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Molecular programming of B cell memory

Key Points

  • High-affinity B cell memory emerges across three separable phases of development. Each phase involves antigen recognition by specific B cells and contact with cognate T follicular helper (TFH) cells.

  • Initial commitment to the memory B cell pathway occurs before germinal centre (GC) formation, following first contact with antigen-specific TFH cells (pre-GC phase). Molecular interactions at the cellular interface involve cell-associated contacts and signals from secreted molecules such as cytokines.

  • The GC reaction supports reiterative cycles of B cell receptor (BCR) diversification, clonal expansion and class-switch recombination (GC phase) that promote the positive selection of high-affinity GC B cell variants into the memory B cell compartment.

  • Following antigen recall, memory B cells require regulation by antigen-specific TFH cells to proliferate and differentiate into memory-response plasma cells (memory phase). Affinity maturation of the antibody response continues at this stage using mechanisms that are poorly understood.

  • Antigen-specific TFH cells regulate each phase of development and consolidate memory B cell fate in high-affinity pre-memory and memory B cells.

  • Beyond antigen recognition, antibody class determines immune function and antibody affinity controls the sensitivity of memory B cells.

Abstract

The development of high-affinity B cell memory is regulated through three separable phases, each involving antigen recognition by specific B cells and cognate T helper cells. Initially, antigen-primed B cells require cognate T cell help to gain entry into the germinal centre pathway to memory. Once in the germinal centre, B cells with variant B cell receptors must access antigens and present them to germinal centre T helper cells to enter long-lived memory B cell compartments. Following antigen recall, memory B cells require T cell help to proliferate and differentiate into plasma cells. A recent surge of information — resulting from dynamic B cell imaging in vivo and the elucidation of T follicular helper cell programmes — has reshaped the conceptual landscape surrounding the generation of memory B cells. In this Review, we integrate this new information about each phase of antigen-specific B cell development to describe the newly unravelled molecular dynamics of memory B cell programming.

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Figure 1: TFH cell-regulated memory B cell development.
Figure 2: Pre-GC phase: commitment to memory.
Figure 3: The antigen-specific GC reaction.
Figure 4: Memory B cell evolution.
Figure 5: Memory response to antigen recall.

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Correspondence to Michael McHeyzer-Williams.

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Glossary

T follicular helper cells

(TFH cells). A distinct class of T helper cells specialized to regulate multiple stages of antigen-specific B cell immunity through cognate cell contact and the secretion of cytokines. There are three separable TFH cell subsets defined in the current literature that correspond to the three phases of memory B cell development. These are pre-GC TFH cells, GC TFH cells and memory TFH cells.

Cognate contact

Contact between a B cell and a T follicular helper cell that recognizes the same antigen. This contact requires antigen-receptor engagement by cell-associated antigens or peptide–MHC complexes and can be modified by secondary interactions that can involve both cell-associated and secreted molecules. Cognate contact functions to initiate bidirectional developmental programming.

Immunoglobulin class switching

A region-specific recombination process that occurs in antigen-activated B cells. It occurs between switch-region DNA sequences and results in a change in the class of antibody that is produced — from IgM to either IgG, IgA or IgE. This imparts flexibility to the humoral immune response and allows it to exploit the different capacities of these antibody classes to activate the appropriate downstream effector mechanisms.

Plasma cells

Terminally differentiated, quiescent B cells that develop from plasmablasts and are characterized by the capacity to secrete large amounts of antibodies.

Germinal centre

(GC). A lymphoid structure that arises within lymph node follicles after immunization with, or exposure to, a T cell-dependent antigen. The GC is specialized for facilitating the development of high-affinity, long-lived plasma cells and memory B cells.

GC reaction

(Germinal centre reaction). A cycle of activity characterized by three stages. First, GC B cells undergo clonal expansion and B cell receptor diversification in the GC dark zone. The B cells then scan follicular dendritic cells for antigens, and finally make contact with cognate GC TFH cells in the GC light zone. Positive selection continues the GC cycle with re-entry into the dark zone or promotes exit from the GC into the memory B cell compartment.

Class-specific memory B cells

Non-secreting memory B cells that express either IgM or downstream non-IgM antibody classes following T helper cell-regulated class-switch recombination.

Subcapsular sinus macrophages

(SCS macrophages). A CD11b+CD169+ macrophage subset that populates the subcapsular sinus region of lymph nodes. These cells function to trap particulate antigens from the lymph and present antigens to follicular B cells.

Follicular DCs

(Follicular dendritic cells). Specialized non-haematopoietic stromal cells that reside in the lymphoid follicles and germinal centres. These cells possess long dendrites and carry intact antigens on their surface. They are crucial for the optimal selection of B cells that produce antigen-binding antibodies.

Activation-induced cytidine deaminase

(AID). An enzyme that is required for two crucial events in the germinal centre: somatic hypermutation and class-switch recombination.

Non-homologous end joining

(NHEJ). A mechanism for repairing double-strand DNA breaks that does not require homologous sequences for ligation. NHEJ is used to complete recombination during antibody class switching.

Somatic hypermutation

A process in which point mutations are generated in the immunoglobulin variable-region gene segments of cycling centroblasts. Some mutations might generate a binding site with increased affinity for the specific antigen, but others can lead to loss of antigen recognition by the B cell receptor or the generation of a self-reactive B cell receptor.

Unfolded-protein response

A response that increases the ability of the endoplasmic reticulum to fold and translocate proteins, decreases the synthesis of proteins, and can cause cell cycle arrest and apoptosis.

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McHeyzer-Williams, M., Okitsu, S., Wang, N. et al. Molecular programming of B cell memory. Nat Rev Immunol 12, 24–34 (2012). https://doi.org/10.1038/nri3128

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