Remembrance of Things Past: Long-Term B Cell Memory After Infection and Vaccination

Abstract

The success of vaccines is dependent on the generation and maintenance of immunological memory. The immune system can remember previously encountered pathogens, and memory B and T cells are critical in secondary responses to infection. Studies in mice have helped to understand how different memory B cell populations are generated following antigen exposure and how affinity for the antigen is determinant to B cell fate. Additionally, such studies were fundamental in defining memory B cell niches and how B cells respond following subsequent exposure with the same antigen. On the other hand, human studies are essential to the development of better, newer vaccines but sometimes limited by the difficulty to access primary and secondary lymphoid organs. However, work using human influenza and HIV virus infection and/or immunization in particular has significantly advanced today's understanding of memory B cells. This review will focus on the generation, function, and longevity of B-cell mediated immunological memory (memory B cells and plasma cells) in response to infection and vaccination both in mice and in humans.

Keywords: B cell memory; infection; influenza virus; mouse vs. human; vaccination.

Figure 1

The generation of memory B cells and plasma cells in a T-dependent response (based on mouse studies). (a) Antigen-activation brings B- and T cells in contact at the T-B border in secondary lymphoid organs. (b) After initial proliferation in the outer follicle, the B cells make their first fate choice: (1) differentiation into extrafollicular (mostly short-lived) plasma cells (higher affinity), (2) differentiation into very early memory B cells (lower affinity), or (3) up-regulation of Bcl-6 and formation of a germinal center (GC). (c,d) In the GC, a similar selection process takes place in the light zone (LZ). Here, high-affinity LZ GC B cells receive strong T-cell help and consequently down-regulate Bach2 and Bcl-6 while turning on the plasma cell transcriptional program (Blimp-1, IRF-4, XBP-1; including up-regulation of CXCR4) (c). The plasma cell precursors will then either enter the circulation as short-lived antibody-secreting cells, or they will upregulate CXCR3, CXCR4, and CXCR5 to allow migration to the bone marrow plasma cell niche (d). Here survival factors produced by stromal cells and other adjacent cells (including eosinophils and macrophages) promote their differentiation into long-lived plasma cells, which continue to secrete antibodies for the duration of the lifetime of the host. (e,f) Due to the weaker T-cell help received by low-affinity LZ GC B cells, these will not be instructed to turn on either the plasma cell or the GC B cell transcriptional program. Instead, up-regulation of Bach2, CCR6, EBI2, Ephrin-B1, and IL-9R, together with down-regulation of Bcl-6 and S1PR2, promote differentiation to memory B cells (e). To maximize the likelihood of secondary antigen encounter memory B cells will then position themselves strategically in secondary lymphoid organs, become tissue-resident at the site of infection, or patrol as recirculating cells (f).

Figure 2

The memory recall response to secondary antigen exposure. (a,b) Pre-existing antibodies secreted by long-lived plasma cells (LLPCs) constitute the first line of defense (a). If this is not sufficient for immediate neutralization and elimination of the antigen, memory B cells will be engaged. This can happen either directly in the affected tissue (tissue-resident memory and circulating memory B cells), or when antigen is carried to secondary lymphoid organs (b). (c) Activated B cells in lymph nodes can form subcapsular sinus proliferative foci (SPF) upon antigen-dependent re-activation. Although it is unclear which memory subset constitute the SPF, it is known that the main output is plasmablasts, but that this is also the fostering site for new memory B cells as well as cells entering GCs. (d–f) Depending on their phenotype, different fate decisions will be made by the reactivated memory B cells: new germinal centers (GCs) are typically formed by IgM⁺, usually unmutated, CD80⁻PD-L2⁻ (double-negative) memory B cells of lower affinity (d). In addition, both IgM⁺ and switched memory B cells that express either CD80 or PD-L2 (single-positive) have retained the capacity to seed GCs (e). However, the bulk of these cells, together with some of the IgM⁺ double-negative memory B cells, will differentiate directly into plasmablasts (c,d). Finally, switched, high-affinity memory B cells that are double positive for CD80 and PD-L2 exclusively form new plasmablasts (f).