Role of Memory B Cells in Hemagglutinin-Specific Antibody Production Following Human Influenza A Virus Infection

Abstract

When influenza A virus infects an immune individual, preexisting memory B cell (MBC) activation and rapid anamnestic antibody production plays a key role in viral clearance. The most effective neutralizing antibodies target the antigenically variable head of the viral hemagglutinin (HA); antibodies against the conserved HA stalk provide broader but less potent protection. In this review, we provide a comprehensive picture of an adult's HA-specific antibody response to influenza virus infection. The process is followed from preexisting HA-specific MBC activation and rapid production of anti-HA antibodies, through to germinal center seeding and adaptation of the response to novel features of the HA. A major focus of the review is the role of competition between preexisting MBCs in determining the character of the HA-reactive antibody response. HA novelty modifies this competition and can shift the response from the immunodominant head to the stalk. We suggest that antibodies resulting from preexisting MBC activation are important regulators of anti-HA antibody production and play a role in positive selection of germinal center B cells reactive to novel HA epitopes. Our review also considers the role of MBCs in the effects of early-life imprinting on HA head- and stalk-specific antibody responses to influenza infection. An understanding of the processes described in this review will guide development of vaccination strategies that provide broadly effective protection.

Keywords: antibodies; germinal centers; hemagglutin stalk; hemagglutinin; imprinting; infection; influenza A virus; memory B cells; original antigenic sin.

Figure 1

The HA-specific B cell response to seasonal IAV infection in an adult with a typical history of influenza exposure. Results from human and animal studies were used to construct a model of events in a responding lymph node. (A) Events in subcapsular proliferative foci (SPF). Influenza proteins (including HA) entering the subcapsular sinus (SCS) are trapped by SCS macrophages. HA-reactive memory B cells (MBCs) beneath the SCS compete for antigen displayed by SCS macrophages. Successful acquisition of antigen enables MBCs to receive cognate T cell help and differentiate along pathways that reflect antigen affinity: high affinity antigen binding (and stronger T cell help) favors formation of Ab-secreting cells; lower affinity cells generate MBCs or seed germinal centers (GCs). (B) Events in GCs. GCs are seeded by activated MBCs or activated naïve B cells. After mutation of immunoglobulin V-region genes, GC B cells that express high affinity receptors are positively selected, a process that involves competition for antigen held by follicular dendritic cells (FDCs) so that sufficiently strong T cell help can be secured. Selected cells repeat the mutation/selection cycle or differentiate into MBCs or Ab-secreting plasma cells and exit the GC. (C) Regulation by MBC-derived Abs. High affinity HA-reactive MBCs differentiate into Ab-secreting cells in SPF. Secreted Abs potentially regulate anti-HA Ab production by facilitating HA removal or by epitope masking. We suggest that anti-HA Abs released in the SPF enter nearby GCs and bind antigen held by FDCs. Since the initial wave of MBC-derived anti-HA Abs generally binds conserved epitopes with relatively high affinity, masking epitopes on FDC-held antigen would drive selection of GC B cells reactive to the more variant epitopes. Circulating Abs could act in a similar way, but perhaps only after development of lung inflammation increases Ab movement from the vasculature into lung tissue and then to lymph nodes via lymphatic vessels.

Figure 2

Composition of the MBC pool reactive to the HA of a seasonal IAV at different stages of the response to infection. MBC pools are represented as pie diagrams, with segments representing the proportions of MBCs reactive to HA head domains of older circulating IAVs (“old”; colored red), more recent IAVs (“recent”; blue), and the current circulating IAV (“current”; green), and to the stalk domain (yellow). Concentric circles identify the proportions of MBCs with high (center), intermediate, or low affinity. Composition of the preexisting HA-reactive MBC pool is based on an analysis of the response to a seasonal H3N2 IAV infection [13]; the pathways of formation and the composition of MBC pools generated during infection are speculations based on multiple studies (see Section 3.5 and Section 3.6). (A) The preexisting MBC pool reactive to the HA of the infecting virus. Activation and differentiation of cells in this pool via extra-GC pathways generates Ab-secreting cells from high affinity MBCs and MBCs from lower affinity precursors. Activated lower affinity MBCs also seed GCs. (B) The MBC pool generated via the extra-GC pathway and early in the GC reaction. Weisel et al. [31] identified an early phase of GC activity that generates primarily MBCs after fewer rounds of mutation and selection. We suggest that this phase, together with the extra-GC pathway, largely reestablishes the preexisting MBC pool. (C) MBCs generated by prolonged GC reactions. Although there is evidence that GCs undergo a switch from MBC to plasma cell formation [31], recent studies [32,33] demonstrate that GCs can be long maintained and that the process of MBC adaptation to novel features of an HA is ongoing. We suggest that MBC-derived anti-HA Abs generated early in the response, and perhaps also circulating anti-HA Abs at a later stage, have an important regulatory role and drive positive selection of GC B cells that bind variant HA epitopes (see Figure 1C).