Fimmu 10 01787

REVIEW
published: 31 July 2019

doi: 10.3389/fimmu.2019.01787
Remembrance of Things Past:

Long-Term B Cell Memory After
Infection and Vaccination
Anna-Karin E. Palm † and Carole Henry*
Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL, United States
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.
Edited by:
Michael Vajdy, Studies in mice have helped to understand how different memory B cell populations
EpitoGenesis, United States are generated following antigen exposure and how affinity for the antigen is determinant
Reviewed by: to B cell fate. Additionally, such studies were fundamental in defining memory B cell
Johannes Trück,
University Children’s Hospital
niches and how B cells respond following subsequent exposure with the same antigen.
Zurich, Switzerland On the other hand, human studies are essential to the development of better, newer
Claude-Agnes Reynaud,
vaccines but sometimes limited by the difficulty to access primary and secondary
Institut National de la Santé et de la
Recherche Médicale lymphoid organs. However, work using human influenza and HIV virus infection and/or
(INSERM), France immunization in particular has significantly advanced today’s understanding of memory B
*Correspondence: cells. This review will focus on the generation, function, and longevity of B-cell mediated
Carole Henry
[email protected]
immunological memory (memory B cells and plasma cells) in response to infection and
vaccination both in mice and in humans.
† Present address:
Anna-Karin E. Palm, Keywords: B cell memory, vaccination, mouse vs. human, influenza virus, infection
Department of Medical Biochemistry
and Microbiology, Uppsala University,
Uppsala, Sweden INTRODUCTION
Specialty section: One of the hallmarks of our immune system is the ability to “remember” past exposure to
This article was submitted to pathogens. Such exposure can be from infection or vaccination, and by remembering we are,
Immunological Memory, ideally, fully protected from infection upon future encounter with the same pathogen (1). Although
a section of the journal
humoral immunological memory is mediated in part by serum antibodies secreted by long-lived
Frontiers in Immunology
plasma cells (LLPCs), these cells are usually not described as memory B cells. Instead, memory B
Received: 14 June 2019 cells are defined as long-lived and quiescent cells that are poised to quickly respond to antigen upon
Accepted: 16 July 2019
recall (2–5).
Published: 31 July 2019
Both memory B cells and antibody-secreting cells (ASCs) are the product of antigen activation
Citation: and, most often, interaction with cognate T helper cells. They can be IgM+ or immunoglobulin
Palm A-KE and Henry C (2019)
class-switched, and display germline or affinity-matured antigen receptors (B cell receptors; BCRs)
Remembrance of Things Past:
Long-Term B Cell Memory After
(2, 6–8). Although generation of memory B cells does require ligation of CD40 (9), an early burst
Infection and Vaccination. of both memory B cells and ASCs can form independently of GCs, as well as in T-cell independent
Front. Immunol. 10:1787. responses (10–16). However, T-cell independent memory responses are beyond the scope of this
doi: 10.3389/fimmu.2019.01787 review and will therefore not be thoroughly discussed here.
Frontiers in Immunology | www.frontiersin.org 1 July 2019 | Volume 10 | Article 1787

Palm and Henry Long-Term B Cell Memory
The terminal differentiation of B cells into ASCs is Affinity

governed by a gene-regulatory network and modified by There is general consensus in the field that initial affinity for the
environmental stimuli as reviewed in Nutt et al. (17). ASCs antigen influences which differentiation pathway will be chosen
can be divided into short-lived ASCs, including short-lived by an antigen-activated B cell. Newly activated B cells with a
plasma cells and plasmablasts, and LLPCs. Plasmablasts are relatively high affinity for the antigen will differentiate into short-
considered a transient population and can be either precursors lived extra-follicular ASCs (39). This ensures that the first burst of
of plasma cells (short- and/or long-lived; mainly in mice) or secreted antibody has enough affinity for the antigen to opsonize
terminally differentiated effector cells activated during ongoing it and form immune complexes that will be directly cleared
immune responses (mainly in humans) (18–23). In mice, by phagocytosis, activate complement, and/or be presented
within 2–4 d after infection, plasmablasts are found in extra- on follicular dendritic cells (FDCs), thereby driving affinity
follicular zones and differentiate into plasma cells that secrete maturation in the GC (30, 40). Conversely, antigen-activated
large quantities of antibodies. This early humoral response B cells of lower affinity typically develop into GC-independent
of lower affinity usually lasts a few days (24). In contrast, memory B cells. These are most often unmutated and unswitched
activation and differentiation of B cells within GCs allow (IgM+), although class-switched GC-independent memory B
the generation of plasma cells of high affinity that will then cells have been described (13). The GC-independent memory B
migrate to the bone marrow, where they can survive for cells provide a means of retaining adaptability potential within
decades and provide long-term humoral protection (25). Such the memory B cell pool, and these cells can either be recruited
LLPCs are key to maintaining long-term humoral immunity later in the same response or recalled upon secondary encounter
after infection or vaccination. They persist in the absence with the antigen.
of antigen for decades after the original exposure (26).
Although they exist in multiple lymphoid organs, the bone GC Responses
marrow is the home of the majority of plasma cells in mice The third fate choice for antigen-activated B cells is to upregulate
(27, 28). Bcl-6 and move deeper into the follicle and start a GC reaction
Most of what we know about the generation of plasma cells [excellently reviewed in Victora and Nussenzweig (30), Mesin
and memory B cells comes from mechanistic studies in mice. et al. (40)]. Briefly, the GC B cells will go through multiple
Because of massive differences between mice and humans in rounds of division in the dark zone (DZ) of the GC, each time
terms of life span and cell populations/phenotypes, the biology introducing mutations in their antigen receptor (B cell receptor;
of mouse and human B cells differs. It is therefore important to BCR). This process of somatic hypermutation (SHM) leads to
also look toward in vivo lessons we have learned from humans. affinity maturation and ensures that B cells will specialize their
binding to a particular antigen. The mutated B cells will then
move to the LZ, where the new BCR will be tested against the
LESSONS FROM MOUSE STUDIES antigen presented on FDCs. The B cells that manage to form a
BCR with high enough affinity will receive survival signals and
The Plasma Cell vs. Memory B Cell Fate either return to the DZ to go through another round of division
Decision and SHM, or exit the GC as a plasma cell or a memory B cell.
Following antigen activation with a T-dependent antigen, naïve B Similarly to extrafollicular fate decisions, BCR affinity to the
cells will interact with cognate T cells at the border between the B- antigen seems to play a role also in the GC (37, 41, 42). High-
and T-cell zones in the secondary lymphoid organs (Figure 1a). affinity B cells can bind and endocytose more antigen, and
Here, the activated B cells will proliferate and make their first consequently present more antigen-derived peptides on class
fate decision: whether to differentiate into extrafollicular ASCs II MHC (MHCII). This higher density of peptide:MHCII on
or germinal center (GC)-independent memory B cells, or to high-affinity B cells gives them an advantage in competing for
move deeper into the follicle to form a GC (Figure 1b). A access to T-follicular helper (Tfh) cells (43–45). In addition,
similar choice must then later be made in the light zone (LZ) each interaction with a Tfh cell is prolonged and intensified due
of the GC, further discussed below. Although the molecular to a feed-forward loop depending on peptide:MHCII density
mechanisms for this decision have been extensively studied and CD40:CD40L ligation (45). This enhanced CD40:CD40L
they have still not been completely elucidated, especially for interaction causes down-regulation of Bcl6 and turning on of
memory B cell generation. Several studies have addressed IRF-4 in the GC B cells, allowing them to differentiate into
the possibility of a “master transcription factor” for memory Bcl6lo CD69hi plasma cell precursors before exiting the GC
B cell differentiation, similar to Bcl-6 for GC B cells and as plasma cells (46) (Figure 1c). In addition, IL-21 secreted
IRF-4/Blimp-1 for plasma cells (29, 30). Although Bach2, or from Tfh cells is required for plasma cell differentiation (47),
specifically high expression of Bach2, in LZ GC B cells has been further demonstrating the importance of long and strong B:T
pointed out as a factor promoting differentiation to memory interactions for this fate decision. A fraction of the plasma cells
B cells, a transcription factor unique to memory B cells is leaving the GC will home to the bone marrow, where their
yet to be found (31–37). As recently reviewed, ZBTB32, KLF2, survival depends on a number of factors in the plasma cell niche
ABF-1, and STAT5 have been associated with memory B cell (Figure 1d). This will be further discussed below.
generation, but further studies are needed to understand their Memory B cells, on the other hand, are generated from low-
role (38). affinity GC B cells in the LZ and will eventually enter the

secondary lymphoid organs

low affinity
weak T-cell help
Bach2
Bcl6
CCR6 f
EBI2
Ephrin-B1 CCR6
tissue-residency
IL-9R
S1PR2
early GC output
LIGHT ZONE e
IL-9
circulation
DARK ZONE
intermediate
affinity later GC output
c d
high affinity CXCR3
strong T-cell help CXCR4
antigen-activation and Ig class switch CXCR6
initial T-cell help Bach2
Bcl-6
IL-21 Blimp-1
CXCR4
Bcl-6 IRF-4 bone marrow
a 3) XBP-1
high affinity low affinity
2)
1) b
secondary lymphoid organs
tissue-residency
circulation
circulation
bone marrow
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).
circulation as patrolling cells or take up residence in lymphoid help, as would be the case for lower-affinity B cells, maintains
or target organs (Figures 1e,f). The observation that memory B a relatively high Bach2-expression in LZ B cells, thus favoring
cells consistently are of lower affinity and have fewer mutations a memory B cell fate (37). It is not clear how Bach2 determines
than plasma cells indicate that the former are generated before memory B cell fate, but it is believed to act as a suppressor of
affinity maturation has allowed for the production of high-affinity transcription, particularly of Prdm1 (encoding Blimp-1) and of
BCRs. Indeed, an extensive study shows that memory B cells are pro-apoptotic factors such as Bim and Puma (37, 48–51). Thus,
formed early in the response whereas LLPCs are a later product it seems likely that lack of strong signaling, and consequently
(15). This temporal discrepancy also fits well with the Bach2 lack of instructions to start the plasma cell or GC B cell
dynamics in memory B cells. Bach2 is required for memory B cell transcriptional program forces activated B cells into memory
differentiation and only early GC B cells express Bach2, with the fate. Interestingly, memory B cells and naïve B cells, which
expression starting to decline from day 10 (37). Moreover, these are both quiescent with persisting differentiation potential, have
experiments show that T cell help, in the form of CD40:CD40L similar transcriptional profiles, with the important exception of
interaction, represses Bach2-expression in GC B cells in a dose- memory B cells seemingly being hardwired for quick responses
dependent manner. Thus, B cells with higher affinity typically (31, 33, 34, 36, 52).
have a lower expression of Bach2 and are therefore predisposed Selection of B cells with a relatively low affinity into the
to choose re-entry to the DZ or commitment to the plasma memory compartment early in the response thus ensures that a
cell transcriptional program. Conversely, relatively weak T cell certain poly-reactivity is maintained within the memory B cell

pool. Indeed, preservation of germline, or close to germline, The Memory B-Cell Niche and Recall
encoded BCRs in memory B cells provides the memory B cell Responses
pool with clones that are able to respond quickly while still Upon re-exposure to an antigen the memory recall response
maintaining a higher degree of flexibility in terms of antigen will be faster, stronger, and more specific than a naïve response.
binding. This flexibility would be lost should only memory B cells Protective memory depends first on circulating antibodies
with high-affinity mutated BCRs persist in the memory pool. This secreted by LLPCs (Figure 2a). When these are not sufficient for
idea can be illustrated by the observation that around 10% of immediate pathogen neutralization and elimination, memory B
memory B cells recognize variant antigen better than wild type cells are recalled. It is therefore of vital functional importance
protein, thus allowing for breadth of protection in a way that that memory B cells are stationed at strategic sites where they
LLPCs do not (53). Conversely, by choosing only the highest- can maximize their chance of encountering antigen (Figure 2b).
affinity GC B cells for plasma cell fate, the quality of the secreted The spleen, including the marginal zone, is a major reservoir
antibodies is ensured to be very high. for memory B cells in both mice and humans (14, 65–67), as
is the subcapsular sinus (SCS) of lymph nodes (68). Both the
Immunoglobulin Isotype splenic marginal zone and the lymph node SCS are abundant
Another proposed determinant factor of plasma cell vs. memory with CD169+ macrophages, which are specialized in presenting
B cell differentiation is immunoglobulin isotype. B cells that have unprocessed antigen to B cells (69, 70). It has been demonstrated
switched to IgG, IgE, or IgA are more prone to differentiate to that both naïve and memory B cells interact with CD169+
plasma cells than memory B cells (54–58). Interestingly, a recent macrophages in the SCS, and that upon antigen recall the
study showed that even when B cells are forced to switch to IgG1 memory B cells quickly form SCS proliferative foci (Figure 2c),
independently of AID, thus uncoupling the effects of SHM and or form new GCs (68). This was also seen in human lymph
class-switch recombination (CSR), the switched GC B cells were nodes. Interestingly, the largest output from the SCS proliferative
predominantly differentiating into plasma cells (58). Moreover, foci is short-lived plasma cells (ASCs), whereas the new GC
transcriptional analysis of IgM+ and IgG1+ GC B cells in the LZ is a site for further affinity maturation and CSR with very
revealed altered signaling through Nur77 in the switched B cells, stringent quality controls that limit plasma cell differentiation
associated with increased expression of chemokines associated (42). Importantly, both the SCS proliferative foci and the GC
with exit from the GC into the plasma cell compartment (58). also foster memory B cells that may participate in another re-
Together, these studies indicate that intrinsic properties of a non- call response or be recruited later in the same response. In
IgM BCR, probably in their signaling capacity, influences the addition to the spleen and lymph nodes, memory B cells are
plasma cell vs. memory B cell fate decision. found in the bone marrow, Peyers’ patches, gingiva, mucosal
epithelium of tonsils, the lamina propria of the gastro-intestinal
Marking Memory B Cell Precursors tract, and in the circulation (67, 71–76). It has not been
Studies aiming at defining memory B cell precursors in the GC convincingly demonstrated that the bone marrow, or any other
have found differential expression of several markers on subsets tissue (apart from the spleen and the lymph nodes) contains
of GC B cells in the LZ. One such marker is the chemokine functional memory B cells or if these memory B cells simply
receptor CCR6, which has been shown to be dispensable for the recirculate from the blood to the tissues. These are all anatomical
initial generation but required for correct positioning of memory sites where antigen may breach the barriers or be carried
B cells as well as for optimal recall responses (59, 60). These to via the circulation, and the memory B cells located here
CCR6+ GC B cells are generally of lower affinity, and have a act as sentinels should pre-existing antibodies not provide
phenotype closely resembling that of memory B cells (e.g., up- adequate protection.
regulated EBI2 and S1PR1, and down-regulated S1PR2) (60). A Importantly, memory B cells can also seed sites of infection,
recent study describes a population of Ephrin-B1high S1RP2low where they are maintained as tissue-resident memory B cells
GC B cells as memory precursor cells in the LZ, positioned close (77–79). Here they are quickly activated after pathogen invasion
to the edge of the GC (61). In addition, a study focused on plasma without the need for antigen transportation to draining lymph
cell precursors in the GC LZ proposes that a fraction of GC B nodes, thus shortening the time for plasma cell differentiation
cells in the LZ presenting as Bcl6low CD69low are memory B cell and antibody production on secondary exposure. Interestingly, in
precursors (46). the case of influenza virus infection, broadly reactive memory B
Finally, IL-9R is expressed on memory B cells as well as on a cells are enriched in the lung-resident pool, thus conferring quick
subset of LZ GC B cells concluded to be memory B cell precursors and cross-reactive protection at the site of infection (80).
(62, 63). In addition to Bach2-requirement, optimal memory B Upon re-exposure to antigen, memory B cells can quickly
cell generation also needs Tfh-derived IL-9 (63), and signaling proliferate and differentiate into plasma cells. Alternatively, they
through IL-9R on memory B cells is required for their recall will re-enter GCs for another round of affinity maturation
response (64). Taken together, memory B cell precursors may and CSR. This decision depends on BCR affinity and isotype
be found in the GC LZ and present as CCR6+ S1PR2low Ephrin- in addition to differential expression of CD80 and PD-
B1high Bcl6low CD69low IL-9R+ . However, further studies are L2 (Figures 2d–f). These surface markers denote functionally
needed to fully elucidate whether this phenotype really different memory B cells independent of immunoglobulin isotype
corresponds to a committed memory B cell precursor. (2, 4, 7, 8, 65). Importantly, the heterogeneity of the memory

bone marrow
secondary antigen exposure
SPF
c
unmutated/very few mutations

tissue-resident memory B cells IgM+
lower affinity
double-negative
d GC
memory
B cell pool
IgM+/IgG+/IgA+
circulating memory B cells
intermediate-high affinity
e single-positive
IgG+/IgA+
memory B cells in secondary lymphoid organs
f higher affinity
double-positive
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).
B cell compartment allows for a functional breadth of memory B cells single-positive for CD80 or PD-L2 can differentiate
recall responses. to ASCs while retaining the capacity to seed GCs, whereas
Unswitched (i.e., IgM+ ) memory B cells are often derived double-positive IgG+ memory B cells only generate ASCs (8).
from GC-independent or very early GC responses. They These findings are further supported by studies demonstrating
frequently do not express CD80 and/or PD-L2, and carry few, if that IgG+ and IgA+ memory cells can engage in new GC
any, mutations (7, 65). The IgM+ memory B cell pool thus keeps reactions (5, 75).
a breadth of reactivity similar to that of naïve B cells but with
the advantage of being able to rapidly respond to antigen (31, 33,
34, 36, 52). This breadth is particularly important for mounting
LESSONS FROM HUMAN STUDIES
rapid recall responses to variant antigens, such as influenza virus. Human Plasmablasts
On the other hand, recalled IgG+ memory B cells tend to rapidly In humans, most studies consider plasmablasts as blood short-
differentiate into plasma cells without re-entering a GC (4). lived ASCs generated in acute B cell responses to infection or
This is comparable to the fate chosen by switched B cells in vaccination that transiently contribute to the serum antibody.
the primary GC response (54–58). However, these observations In a secondary systemic immune response to a protein antigen
may not be exclusively dependent on immunoglobulin isotype. such as tetanus toxoid or an inactivated influenza virus vaccine,
Indeed, when further dissecting the memory B cell compartment, antigen-specific IgG-secreting plasmablasts with somatically
it becomes apparent that CD80− PD-L2− IgM+ memory B cells mutated VH gene rearrangements are generated from memory
preferentially enter GCs upon recall, whereas those expressing B cells (20, 82). It is also the case following influenza, Ebola, or
CD80 and/or PD-L2 typically generate rapid IgM+ and IgG+ Dengue virus infection (22, 83–85). It remains an open debate
plasma cell responses (4, 7, 8, 74, 81). Similarly, IgG+ memory whether human plasmablasts are precursors of and how many

do become LLPCs. Evidence suggests that once the infection is long-term survival in the bone marrow (98). An interesting
cleared, the majority of ASCs undergo apoptosis, while a small study demonstrated that extracellular vesicles from bone
proportion may go on to further differentiate into LLPCs (86). marrow-derived MSCs support ex vivo survival of human
The heterogeneity seen in human ASCs from tonsil, blood, and ASCs (99).
bone marrow reveals stages of increasing maturity, and local In humans, the bone marrow contains both CD19+ and
profiles of adhesion molecule expression suggest a multi-step CD19− LLPCs (26). The majority of CD19− LLPCs are actually
model for plasma cell differentiation (82, 87). In human blood found in the bone marrow, compared to the blood, spleen and
when plasmablasts appear between days 6 and 8 after vaccination, tonsils. Interestingly, CD19− LLPCs are enriched in IgG+ cells
they are migratory and attracted by CXCL12 and could migrate and carry fewer VH mutations compared to CD19+ LLPCs. Only
to tissues, such as the bone marrow (88, 89). CD19− LLPCs resist to mobilization into the blood following
Plasmablasts have also been described as a “steady state” immunization, and are resistant to depletion by Rituximab. In
population where the majority express IgA. They express CCR10 addition, CD19− LLPCs were not found in the bone marrow
and the adhesion molecule β7 integrin and they are attracted of 5–7 months old infants while CD19+ LLPCs were present.
by CXCL12 suggesting that they come from mucosal immune This study suggests a multi-layer model of LLPCs in the
reactions and can return to mucosal tissue. Approximately human bone marrow with CD19+ LLPCs being a dynamic
40% of LLPCs in human bone marrow are IgA+ , non- component and CD19− a more static component permitting
migratory, and express β7 integrin and CCR10, suggesting a both adaptation and stability of humoral protection (100). A
substantial contribution of mucosal plasma cells to bone marrow more recent study of the same populations but this time in
resident LLPCs (90). After tetanus vaccination, IgG+ CD62L+ β7 response to influenza virus vaccination suggests that newly
integrin− dividing, vaccine-specific, and migratory plasmablasts generated ASCs can acquire a mature plasma cell phenotype
appear in the blood, as do non-dividing, non-migratory, CD62L− that is accompanied by loss of CD19 expression at an early
plasma cells of different specificities (90). stage of differentiation, and that aging is not an obligate
A recent study identified survival factors from the bone requirement for a CD19− state to be established (101). Finally
marrow niche that favors maturation of human blood ASCs both CD19+ and CD19− vaccinia-specific LLPCs were detected
to LLPCs in vitro (91). IL-6 and two members of the tumor in the BM more than 35 years after the eradication of smallpox,
necrosis factor (TNF) superfamily: BAFF (B-cell activating factor suggesting that the LLPC pool may be maintained by a process
of the TNF family; also known as BLyS in humans) and APRIL in which vaccinia-specific B cells differentiate into LLPCs in the
(a proliferation-inducing ligand) are known to be important BM (26).
survival signals (92), as well as is CXCL12 (93). Additional factors
secreted by the bone marrow niche such as fibronectin and Outside of the Bone Marrow
YWHAZ are important for LLPC maturation (91). Compared to the bone marrow niche, fibroblasts from the lymph
nodes and the spleen have been poorly characterized in both
LLPCs mice and humans. A few studies have shown that stromal cells in
Migration to and From the Bone Marrow the spleen and lymph nodes might promote plasma cell survival
Human LLPCs freshly isolated from the bone marrow have high in vitro (102, 103). Recently, a new subset of fibroblasts (FRCs
expression of the chemokine receptors CXCR4 and CXCR6 and for fibroblastic reticular cells) in the lymph nodes have been
responsiveness in in vitro migration assays to the chemokines described both in mice and humans as the main cell type in
CXCL12 and CXCL16. The chemokine CCL28 has also been contact with plasma cells to guide them in their migration (104).
shown to attract human bone marrow plasma cells in vitro
(94). Two interesting populations have been observed in the Mucosal Plasma Cells
blood of tetanus toxoid immunized individuals: a population of Plasma cells are very abundant in mucosal tissues. They are
migratory plasmablasts expressing CXCR3 and CXCR4, and a located both in the connective tissue (lamina propria) and in
population resembling mature plasma cells of the bone marrow. lymphoid organs such as the tonsils in the oral cavity and Peyer’s
These findings suggest that these cells are likely to be resident patches in the gut. The majority of these plasma cells secrete
LLPCs mobilized from their survival niches in the bone marrow, IgA antibodies, and humans also have a substantial IgM+ plasma
in competition with newly generated plasmablasts (88). cell population in the mucosa (105). B cells in the respiratory
tract and IgA responses in the gastrointestinal tract in have
In the Bone Marrow been nicely reviewed in Kato et al. (106) and Bunker and
Mesenchymal stromal cells (MSC) in the human bone Bendelac (107), respectively, and are both beyond the scope of
marrow microenvironment provide factors that support this review.
LLPC survival (95–97). Cytokines of the TNF superfamily
(BAFF, APRIL and TNF-α), IL-6 family, CD80/CD86, CD44 Human Memory B Cells
binding to hyaluronic acid, and VLA-4 binding to VCAM- A great variety of B cell subsets have been identified
1/fibronectin promote survival of plasma cells. CXCL12 in the tonsil, spleen, and peripheral blood and represent
promotes entry of cells to the bone marrow as well as plasma different stages of development of a naive B cell into a
cell survival (86). BAFF seems to be important for human memory B cell. In the human tonsil, at least five distinct
plasmablast differentiation whereas APRIL is the key to subpopulations of mature human B cells (Bm1–Bm5) have

been identified. Concisely, naive B cells belong to the Bm1 during childhood, suggesting a developmental diversification
and Bm2 subpopulations whereas fully differentiated memory outside of T-dependent and T-independent responses (125).
B cells belong to the Bm5 subset (108–110). Interestingly
IgG transcripts in the tonsil had accumulated twice as many CD19+ CD27+ IgM+ IgD− (IgM-Only) and
mutations as the IgM transcripts suggesting that reentry of Class-Switched CD19+ CD27+ IgM
selected B cells in the GC to generate higher affinity BCRs is a By tracking tetanus toxoid-specific memory B cells
possibility (109). (CD3− CD19+ CD20+ CD27+ ) at steady state, it has been
As we previously stated, memory B cells are mainly generated showed that the spleen is the largest reservoir of memory B
in the GCs in secondary lymphoid organs. After leaving the cells followed by the tonsil. Bone marrow and blood memory B
GCs, memory B cells either join the recirculating pool of cells express surface IgG and IgA at similar frequencies, while
lymphocytes, or home to antigen draining sites. Memory B the tonsil contained more IgA memory B cells compared to
cell niches outside of the blood have been described and other locations. IgG+ memory B cells were enriched in the
memory B cells have been found in the bone marrow, the spleen and the tonsil compared to the bone marrow and the
tonsil and the spleen (111). Additionally a population of tissue blood and IgM+ IgD+ memory B cells were reduced in the
based memory B cells expressing Fc receptor-like 4 (FCRL4) tonsil compared to other locations. Interestingly, the absence of
instead of CD27 has been described (112, 113). In the blood spleen and tonsils does not affect secondary responses to tetanus,
and bone marrow, human memory B cells can be divided suggesting an organ independent maintenance and reactivation
in three main populations: CD19+ CD27+ IgM+ IgD+ (similar for human memory B cells (111). Memory B cells that reside in
to marginal zone (MZ) B cells), CD19+ CD27+ IgM+ IgD− lymphoid organs and recirculate after re-exposure to antigen are
(IgM-ONLY) and class-switched CD19+ CD27+ IgM− (IgG+ phenotypically the same and do not represent different stages
or IgA+ ) (114, 115). An in-depth flow cytometry analysis of maturity. Additionally, it has been demonstrated that the
of human bone marrow and blood samples showed that human spleen is a major reservoir of long-lived vaccinia-specific
compared to the blood, the bone marrow was enriched in memory B cells (66). Indeed, anti-smallpox IgG+ memory B
both MZ and switched B-cells (116). In the spleen, two cells were specifically enriched in the spleen, confirming that the
main phenotypically distinct B cell populations exist and spleen is a major reservoir for long-lived memory B cells.
localize to separate areas of the lymphoid tissue. Mantle Finally, high-throughput VH sequencing on paired blood
zone B cells (IgDhigh IgM+ CD21+ CD23+ ) are unmutated and and spleen samples revealed that IgM sequences from clones
believed to be naive B cells, whereas MZ B cells are shared between the MZ and the memory IgG/IgA (switched)
IgD+ IgMhigh CD21high CD23± and exhibit somatic mutations compartments displayed a mutation and repertoire profile
(117–119). It has been demonstrated that CD148, as well as of IgM-only and not of MZ B cells. Thus the “IgM-only”
CD27, are markers for memory B cells present in the human subset appears as the only subset showing precursor–product
spleen (120). More recently, a population of IgG+ memory B cells relationships with CD27+ switched memory B cells, indicating
residing in the MZ of the spleen have been found and examined. that they represent GC-derived IgM memory B cells and that
IL-21 and BAFF have been demonstrated to be important for the IgM-only and MZ B cells constitute two distinct entities (126).
differentiation of these IgG+ splenic memory B cells into plasma
cells (121). Human IgG and IgA Responses Induced by
Infection and Vaccination
The route by which an antigen enters the body (systemic vs.
CD19+ CD27+ IgM+ IgD+ (Also Called Human MZ B mucosal) and the nature of the antigen are factors that direct
Cells) the immune response class-switching patterns. Protein antigens
The spleen is an important organ in the defense against usually trigger B cells receiving T-cell help while polysaccharide
encapsulated bacteria. A population of “IgM memory B cells” antigens induce CSR in the absence of T-cell help. Moreover,
controlling Streptococcus pneumoniae is observed in the spleen BAFF and APRIL have been shown to stimulate CSR to IgG
(122). Additionally, the human peripheral B-cell compartment and IgA in human B cells (127). Polysaccharide B cell responses
displays a large CD19+ CD27+ IgM+ IgD+ memory B cell to vaccination in humans have been reviewed in Mitchell et al.
population, resembling the splenic MZ B cells. In fact, by (23), while the kinetics of ASC responses to infection have been
CDR3 spectratyping and gene-expression profiling, it has been reviewed in Carter et al. (128).
demonstrated that CD19+ CD27+ IgM+ IgD+ memory B cells are
circulating splenic MZ B cells. These memory B cells have a IgG
mutated BCR, provide a pre-diversified immune repertoire and Antibody responses to soluble protein antigens and membrane
are involved in T-independent responses (123). They can develop proteins primarily induce IgG1, but are accompanied with
in the absence of a spleen, but splenectomy in older individuals lower levels of the other subclasses. Viral infections in general
dramatically reduces the number of blood MZ B cells (122, 124). lead to IgG antibodies of the IgG1 and IgG3 subclasses (129).
Finally, when compared to switched memory B cells in children On the other hand, antibody responses to bacterial capsular
<2 year of age, CD27+ IgM+ IgD+ memory B cells in the spleen polysaccharide antigens is almost only restricted to IgG2 (130).
and blood do not display any signs of antigen-driven activation IgG4 antibodies are often formed following repeated or long-
and expansion despite the many antigenic challenges experienced term exposure to antigen in a non-infectious setting (131).

IgA the development of antibody potency and breadth following

Homeostatic IgA responses employ a polyreactive repertoire to immunization is crucial in this context, not only to the HIV
bind to a broad subset of microbiota species and tend to be of low community (141). The success of most vaccines relies on
affinity. In contrast, mucosal pathogens and vaccines elicit high- the generation of antibodies to provide protection against
affinity, T-cell dependent antibody responses (107, 132). Mucosal subsequent infection. As discussed earlier in this review, Tfh cells
IgA responses through a T-cell dependent reaction that place are critical for the production of high-affinity B cell clones in the
in mucosal lymphoid follicles, such as intestinal Peyers’ patches GC and thus the generation of long term memory, i.e., memory
and mesenteric lymph nodes (together called MALT for Mucosa- B cells and LLPCs (142).
Associated Lymphoid Tissues) (132). Human IgA subtypes show The feasibility of assessing GCs and Tfh responses from
distinct anatomical expression patterns, with monomeric IgA1 human lymph nodes has been limited, as GC B cells do not
dominating in the serum and dimeric IgA2 in the gut (133). circulate in the blood, and lymph nodes are rarely sampled (143).
Very few studies in humans have compared the induction Recently, fine needle aspirates of the draining lymph nodes were
of IgA and IgG secreting cells following various routes of used to longitudinally sample GC B cells and GC Tfh cells in
immunization. An early study compared oral, intranasal and non-human primates. The lymph node fine needle aspiration
systemic influenza virus vaccines in healthy adults. Both systemic technique has proven effective in terms of how many cells were
and intranasal immunizations induced mainly IgG+ influenza- recovered from the biopsy as well as in not disrupting the ongoing
specific B cells in the blood after vaccination while the oral GC. The authors found that neutralizing antibodies in non-
route induced IgA+ influenza-specific B cells in the blood. human primates correlate with GC B cell magnitude and Tfh
Additionally, oral and intranasal administration of antigen- help quality (144). They also found that GCs peak weeks after
induced IgA influenza-specific antibodies in external secretions the initial immunization. This means that a classic immunization
(134). These results were confirmed later on by multiple (one injection of antigen) is not optimal for “feeding” the peak
studies reporting a bursting population of IgG+ antigen- GC response. Proteins that are not of extreme stability can be
reactive plasmablasts in the blood after secondary tetanus toxoid degraded, exposing epitopes that would normally be hidden
vaccination (88), influenza virus vaccination or infection (20, 83, or non-existent on a more native protein conformation. Slow
135), as well as acute dengue virus infection (22). In addition, immunogen release could improve the availability of intact
immunization of African green monkeys with a live-attenuated antigen and epitopes of interest for the duration of the GC
H5N1 influenza vaccine resulted in more serum IgG neutralizing response (145).
antibodies than IgA (136). Germline-targeting strategies aim to activate B cell precursors
A study employing Ad26/Env (HIV) vaccination in rhesus with potential interest for bNAbs generation, so that they will
macaques demonstrated highly coordinated IgG and IgA enter the GC, be selected and affinity matured and will generate
responses in both peripheral blood and mucosal compartments memory B cells. Studying HIV-reactive B cell lineages to infer
(137). It remains unclear to this day how related IgG and unmutated ancestral BCRs that represent what a naïve B cell
IgA plasmablasts/plasma cells are and what the relationship would express is the key to a B-cell lineage vaccine strategy (146).
between mucosal and systemic antibody responses looks like. A vaccination protocol based on B-cell lineage differs from classic
While a study suggested that mucosal and systemic humoral protocols in the fact that they may prime with one immunogen
immune responses are regulated independently of each other and boost with another or with a sequence of several different
based on the observation that systemic vaccination does not immunogens (147–150).
seem to impact peripheral IgA+ plasmablast numbers (90, 138), It has been recently demonstrated that only immunogens
another study revealed that in celiac disease patients, the same above a certain affinity and in multimeric form are capable
antigen-reactive B cell clones that give rise to gut plasma of inducing GCs dominated by B cells from a bNAb
cells also contribute to the serum IgG and IgA antibody pool. precursor starting with low precursor frequency (151). These
However, serum IgA antibodies had a molecular composition B cells successfully competed in GCs, underwent somatic
(IgA1 vs. IgA2 and J chain level) distinct from that of IgA hypermutation and differentiated into memory B cells. Overall
antibodies secreted in the gut, suggesting the involvement of this study demonstrates that germline-targeting immunogens
different plasma cell populations (139). Finally, analysis of can overcome affinity, avidity, and inter-clonal GC competition
long-term transcriptional profile between blood IgG and IgA challenges with high-affinity multimeric designs.
influenza-reactive plasmablasts as well as influenza-negative
IgA plasmablasts did not reveal any specialization based on Lessons From Influenza
isotype. These data suggest that IgG and IgA vaccine–positive Plasmablasts have been extensively studied in humans, especially
plasmablasts are largely similar, whereas IgA vaccine–negative in the context of influenza vaccination and infection. Little
plasmablasts appear to be transcriptionally distinct from antigen- is known about B cells that become activated but do not
induced peripheral blood plasmablasts (140). differentiate into plasmablasts. A subset of antigen-reactive B
cells called ABCs for “Activated B Cells” has been described
Lessons From HIV and was found to be transcriptionally distinct from the ASC
Significant efforts in the HIV field are focusing on the design of population and committed to the memory lineage (152). ABCs
vaccines that would induce the generation of broadly neutralizing and ASCs share hemagglutinin (HA)-reactive clones following
antibodies (bNAbs). Understanding the immunology behind influenza vaccination. Our laboratory also described a post-GC

population of B cells that phenotypically resemble memory B Most studies have been done with alum and it remains
cells but that have low expression of CD21 (classical memory unknown how other adjuvants (such as AS03 and MF59)
B cells are CD19+ CD27+ CD21high ). We demonstrated that the act on GCs and antigen release (159). In the context of
CD21low population was comprised of recent GC graduates that influenza vaccines, adjuvanted vaccines administered in
were refractory to GC reentry and seemed to be predisposed patients with impaired immune responses, such as infants
to differentiation into long-lived plasma cells (153). Although and the elderly, were shown to be beneficial (160–162).
clonally related to memory B cells and plasmablasts, CD21low Additionally a study showed that the adjuvant AS03
B cells form distinct clades within phylogenetic trees based on induced an increased activation of naïve B cells and an
the accumulation of variable gene mutations. Another study increased adaptability of recalled memory B cells, improving
demonstrated that HA-reactive CD21low B cells are enriched in immunogenicity (163).
the blood compared to the tissues while there was an enrichment
of CD27+ CD21high HA+ B cells in all tissues. Both CD21+ and CONCLUSION
CD21low populations were not maintained in the peripheral
blood at 1 year post-vaccination (154). The generation of memory B cells and long-lived plasma cells is
Additionally, it is of great interest to understand how different crucial to the long-term effectiveness of vaccines. Understanding
vaccine compositions will affect the generation of memory B cells how to induce these different populations and modulate their
and LLPCs. Seasonal influenza vaccines exist as live-attenuated effects both in animal models and human is essential to the
influenza virus (LAIV), which more closely resembles natural design of better vaccines. Thus, the design of new immunogens,
immunity after infection, or as inactivated vaccines. LAIV have how to release them, as well as the mechanisms of actions of
been used mostly in children but do not induce strong systemic various adjuvants are the future of vaccines protecting against
antibody responses in adults (155). The same was true for challenging or emerging infectious diseases.
two different avian pandemic LAIV vaccines (H5N1, H7N9),
although these vaccines elicited a long-term immune memory AUTHOR CONTRIBUTIONS
that was revealed after administration of a matched inactivated
vaccine (156–158). To understand how LAIV vaccines can prime A-KP and CH contributed ideas and wrote the review. A-KP
such a memory response, a detailed analysis of B cell responses designed the figures.
in systemic and local lymphoid tissues in a non-human primate
model was performed (136). Interestingly, the authors found that ACKNOWLEDGMENTS
the LAIV vaccine induced robust GCs in the mediastinal (lung-
draining) lymph node and that both HA-reactive plasmablasts We thank Patrick C. Wilson and Christopher T. Stamper
and memory B cells were found in the mediastinal lymph nodes for critical discussion. CH is supported by the National
after immunization. Institute of Allergy and Infectious Disease, National Institutes
Finally, it is believed that adjuvants can modulate of Health, Department of Health and Human Services, CEIRS
humoral responses and retain antigen at the site of injection. contract HHSN272201400005C.
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broadly neutralizing antibodies and their inferred unmutated common in this journal is cited, in accordance with accepted academic practice. No use,
ancestors. J Virol. (2011) 85:9998–10009. doi: 10.1128/JVI.05045-11 distribution or reproduction is permitted which does not comply with these terms.

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published: 31 July 2019

Remembrance of Things Past:

The success of vaccines is dependent on the generation and maintenance of

Frontiers in Immunology | www.frontiersin.org 1 July 2019 | Volume 10 | Article 1787

The terminal differentiation of B cells into ASCs is Affinity

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secondary lymphoid organs

high affinity low affinity

secondary lymphoid organs

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secondary antigen exposure

unmutated/very few mutations

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IgA the development of antibody potency and breadth following

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REFERENCES 8. Zuccarino-Catania GV, Sadanand S, Weisel FJ, Tomayko

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Frontiers in Immunology | www.frontiersin.org 10 July 2019 | Volume 10 | Article 1787

Frontiers in Immunology | www.frontiersin.org 11 July 2019 | Volume 10 | Article 1787

Frontiers in Immunology | www.frontiersin.org 12 July 2019 | Volume 10 | Article 1787

Frontiers in Immunology | www.frontiersin.org 13 July 2019 | Volume 10 | Article 1787

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