capacity for early antibodies to augment B cell responses. Here, we review the mechanisms whereby antibody feedback shapes B cell responses, integrating findings in humans and in mouse models. We consider the major influence of epitope masking and the diverse actions of complement and Fc receptors and provide a framework for conceptualizing the ways antigen-specific antibodies may influence B cell responses to any form of antigen, in conditions as diverse as infectious disease, autoimmunity, and cancer.

Figure 1.. Types of antibody feedback on the B cell response.

The different mechanisms of feedback have been classified as “Positive” and “Negative” for simplicity. However, whether an effect is positive or negative can depend on whether the epitope-specific or antigen-specific response is being considered, or whether antibody response affinity versus breadth is being considered. For example, epitope masking has a negative effect on B cells recognizing the same epitope as the secreted antibody but may have a positive effect on the response of B cells recognizing other epitopes in the antigen. FDC capture of opsonized antigen can increase the ability of B cells to participate in the response (“positive” feedback) but by increasing antigen availability and avidity it may, at least transiently, support responses that are of lower affinity. The antibody isotype mediating a given type of feedback is shown above each arrow. Effector molecules (C’, receptors) involved in each type of feedback are shown below each arrow. The antibody diagram is shown as IgG for simplicity. Receptors present on FDCs (CR1 and lower amounts of CR2 and FcγRIIb) are not shown for clarity. The B cell is only shown in the cases where an additional receptor (CR2 or FcγRIIb) is engaged in cis with the BCR. In all cases the feedback impacts the extent of BCR engagement occurring in responding B cells, except antigen uptake by DCs that impacts on TCR engagement in helper T cells. Although not shown, in some cases FcγR⁺ myeloid cells may also make opsonized antigen available to B cells. Several additional less studied feedback mechanisms that are discussed in the text are not depicted.

Figure 2.. Epitope masking drives diversity of the B cell response.

Accumulation of serum antibody in the current or from past immune responses can sterically block B cells from binding to epitopes. This blocking effect can inhibit B cell activation to shared epitopes. This blocking will in turn prioritize targeting of additional, less accessible, or subdominant epitopes as responses progress over time, or will block memory B cell responses upon re-exposure to the same or similar pathogens. In recent years epitope masking has been shown to be particularly important for immunity to evolving viruses such as influenza, HIV, and SARS-CoV-2.

Figure 3.. Immune complex and C’ fixation affect B cell responses.

(A) Antibody both fixes C’ and cross-links antigen to form immune complexes (ICs) that are strewn with C3b, C4b, and C3d complexes. (B) Through CR1 and CR2 interactions, IC is transported by B cells and deposited on FDC networks in GCs. Interaction with CR1/2 also increases antigen persistence and half-life on FDCs to allow a persistent source of whole antigen for GC B cell uptake and presentation to TFH cells, driving affinity maturation. (C) Activation of B cells specific to the antigen in IC is amplified by increased BCR and CR1/2 cross-linkage. (D) C’ mediated direct lysis of enveloped virus (virolysis), bacteria, or infected cells through membrane attack complex (MAC) formation can decrease antigen available.

Figure 4.. FcγR and antibody isotype diversity orchestrates immune responses.

The balance of FcγR types on various leukocytes, the accumulation of IgG subclasses in serum and IgG Fc glycosylation status can dictate which and how strongly cells are activated (i.e., human FcγRIIIa binds IgG3>IgG1 but not well to IgG2, and IgG3 binding is dramatically improved by Fcγ fucosylation). (A) This interplay can affect APC activation status which in turn drives CD4 T cell responses and B cell activation. (B) FcγR can also mediate clearance of antigen or of infected cells by antibody dependent cellular phagocytosis (ADCP) or antibody-dependent cellular cytotoxicity (ADCC). (C) Antigen half-life is believed to be increased through Fcγ interaction with FcRN that increases in the acidic environment of endosomes, allowing IC recycling to the cell surface. (D) FcγRIIb interactions with BCR cross-linkage directly inhibit B cell signaling capacity and can be differentially inhibiting with FcγRIIb variants.