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Memory B cells
Takeshi Inoue 1
& Tomohiro Kurosaki 1,2,3,4

Abstract Sections

Recent advances in studies of immune memory in mice and humans Introduction

have reinforced the concept that memory B cells play a critical role Memory B cells in protection
in protection against repeated infections, particularly from variant and pathology

viruses. Hence, insights into the development of high-quality memory Generation of memory B cells
B cells that can generate broadly neutralizing antibodies that bind Phenotypic heterogeneity
such variants are key for successful vaccine development. Here, we of memory B cells

review the cellular and molecular mechanisms by which memory B cells Reactivation of memory B cells
are generated and how these processes shape the antibody diversity Lessons from SARS-CoV-2
and breadth of memory B cells. Then, we discuss the mechanisms
Memory B cells, TFH cells
of memory B cell reactivation in the context of established immune and vaccines
memory; the contribution of antibody feedback to this process has Outlook
now begun to be reappreciated.

1
Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka,
Japan. 2Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan. 3Center for Infectious Disease
Education and Research, Osaka University, Osaka, Japan. 4Laboratory for Lymphocyte Differentiation, RIKEN
Center for Integrative Medical Sciences (IMS), Kanagawa, Japan. e-mail: kurosaki@ifrec.osaka-u.ac.jp

Nature Reviews Immunology

Review article
Introduction
There is good evidence that the overall number of human memory
B cells (defined as canonical class-switched CD27+ B cells) is larger than
that of naive B cells in peripheral blood, particularly in aged individu-
als1,2. This, together with their remarkable stability (at least decades)3,4
and their heightened in vitro activation kinetics compared with naive
cells5, has evoked the idea that memory B cells are the more direct pre-
cursors for plasma cells that exert both antibody-mediated protection
and pathology than naive B cells. Thus, it is important to identify the
unique properties of memory B cells and clarify how such properties
are acquired6.
Advances have been made in tracking antigen-experienced
memory B cells, and it has become apparent that at least two distinct
classes of memory B cells coexist — for example, germinal centre (GC)-
dependent and GC-independent. Importantly, based on the results of
adoptive transfer experiments, these subsets were found to possess
considerable intrinsic functional differences. In reviews published
in 2013 and 2015 (refs. 5,7), we and others summarized progress in
the field and emphasized the importance of the interaction between
memory T follicular helper cells (TFH cells) and memory B cells in recall
responses. In the approximately 10 years since then, our understanding
of memory B cells has progressed significantly, with great advances in
their in vivo characterization and new insights into the mechanisms by
which they develop diversity, and the molecular details of their genera-
tion and reactivation. This fundamental knowledge has mainly relied
on mouse experimental systems and focused on IgG+ memory B cells;
but now, data from human studies have also been forthcoming. Here,
by integrating such human data, we summarize the advances over the
past decade in our understanding of memory B cell generation and
reactivation. In this Review, unless otherwise indicated, we focus on
mouse studies.
Memory B cells in protection and pathology
The memory compartment of the humoral immune system is composed
of long-lived plasma cells (LLPCs) and memory B cells (Fig. 1a, left).
The functional dissection of these two compartments has allowed to
decipher the roles of these cells in protection from reinfection with
a particular pathogen. For example, in a mouse model of West Nile
virus infection, pre-existing protective antibodies secreted by LLPCs
were shown to act as a first line of defence against reinfection with the
homologous virus, whereas memory B cells encoded antibodies that
were capable of binding viral variants8. Consistent with this observa-
tion, two recent lines of in vivo evidence from mouse models show that
memory B cells indeed act as defence against re-challenge with variants
of influenza virus and flavivirus9,10 and that pre-existing cross-reactive
clones contained in the memory B cell, but not in the LLPC compart-
ment, are positively selected and directly differentiate into plasma
cells after re-challenge with a variant virus (Fig. 1a, right). As both LLPC
and memory B cell compartments undergo somatic hypermutation
(SHM) during the primary infection, these data suggest differences in
the selection mechanism between these two memory compartments
during GC responses.
The importance of memory B cells in protection against variant
virus infection has also been well substantiated in vaccination stud-
ies in humans. In the case of vaccination against the pandemic 2009
H1N1 influenza strain, individuals who have pre-existing cross-reactive
antibodies (even at very low levels) were shown to generate antibodies
from the memory B cell compartment that were cross-reactive with
both previously encountered viruses and the novel 2009 influenza
Nature Reviews Immunology
strain11. In addition, a recent study analysed individuals immunized
with the 2018–2019 influenza seasonal vaccine12 and found that mem-
ory B cells, formed in response to a previously encountered different
influenza strain, contained clones that were cross-reactive with the
new 2018–2019 strain. Upon vaccination with the 2018–2019 influ-
enza vaccine, some of these cross-reactive memory B cells became
plasmablasts, whereas others entered GCs (Fig. 1a). Similarly, in the
mouse intestinal immune system, pre-existing cross-reactive IgA+
memory B cells appear to re-enter the GC in response to changes in the
microbiota, thereby reshaping their B cell receptors (BCRs) through
somatic mutations13,14 (Fig. 1b). Therefore, it is reasonable to conclude
that pre-existing memory B cell clones can deal with relatively minor
structural changes, for instance in the influenza haemagglutinin (HA)
stem region, by somatic mutations9, but not with major changes, for
instance strain-specific changes in the influenza HA head region15
(Fig. 1a). In the latter case, new naive B cell clones are recruited and
participate in the response, a phenomenon that has been observed in
humans as well as in mouse studies12.
Historically, studies of memory B cells have been carried out in the
context of infection or immunization. In autoimmune settings, there is
also increasing evidence that memory B cells are the direct precursors
of plasma cells that produce pathogenic antibodies.
Generation of memory B cells
It has generally been assumed that the memory B cell compartment in
mice is exclusively derived from conventional B2 B cells and not from
B1 B cells, given that the remaining small subpopulation of B1 B cells is
unable to proliferate in response to BCR-mediated stimulation in vitro16.
However, recent data demonstrate that some B1 B cells also proliferate
in an antigen-dependent manner in vivo and can form a memory pool,
likely in a T cell-independent manner17. This conclusion was further
substantiated by ‘time-stamp’ lineage tracing experiments showing
that B1 B cells contribute to intestinal IgA+ memory B cells that are
specific for commensal microbiota14. Hence, clarifying how B1 B cells
form memory B cell and LLPC pools is one of the important unresolved
issues in B cell biology. This is particularly relevant given that mouse
B1-derived antibodies, such as anti-α-1,3-glucan IgA antibodies that
bind cockroach antigens, have been shown to have a protective role
in allergic reactions18,19.
We focus on the development of memory B cells from conven-
tional B2 B cells, which is dependent on interactions with T cells.
Here, fate decisions of activated naive B cells take place at two distinct
stages: at the interface between the B cell follicle and the T cell zone
(T–B border; the pre-GC state), recently activated B cells either
differentiate into plasma cells, enter the GC to become CG B cells
or differentiate into GC-independent memory B cells20,21; and after
the T cell–B cell interactions at the T–B border, within the GC itself, GC
B cells continue the light zone–dark zone re-entry cycle or interrupt
this cycle to exit the GC, again differentiating into either plasma cells
or GC-derived memory B cells20 (Fig. 2). As isotype switching initiates
early at the pre-GC stage22–24, switched IgG+ and IgA+ memory B cells
are also generated during the pre-GC stage, although the majority of
pre-GC-derived memory B cells are IgM+.
Interactions between TFH cells and B cells
TFH cells are a specialized subset of CD4+ T cells that are required for the
activation and maintenance of pre-GC and GC B cells25. Importantly,
and in contrast to non-TFH effector cells such as T helper 1 (TH1) cells,
TH2 cells or TH17 cells, which are destined to leave lymphoid tissues and
Review article

a
Memory B cell
(strain-specific)

Memory B cell
(cross-reactive)
Virus

Primary virus infection Variant virus reinfection

Variant
BCR Memory B cell virus
(strain-specific)
Memory B cell
GC B cell (cross-reactive, mature)
Naïve Light Memory B cell
B cell zone (cross-reactive)

Dark
zone Long-lived
plasma cell Antibody
Germinal centre

b Secretory IgA

GC B cell

GC

IgA+ memory B cell Memory B cell

(cross-reactive) (cross-reactive, mature)

Fig. 1 | GC dynamics and memory B cell selection. a, The humoral memory
compartment is composed of memory B cells and long-lived plasma cells
(LLPCs). After primary virus infection, antigen-specific naive B cells enter
the germinal centre (GC) reaction and differentiate into strain-specific
or cross-reactive memory B cells and LLPCs. Upon variant virus infection,
the cross-reactive memory B cells are selected to differentiate into plasma
cells or recruited to the GC reaction for further affinity maturation. The figure
illustrates how influenza virus infection induces the generation of memory
B cells against haemagglutinin (HA) antigen. Here, B cells can either bind the
immunodominant strain-specific epitopes to become strain-specific memory
B cells or the subdominant cross-reactive epitopes to become cross-reactive
memory B cells. b, In the mouse gut immune system, pre-existing IgA+ memory
B cells can re-enter the GC reaction in response to a change in the composition
of the microbiota and accumulate somatic hypermutations (SHMs) over time
to generate cross-reactive memory B cells. BCR, B cell receptor.

traffic to sites of infection, TFH cells remain resident in lymph nodes and
the spleen25 and their primary purpose is to help B cells.
In response to immunization with virus-like particles, B cells can
act as the dominant first ‘professional’ antigen-presenting cells to
initiate naive CD4+ T cell activation26. Similarly, memory TFH cells do
not require dendritic cells for their activation; instead, the antigen-
presenting function of B cells is sufficient27. However, during a standard
protein-immunization regimen of naive mice, TFH cell differentia-
tion begins with the interaction of naive CD4+ T cells with antigen-
presenting dendritic cells in the T cell zone (‘pre-TFH cells’), where in
the presence of TFH cell-inductive signals such as IL-6 they upregulate
BCL-6, a key transcription factor for TFH cell identity28,29. This facili-
tates the maintenance and upregulation of the chemokine receptor
CXCR5 and repression of CCR7, allowing their migration to the T–B
border where they differentiate into non-GC TFH cells in response to
T cell–B cell interactions (Fig. 2a). A key cytokine produced by TFH
cells is IL-21, which promotes GC B cell proliferation, maintenance
and the generation of plasma cells30,31. The current hypothesis is that
this basic TFH cell programme (BCL-6+IL-21+) can be modified by the
cytokine milieu towards TFH1 cells (these produce IFNγ/IL-21, which is

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a
Extrafollicular/pre-GC process GC process b

‘Trifurcation’ ‘Stepwise’

Plasma cell Plasma cell

Antibody

B cell follicle
Non-GC Non-GC
TFH cell Cytokine GC-dependent TFH cell
receptor memory B cell GC-independent
Cytokine
memory
GC-independent GC B cell GC TFH cell B cell
memory
B cell

FDC
CD40 CD40L Precursor for GC B cell
TCR MHC II GC/memory
BCR B cell
Light
zone
Pre-TFH cell B cell Dark
zone
Antigen

Naïve
B cell

T cell
CD25+ T cell zone
dendritic cell

Naïve
CD4+ cell

Fig. 2 | Generation of GC-independent and GC-dependent memory B cells.
a, Simultaneous trifurcation model. b, Stepwise differentiation model. Naive CD4+
T cells interact with antigen-presenting dendritic cells. These activated T cells
are thought to interact with the CD25+ dendritic cell subset before differentiation
into pre-T follicular helper (pre-TFH) cells143 and further interacting with antigen-
engaged B cells to form TFH cells. In contrast to the highly proliferative non-
germinal centre (non-GC) TFH cells, GC TFH cells are specialized to contribute to
the affinity maturation of GC B cells by providing cytokines, such as IL-4 and IL-21.
In the simultaneous trifurcation model (panel a), non-GC TFH cells induce antigen-
activated B cells to differentiate into plasma cells, GC B cells or GC-independent
memory B cells simultaneously, whereas in a stepwise differentiation model
(panel b), plasma cell induction precedes the generation of a precursor for GC
B cells and GC-independent memory B cells. BCR, B cell receptor; FDC, follicular
dendritic cell; TCR, T cell receptor.

important in immune responses against intracellular pathogens such
as viruses and promotes class switching in mice to IgG2a/c), TFH2 cells
(these produce IL-4/IL-21, which is important in immune responses
against helminths and promotes class switching to IgG1 and IgE) and
TFH17 cells (these produce IL-17/IL-21, which is important in immune
responses to extracellular pathogens and promotes class switching
to IgA)32. However, a definitive role for TFH17 cells in the induction
of IgA in the mouse gut immune system has not yet been demon-
strated33. This model is largely based on results in mice. Circulating
TFH cells from human blood can similarly be classified as circulating
TFH1 cells (CXCR3hiCCR6low), circulating TFH2 cells (CXCR3lowCCR6low)
and circulating TFH17 cells (CXCR3lowCCR6hi).
In order to interact with T cells at the T–B border, antigen-
engaged B cells in the follicular zone upregulate CCR7 and EBI2,
which act together to facilitate trafficking to the T–B border, where
the B cells then interact with pre-TFH cells in an ICOS–ICOSL and
peptide–MHC-dependent manner34,35. An additional signal such
as from ICOS–ICOSL interaction from cognate B cells at the T–B
border likely promotes the differentiation of non-GC TFH cells, eventu-
ally contributing to GC formation and maintenance (Fig. 2). Recent
detailed analysis of TFH cells in mice identified subsets of non-GC
TFH cells (CD90hiS1PR2−) and GC TFH cells (CD90lowS1PR2+)36. The dif-
ferentiation of non-GC TFH cells into GC TFH cells has been thought to
require sustained cognate interactions with GC B cells, and GC TFH
cells were found to be required for the efficient generation of GC
B cells37. Clearly, it will be important to clarify how these non-GC or GC
TFH cells become memory-type T cells that can be reactivated during
a secondary infection.
The clonal level of TFH cell selection is thought to take place dur-
ing the GC reaction. In fact, there is evidence that TFH cells divide in
response to a peptide antigen to an extent proportional to their TCR
affinity, leading to the increased representation of high-affinity GC TFH
cells over time38. Thus, it is possible that such affinity-selected T cells
with increased sensitivity to peptide–MHC during the GC reaction
are likely to prolong the immune responses even in the presence of
decreased amounts of antigen.

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Review article
Pre-GC memory B cells
With regards to activated B cell fates at the pre-GC selection phase, an
elegant study tracing the fates of single antigen-specific naive B cells
with differing affinity for antigen provided significant insights39. After
stimulation with the protein antigen allophycocyanin with complete
Freund’s adjuvant, half of the B cells produced only one type of effector
cell among three possible fates (plasma cells, GC B cells and memory
B cells) (Fig. 2), suggesting, at least to some extent, a role for BCR affinity
in the subsequent T cell help-mediated selection of B cells. The general
rule seems to be that higher or lower affinity predisposes the activated
B cells to differentiate into plasma cells or memory B cells, respectively;
positively selected and probably intermediate affinity B cells are more
likely to enter the GC. This is consistent with a previous study showing
that a decrease in BCR affinity blocks the generation of plasma cells but
leaves intact the differentiation into GC B cells40. BCR affinity affects the
strength of T cell help as B cells with higher affinity endocytose more
antigen and present it to cognate T cells more efficiently. In this regard,
a report showing that T cell help is necessary to generate the immedi-
ate precursors for GC cells but must cease in order to allow for GC
B cell progression41 supports the idea that there is an optimal window
of BCR affinity (presumably intermediate affinity) in the TFH cell–B cell
interaction that allows for GC differentiation.
However, given that microenvironmental states such as antigen
accessibility undergo dynamic spatiotemporal alterations, particularly
early in the immune response, other factors besides affinity should
be considered in the determination of fate decisions. For instance, in
the single-cell adoptive transfer experiments described above, about
5–10% of clones gave rise to all three effector cell types39. Such multi-
plicity of fates correlates well with a large clonal burst size. The high
bursting clones can be evoked by their high BCR affinity and/or by a
B cell-extrinsic highly inflammatory milieu, where bystander TFH cells
provide survival signals regardless of their BCR affinity. Hence, it is pos-
sible that even a high-affinity B cell clone can give rise to the memory
fate and that, on the other hand, even low-affinity B cells can join in the
GC reaction, which can explain the fact that the unmutated ancestors
of matured mutated broadly neutralizing BCRs to influenza virus or
HIVs can enter the GC, even though they show limited or, apparently,
even no antigen binding to the respective viruses42.
Other types of experiments that involve the adoptive transfer
of naive B cells with fixed BCR affinity (high affinity for hapten NP;
B1-8hi) into recipient mice have provided new insights into fate deci-
sion mechanisms at the pre-GC stage43 (Fig. 2b). Activated B cells
were shown to initially give rise to plasma cells, and then many acti-
vated B cells exited the cell cycle, giving rise to precursors for GC and
memory B cells. This cell cycle exit is caused by limited antigen avail-
ability. Hence, in such settings, the provision of antigen for a sufficient
amount of time, evoking high BCR signalling and subsequent high
T cell help, facilitates plasma cell differentiation, whereas exposure
to antigen for a relatively limited period causes the B cells to become
precursors for GC and memory B cells (GC/memory precursor). In
this regard, rather than a simultaneous trifurcation model (Fig. 2a),
the current data appear to fit better with a stepwise model (Fig. 2b)
in which GC/memory precursors are generated before bifurcation of
memory and GC B cells. Taken together, at least three determinants
participate in fate decisions at the pre-GC phase in wild-type settings:
affinity for antigen; duration of interaction with antigen and cognate
T cells; and the provision of survival signals by the microenvironment.
These factors are interrelated and further work is required to dissect
their individual and joint contributions. Given that SHM occurs even
Nature Reviews Immunology
during pre-GC responses, although less robustly44, qualitative and
quantitative changes in pre-GC memory B cells are likely to affect
secondary immune responses.
Diversity of GC B cells
As many excellent reviews about the dynamics of GC responses have
been published recently44–46, here, based on the recently emerged con-
cept that GC-dependent memory B cells are more diversified relative to
LLPCs10,47,48, we rather focus on how diversified GC B cells are generated
and differentiate into the memory B cell pool.
Historically, the aim of studies of GCs has been to understand
how they support maturation of B cells towards producing the highest
affinity antibodies. The increase in the average affinity of GC B cells
over time requires that B cells with higher affinity for antigen clonally
expand, whereas those of lower affinity proportionally contract46. Such
positive selection of higher-affinity GC B cells has been thought to
take place through two (not necessarily mutually exclusive) potential
mechanisms. One is that higher-affinity cells might receive stronger
BCR signals that favour their survival compared with lower-affinity
cells. The second is that higher-affinity cells could be more effective
in subsequently engaging GC TFH cells and receiving stronger survival
and proliferation signals through cognate T cell help. Although it is
hard to dissect the effects of the two signals (BCR versus T cell help
driven), various studies suggest that the integration of these two signals
determines the positive selection in GCs45,49. In the case of T cell help
for GC B cells, two types of signals, mediated by CD40L–CD40 and
cytokine–cytokine receptor interactions, have been well appreciated
and both receptor/ligand interactions were previously thought to act
on a cognate (1:1) interaction basis. However, recent experiments show
that T cell-derived IL-21 may also act in a paracrine manner and function
as a general GC growth and maintenance factor, rather than only as a
cognate regulator50. In vitro imaging data also suggest this possibility
for IL-4 (ref. 51). However, the caveat in these observations is that such
paracrine activity may only take place in an experimental environment
where many TFH cells and GC B cells do not express the IL-21 receptor
or may only occur in vitro.
In addition to promoting the maturation of high-affinity anti-
bodies, emerging evidence has indicated that GC responses also sup-
port the development of a diverse population of antigen-specific GC
B cells52–54. The generation of diverse antigen-specific GC B cells is
thought to be promoted in the following, at least, five ways45. First,
as GC B cells cannot traffic between separate ‘GC islands’, clones are
confined to individual GCs and clonal evolution takes place in each
independent GC; these clones are not competed out by a stronger
clone residing in a neighbouring GC45,52. Second, some GCs undergo
clonal bursting and are taken over by one or a few clones, whereas
other GCs in the same lymphoid tissue do not undergo a clonal burst,
thereby creating a diverse group of surviving clones52. Third, GC
B cell diversity may be promoted by antibody-mediated feedback, as
dominant GC B cell clones with BCRs specific for particular antigen
epitopes give rise to plasma cells that secrete antibody which, in turn,
masks these epitopes, thereby halting evolution of the correspond-
ing clone, and instead enhancing the selection of clones that bind
different epitopes55–58. Fourth, studies have shown that some naive
B cells enter the GC at later stages during immune responses and that
these late participants possess very low affinity for the original immu-
nogen54,59,60. Last, it is now clear that some B cells in the naive reper-
toire have measurable autoreactivity (they are generally anergic) and
are able to enter the GC61,62. These GC B cells are initially selected for
Review article

a Affinity Mechanisms that promote diversity are particularly important

for allowing sufficient breadth in the B cell response to protect from
rapidly evolving pathogens such as HIV and influenza. Hence, this issue
Cytokine Cytokine requires further investigation.
receptor
MHC II
BCR TCR GC-dependent memory B cells
GC Antibody With regards to the mechanism of memory B cell generation in the GCs,
TFH cell
B cell and by combining older and current data, we have previously proposed
Memory
CD40 CD40L the affinity instruction model. In this model, a low-affinity BCR, which
B cell
means that the B cell will subsequently receive no or low T cell help
upon encountering antigen, is the primary determinant for memory
Plasma cell
B cell generation47,48,66–68. At any given time, GC B cells with no or low
Light affinity for antigen have generally been thought to undergo apoptosis.
zone However, those that do not die exit the GC as memory B cells, whereas
Dark
zone B cells with high affinity re-enter the dark zone for further proliferation
and SHM or exit the GC as plasmablasts (Fig. 3a). This model is further
supported by recent experiments in mice in which the availability of IL-4
and IL-21 in GCs was manipulated50,69. Follicular dendritic cells (FDCs)
b express the IL-4 receptor, which acts similar to a decoy, restricting IL-4
availability to GC B cells and augmenting memory B cell generation.
Conversely, increased IL-21 bioavailability reduces memory B cell gen-
eration. As an alternative to this affinity instruction model, Shlomchik
and colleagues proposed a temporal switch model, in which pre-GC and
early GC B cells tend to differentiate into memory B cells, whereas the
LLPCs are generated preferentially from the late GC reaction70. Given
Memory Memory GC B cell that memory B cells progressively accumulate SHMs with time, these
B cell precursor
two models are not mutually incompatible with each other46.
Bcl6low Bcl6int Bcl6hi
Recent detailed analyses using native proteins with multiple
Bcl2 Bcl2 epitopes as antigens have provided important insights into the memory
Hhex Survival
BCR BCR B cell selection mechanism. First, the selection of low-affinity B cells
EBI2 into the memory compartment takes place both in the late GC phase
Bach2hi
S1pr1 as well as in the early GC phase. Second, the germ-line BCR affinity of
c-Myc
Anti-proliferative
mTORC1 memory B cells is lower than that of LLPCs10,47. Finally, with regards to
clonal diversity, memory B cells have turned out to be more diverse than
Fig. 3 | Memory B cell generation from GCs. a, The affinity instruction model
suggests that memory B cell selection is primarily determined by the affinity of
LLPCs. The more diverse memory B cell population is, thus, most likely to
B cell receptors (BCRs) of germinal centre (GC) B cells for antigen. GC B cells with contain the usually non-immunodominant clones that cross-react with
low-affinity BCRs are more likely to enter memory B cell fate, whereas those different viral variants, such as those specific for the influenza HA stem
with high affinity re-enter the dark zone or exit the GC as plasma cells. b, Memory in the case of influenza-specific B cells, a prediction that has been veri-
B cell precursors are characterized by high BACH2 expression, which can fied experimentally8–10 (Fig. 1a, upper left). Collectively, the properties
mediate an anti-proliferative effect by restraining MYC and mTORC1 activation. of GC-dependent memory B cells as described above appear to fit well
These cells also start to downregulate BCL-6, which enables the induction of with the concept that one of the important functions of the memory B cell
BCL-2 expression and cell surface BCR expression, which together provide compartment is to deal with reinfection by variant pathogens.
survival signals, as well as the induction of EBI2 and S1PR1, which regulate B cell One of the unanswered questions for the lower-affinity model for
migration. Upregulation of HHEX also supports the repression of BCL-6 during selection towards memory B cells is why high-affinity cells are occasion-
the maturation of memory B cells from their precursor cells. TCR, T cell receptor;
ally included in the memory B cell compartment. Considering that the
TFH cell, T follicular helper cell.
numbers of GC TFH cells are much lower than light-zone GC B cells46,
some of the high-affinity light-zone GC B cells may not encounter TFH
cells because of their limited number, thereby allowing these B cells
mutations that diminish self-reactivity, in a process called redemp- to differentiate into memory B cells, even though they still retain the
tion, while preserving foreign antigen reactivity63. In some cases, this potential for being positively selected for GC or plasma cell fate71,72.
might induce a paradoxical decrease in overall affinity for the foreign GC B cells that recognize autoantigen are also thought to not interact
antigen, potentially enhancing the diversity of GC B cells. Given that with cognate TFH cells, because such cognate autoreactive T cells usually
human mature broadly neutralizing antibodies (bnAbs) against HIV undergo stringent negative selection. Hence, as in the case of the occa-
and influenza possess many mutations and that most of their germ-line sional selection of high-affinity cells into the memory compartment,
precursors are polyreactive and/or autoreactive11,64, B cells producing such autoreactive GC B cells might enter the memory pool as well.
such antibodies are likely to have undergone redemption during their Nevertheless, these polyreactive memory B cells have a disadvantage
maturation. In support of this mechanism, it was shown that facilitating for their persistence73.
redemption by using CTLA4-targeted checkpoint inhibitors increased The other possibility for the inclusion of high-affinity cells in the
bnAb responses against influenza virus65. memory B cell compartment is that, particularly in the late phase of

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the GC reaction, antigen accessibility might be limited, for instance, how BCL-6 is downregulated in the process of differentiation towards
through antigen clearance or due to antigen masking by antibodies. memory B cell fate.
This may allow even high-affinity GC cells to differentiate into the
memory pool. Hence, we propose that, despite the importance of Phenotypic heterogeneity of memory B cells
affinity instruction, this instruction is not absolute, allowing a few Several distinct classes of memory B cells have been reported, even in a
high-affinity cells to enter the memory compartment. simple immunization regimen with a protein model antigen. Shlomchik
Another question concerns the molecular mechanisms that drive and others differentiated mouse memory B cell subsets according to
memory B cell differentiation and whether these are consistent with their expression patterns of CD80, PDL2 and CD73 (refs. 85–88). About
the affinity instruction model described above. Such studies had been 80% of the IgM-expressing memory B cells lacked CD80 and CD73 and,
hampered by the lack of a known master transcription factor for mem- upon transfer to naive mice, produced abundant GC B cells, whereas
ory B cell differentiation, but the recent characterization of memory CD80+CD73+ IgG1 memory B cells rapidly produced plasmablasts,
B precursors and the identification of key molecules by employing and later, only a small population of GC cells. The majority of the IgM-
CRISPR–Cas9 screening have started to clarify this issue66,68,74–76. For expressing memory B cells are generated in a GC-independent manner89
positively selected light-zone GC B cells to begin proliferating and to and the remaining 20% of CD80+CD73+ IgM memory B cells are likely
re-enter the dark zone, high levels of expression of the transcription derived from GC B cells. With regards to the mechanisms responsible
factor MYC and a high activity of the metabolic sensor mTORC1 are for such functional differences, given the evidence that switching of GC
required. Here, MYC activates cell division and mTORC1 is required for B cells to IgG1 strongly biases them towards the plasma cell and against
increasing biomass77,78. Unlike these cells, memory B precursor cells, the memory B cell fate73, these differences between CD80−CD73− and
which we have called pro-memory B cells, are in the G0 phase of the cell CD80+CD73+ memory B cell subsets might be caused by differences
cycle and express high levels of the transcription factor BACH2; this is in the signalling capabilities through IgM and IgG1 BCRs. However,
due to the low levels or absence of T cell help, which would otherwise nuclear transfer experiments also indicate another, not mutually exclu-
suppress BACH2 expression66,79. High BACH2 expression appears to be sive, possibility that cellular factors such as epigenetic changes due
required for differentiation into memory B cells, as BACH2-deficient to antigen experience contribute to these differences90. Thus, the key
GC B cells, which have constitutively active mTORC1 and high MYC driver that induces such functional differences among memory B cell
expression, are unable to generate memory B cells66. Hence, a high subsets remains to be clarified.
level of BACH2 expression contributes to memory B cell generation
through restraining MYC and mTORC1 pathways (Fig. 3b). Supporting
this conclusion is the observation that, when MYC function is perturbed Glossary
by the absence of its co-activator MIZ1, differentiation to memory
B cells is enhanced80.
The anti-proliferation programme, which is maintained at least Affinity maturation B1 and B2 B cells
partly by BACH2, is required but not sufficient for memory B cell gen- A process, as a result of somatic B cell populations that differ in
eration. A large portion of the light-zone GC B cells that fail to be posi- hypermutation (SHM) and B cell development, tissue localization and
tively selected undergo apoptosis. Only a small population of cells, the selection in the germinal centre (GC), by function. B2 B cells are the major
memory precursor B cells, express low levels of the transcription factor which B cells increase their affinity and and conventional B cell population
BCL-6 and high levels of BACH2, together with increased expression of avidity for the antigens. abundant in the spleen, lymph nodes
the anti-apoptotic regulator BCL-2 and cell surface expression of BCR81. and peripheral blood, which participate
As enforced downregulation of BCL-6 results in increased expression Age-associated B cells in the germinal centre (GC) reaction
of BCL-2 and the BCR, we speculate that downregulation of BCL-6 (ABCs). A subset of B cells expressing to produce high-affinity antibodies.
is a potential driver of memory B cell generation by, at least partly, CD11c and the transcription factor T-bet, B1 B cells are enriched in the peritoneal
provision of a BCL-2-mediated survival signal66. and lacking CD21 in mice. ABCs are and pleural cavities, which recognize
The importance of BCL-6 downregulation is further substantiated shown to increase during both ageing self-components and common
by experiments demonstrating the requirement for a key transcription and autoimmunity. bacterial antigens, and are the major
factor, HHEX, for memory B cell differentiation79. Here, ablation of Hhex source of natural IgM antibodies.
results in increased expression of BCL-6 and decreased expression of Antibody feedback
BCL-2, leading to cell death74. An immunological phenomenon in T follicular helper cells
The requirement for downregulation of BCL-6 might also explain which antibodies can either enhance (TFH cells). A subset of activated CD4+
the observation that memory precursor B cells reside on the edge or suppress the antigen-specific B cell T cells expressing the chemokine
of the GC light zone, because the G protein-coupled cell migratory responses. receptor CXCR5 and the transcription
receptors EBI2 and S1PR1, which control B cell positioning and facili- factor BCL-6. TFH cells provide help to
tate the movement to the edge of the GC light zone, are known to be Atypical memory B cells B cells for activation, germinal centre
directly repressed by BCL-6 (refs. 82,83) (Fig. 3b). Overall, as proposed A subset of memory B cells expressing (GC) formation and affinity maturation.
by Laidlaw and Cyster84, BACH2 and BCL-6 appear to be key participants inhibitory molecules and lacking
in modulating memory B cell differentiation. surface CD21 and CD27 in humans. Somatic hypermutation
Despite the progress with regards to the molecular mechanisms Atypical memory B cells often develop (SHM). A process by which B cells
of memory B cell generation, it is still unknown whether the small in individuals with chronic infection accumulate point mutations in their
portion of memory precursor B cells among the large pool of B cells or autoimmune disease, and are immunoglobulin genes, thus diversifying
that is undergoing apoptosis is selected stochastically or whether characterized by their reduced effector the specificity and affinity of their B cell
it receives an instructive signal. In addition, it needs to be clarified function. receptors (BCRs) for the antigens.

Nature Reviews Immunology

Review article
Atypical memory B cells
Atypical memory B cells were first identified as a B cell population
with unique morphology, functional capabilities and tissue localiza-
tion in humans91. They were called ‘atypical’ as they express inhibitory
receptors including FCRL4 and are relatively insensitive to in vitro
antigen stimulation. In humans, the non-plasmablast B cell population
contains CD21+CD27+ ‘typical’ memory B cells and two poorly under-
stood subsets: a population of CD21−CD27+ B cells, which contains a
plasmablast-like subset, and a CD21−CD27− ‘atypical’ memory B cell
population that contains a CD11c+ subset, which shares features with
CD11chiCD21low age-associated B cells (ABCs) described in mice.
ABCs have been a focus of growing interest over the past decade,
particularly in autoimmune settings92,93. In mice, the numbers of ABCs
increase with age, as well as after chronic infection and in the context
of autoimmunity. Indeed, the depletion of ABCs in a mouse model of
systemic lupus erythematosus (by putting diphtheria toxin receptor
(DTR) under the control of the CD11c promoter) abrogated the pro-
duction of autoantibodies, albeit with the caveat that this system can
potentially also deplete other activated B cells including GC B cells and
plasma cells94,95. Recent single-cell RNA-sequencing data from humans
demonstrate that the transcriptomic profiles of malaria-derived atypi-
cal memory B cells and systemic lupus erythematosus-derived ABCs
are highly similar, although not identical96. Importantly, pseudotime
trajectory analysis of B cells in malaria infection shows that the dif-
ferentiation pathway towards typical and atypical memory B cells
becomes bifurcated as a consequence of their differentiation from
naive B cells, and that atypical memory B cells have higher expres-
sion of an IFNγ-driven gene signature than typical memory B cells97.
Together, it is reasonable to conclude that, regardless whether reac-
tive to non-self or self-antigen, ABCs can be categorized as a type of
memory B cell. The systematic analysis of human B cells across differ-
ent tissues also supports this conclusion by showing that the ABC-like
CD11c+CD21−CD27− B cells in humans are memory B cells98.
With regards to the development of mouse ABCs, two groups
have identified ZEB2, which is not expressed by conventional memory
B cells, as a key transcription factor for ABC generation99,100. ZEB2
appears to affect cytokine receptor signalling pathways by transacti-
vating the genes encoding suppressor of cytokine signalling 5 (SOCS5)
and the IL-21 receptor100.
In addition to chronic infections, CD11c+CD21lowT-bet+ ABCs also
appear following acute influenza and lymphocytic choriomeningitis
virus (LCMV) infection in mice. In the case of LCMV infection101, mouse
CD11c+T-bet+ memory B cells, which correspond to ABCs, arise mainly
during extrafollicular B cell responses (pre-GC phase) in the spleen, and
probably require non-GC TFH1 cells (IFNγ/IL-21 producing) for their devel-
opment. Then, at the memory phase, these cells become localized at the
splenic marginal zone and express transcripts of plasma cell-associated
genes (such as BLIMP1, XBP1), suggesting that they are memory-type
pre-plasma cells36, as initially proposed by McHeyzer-Williams and
McHeyzer-Williams102. Indeed, although very few of these cells spon-
taneously produce IgG in vitro, they rapidly differentiate into LCMV-
specific plasma cells in response to stimulation with Toll-like receptor
7 (TLR7) ligand only103,104. In the case of the influenza infection model,
CD11c+T-bet+ memory B cells are generated in a GC-dependent manner
and are located, similar to the LCMV acute infection model, in the spleen,
probably in the marginal zone105. Given the importance of marginal
zone B cells for the initial recognition of blood-borne pathogens106,
these CD11c+T-bet+ memory B cells might play a more important role
for initiating protection against systemic rather than local infections.
Nature Reviews Immunology
More recently, analyses of data from humans with SARS-CoV-2
infection and individuals who received COVID-19 mRNA vaccination
have indeed identified, in both cases, CD21lowCD27− atypical memory
B cells corresponding to the CD11c+T-bet+ ABC subset in mice107. Given
that these atypical memory B cells are also generated in individuals
with other viral infections or with malaria, but not in those who receive
simple protein immunization, we speculate that B cells exposed to a
more inflammatory milieu (as is also the case for current COVID-19
vaccines) are more prone to differentiate into atypical memory B cells.
As for the inflammatory mediators, mouse studies indicated an
important role for TLR7 and IL-21 as described above102,103; B cell specific
deletion of Tlr7 or Myd88 abolished the development of ABCs in aged
mice94, and IL-21 transgenic mice had spontaneous ABC formation108.
The function of ABCs has not been fully elucidated so far. Nevertheless,
three potential functions have been proposed: ABCs may be exhausted
cells and non-functional, similar to CD8+ exhausted memory T cells; ABCs
may be able to differentiate in a less antigen-dependent manner com-
pared with conventional memory B cells; and ABCs may be specialized
for antigen presentation, their primary role being to activate T cells.
Reactivation of memory B cells
Experiments in which memory B cells are adoptively transferred into
naive recipient mice without memory lymphocytes or pre-existing
antibodies revealed differences in the functional capabilities of dif-
ferent memory B cell subsets87,89,109,110. However, these experiments
did not necessarily reflect a natural secondary immunization/infec-
tion. In contrast to the naive state, mice that have experienced primary
immunization/infection harbour memory B cells, memory TFH cells and
antigen-specific antibodies, all of which likely affect the subsequent
recall humoral responses.
In situ reactivation
In situ re-immunization methods can model the natural situation of
memory B cell recall more closely than the adoptive transfer described
above and can reveal the location of memory B cells and T cells before
reactivation, as well as their fates upon recall. In the lymph node, rest-
ing memory B cells reside in a specialized niche in the subcapsular sinus
(SCS) region where they are closely associated with memory TFH cells
(Fig. 4). The SCS also contains a subset of CD169+ macrophages that
display captured particulate antigens such as viruses and immune
complexes111,112. Once memory B cells bind antigens trapped by
CD169+ macrophages, it is likely that these memory B cells present
them via MHC II molecules and swiftly activate memory TFH cells in a
cognate manner27, which is critical for secondary humoral responses
(Fig. 4). Hence, the close proximity of antigen-presenting CD169+
macrophages, memory B cells and memory TFH cells is likely to allow
for the generation of robust recall responses. Indeed, memory B cells
frequently make serial contacts with CD169+ macrophages via CCL21/
CCR7 interactions; CCL21 is expressed by stromal cells located close to
the SCS and CCR7 is upregulated by memory B cells. The S1P–S1PR axis
is thought to direct the migration of memory B cells into the periphery,
leading to their appearance in other lymphoid organs. On the other
hand, CCL21 directs memory B cells to remain in the original lymph
node112. It has been reported that a subpopulation of memory B cells
does not recirculate and instead resides long-term in the draining
lymph node111,113. This might be explained by higher expression of CCR7
and lower expression of S1PR2. Similarly, a subpopulation of memory
TFH cells was reported to reside long-term in the draining lymph node113.
The continued residence of memory B cells and/or possibly memory
Review article
Subcasular
sinus
Patrolling
SCS Subcapsular
BCR
macrophage niche
TCR
Memory
CCL21 Resting TFH cell
memory
B cell
CCR7
Follicle
Fig. 4 | Memory B cell reactivation. At the memory state in the lymph node and
before encountering antigens, resting memory B cells reside in a specialized
niche in the subcapsular sinus (SCS) region and are closely associated with
memory T follicular helper (TFH) cells and SCS macrophages. CCL21 expressed
by stromal cells near the SCS attracts memory B cells that express CCR7. After
pathogens are captured by SCS macrophages, resting memory B cells are
activated in the subcapsular niche and can enter the germinal centre (GC)
TFH cells in the draining lymph node may explain the observations that
local antigen boosts facilitate recall GC responses better than distal
ones114. Considering that many vaccines are administered as boosters,
clarifying what fractions of the populations of memory B cells and
T cells that are generated in a draining lymph node remain resident
versus entering circulation is an important unresolved issue.
Response to vaccine boosters or re-exposure to a pathogen has
also been characterized in peripheral tissues. In the influenza infec-
tion system, reinfection induces the formation of tertiary lymphoid
structures (iBALT in the lung) where GC reactions can occur, thereby
generating resident memory B cells as well as resident memory TFH cells
in the lung115. With regards to resident memory B cells, after primary
influenza infection both antigen-specific CXCR3+CCR6+ B cells and
CXCR3−CCR6+ bystander resident memory B cells are generated116.
This observation is not specific for influenza infection but has also
been reported in SARS-CoV-2 infection117, and is likely to be a gen-
eral phenomenon in lung infection. Although the exact function of
bystander memory B cells is not clear at this point, the data suggest
that higher expression of the IgM Fc receptor, particularly by bystander
CXCR3−CCR6+ resident memory B cells, might contribute to booster
reactions through binding of IgM immune complexes.
In the case of influenza reinfection, alveolar macrophages are
key initiators for humoral recall responses through the secretion of
IFNγ and CXCR3 ligands (CXCL9/CXCL10), which activates the recruit-
ment of CXCR3+ resident memory B cells into foci of infected cells118.
Although it has not yet been clarified whether memory TFH cells are
required for the initiation of these recall responses, it is reasonable to
speculate that the resident memory B cells, as well as resident memory
TFH cells, are recruited close to alveolar macrophages, where these
immune cells interact together, thereby exerting protective immunity.
Nature Reviews Immunology
Antigen
Cytokine
receptor
Cytokine
MHC II
TCR
Reactivated
memory TFH cell
Reactivated
memory B cell CD40 CD40L GC entry
Plasma GC B cell
differentiation
Antibody
feedback
to form GC-dependent memory B cells or differentiate into plasma cells.
Memory TFH cells are also activated in contact with SCS macrophages. Such
close localization of SCS macrophages, memory B cells and memory TFH cells
may contribute to the robust recall responses. Pre-existing antibodies or those
produced by boosted memory B cells can mask specific epitopes on antigen,
thereby impairing the activation of cognate memory B cells. BCR, B cell receptor;
TCR, T cell receptor.
Characteristics of in vivo reactivated memory B cells
Detailed clonal analysis of memory B cells in mice using homologous
in situ influenza HA protein boosts clarified that a very strict bot-
tleneck to clonal diversity operates at the time of recall of memory
B cells to the secondary plasmablast response46. Of the hundreds of
memory B cell clones that are generated during priming, only a few
clones are activated and develop into secondary plasmablasts through
repeated recruitment of a few higher-affinity dominant clones to sec-
ondary GCs119. Whereas most secondary plasmablasts are derived
from memory B cells, secondary GCs in the prime-boost setting are
predominantly composed of naive B cells, with only a minor memory
B cell compartment. This leads to the formation of early secondary
GCs, which contain B cells that are just as diverse and poorly mutated
as those in early primary-immunized GCs. Such recruitment of naive
B cells into secondary GCs was also observed in humans12, but the
ratio of memory B cells versus naive B cells in secondary GC reactions
is generally higher in humans compared with mice. This may reflect
extensive histories of influenza antigen exposure in humans or pro-
found biological differences in the reactivation of memory B cells
between humans and mice.
One important question is why there is such a paucity of memory
B cell-derived B cells in recall GC responses in the mouse. Given that the
GC is the most important environment for generating BCR diversity and
antibody breadth, it is important to understand how memory B cells
can re-enter GCs. Similar to the importance of precursor frequency and
affinity of naive B cells for entering GCs, the numbers of memory B cells
generated by a single antigen encounter might be small120. In addition,
given that CD80+CD73+IgG+ memory B cells are prone to differentiate
into plasma cells rather than enter the GC87, the numbers of functional
memory B cells that are capable of entering GCs might be even smaller.
Review article
Other possibilities should be considered, such as negative
feedback by antigen-specific antibodies121, as initially proposed by
Smith in 1909 (ref. 122). Recent studies also indicate that antibody
feedback is particularly important in determining booster-mediated
B cell fates. For instance, it was shown in adoptive transfer experiments
that antibodies produced by IgG+ memory B cells could inhibit the
formation of IgM+ memory B cell-derived secondary GCs110. Then, by
using adoptive transfer of BCR knock-in memory or naive B cells, these
donor B cells were only activated in naive mice, but not in immunized
mice123, because of the existence of pre-existing masking antibodies
in the latter. Together with the data obtained from experiments in
which either antigen-specific or irrelevant antibodies were adminis-
tered124,125, antibodies either present prior to boosting or produced
acutely by boosted memory B cells are thought to compete with cog-
nate naive as well as memory B cells for binding a specific epitope
through antibody-mediated epitope masking (Fig. 4, right).
Lessons from SARS-CoV-2
Many excellent reviews of the insights gained from SARS-CoV-2 infec-
tion and COVID-19 vaccines with regards to B cell differentiation have
been published126–128. Here, we focus on human memory B cells and,
in particular, how they acquire neutralizing antibody (nAb) breadth.
Acquiring such a feature after only a single viral infection129 or after two
or three doses of mRNA vaccines encoding the ancestral SARS-CoV-2
spike protein would not be expected.
Two doses of mRNA vaccine or one incidence of SARS-CoV-2 infec-
tion induces similar frequencies of IgG+ memory B cells that bind the
spike receptor-binding domain (RBD), with comparable SHM levels.
Given that a substantial fraction of RBD+IgG+ memory B cells from
individuals who have been vaccinated with two doses of mRNA-based
COVID-19 vaccines can also bind to RBDs of variants of concern130,131,
it appears that this vaccine regimen generated substantial numbers of
affinity matured memory B cells132,133. However, the affinity maturation
after a standard two-dose mRNA vaccine regimen is qualitatively poorer
than that after a single SARS-CoV-2 infection. These differences may
be related to the narrow window of time between dose 1 and dose 2 of
the mRNA vaccines of usually 3 or 4 weeks, as experimental models
of vaccination against HIV have shown that extending the priming
period can result in better nAb responses126,134.
After mRNA vaccination, GCs were observed to persist for at least
6 months in draining lymph nodes of healthy individuals after the sec-
ond dose of COVID-19 mRNA vaccine135–137. GCs have been shown to play
a central role in the generation of nAb breadth of memory B cells132,133.
Indeed, nAb responses are substantially reduced in many individuals
who are immunocompromised, such as recipients of kidney trans-
plants138. The lower GC responses in recipients of kidney transplant
could be due to weaker GC TFH cell responses, as the frequency of GC
TFH cells in these patients was severely reduced and associated with
poor nAb titres.
Thus, the question arises of why memory B cells acquire nAb
breadth much more easily in the case of SARS-CoV-2 infection and
COVID-19 mRNA vaccination compared with HIV or influenza infec-
tion. Two types of studies have recently demonstrated the importance
of antibody feedback in GC responses. First, in the context of mRNA
vaccination, the introduction of high-affinity epitope-specific mono-
clonal Abs affected memory B cell selection by two mechanisms: the
affinity threshold for the entry into the memory and GC compart-
ment was altered, and the epitopes targeted on RBD were changed
by direct masking125. Second, we and others have shown that, after
Nature Reviews Immunology
a two-dose or three-dose mRNA vaccine regimen, the distribution
of epitopes recognized by memory B cells is shifted away from the
initial immunodominant RBD epitopes58,123. Thus, masking of these
immunodominant epitopes by pre-generated antibodies diversifies
immunogenicity of otherwise subdominant epitopes on the RBD. In
the case of mRNA vaccination, these second-layer antibodies target
RBD epitopes conserved between variants and acquire high-potency
neutralizing activity through GC reactions, together contributing to
the development of functional breadth. However, in the case of HIV or
influenza vaccination, the antibody feedback mechanism might halt
the maturation of memory B cells with potential bnAb BCRs11,123,139. For
example, in the case of influenza vaccination and the response to the
key conserved stem epitope, critical specific on-target neutralizing
antibodies coexist with many off-target non-neutralizing antibodies11.
Hence, the efficient generation of off-target antibodies probably limits
access to this conserved epitope by memory B cells with on-target
BCRs, thereby not allowing them to re-enter the GC. Eventually, this
mechanism seems to operate by diverting immunity away from mak-
ing memory B cells with on-target bnAbs, and instead towards those
with strain-specific ones.
Memory B cells, TFH cells and vaccines
How can we overcome the obstacles to bnAb development when design-
ing vaccines? In the case of anti-stem influenza HA bnAbs, three poten-
tial obstacles exist with regard to B cell maturation: germ-line ancestors
of matured broadly neutralizing BCRs may have extremely low affinity
for the native epitopes; naive B cells with these ancestor BCRs may be
extremely rare; and these bnAbs are immunosubdominant. So, in the
competitive situation of a polyclonal naive B cell setting, knowing how
such rare naive B cells specific for the conserved epitope (such as the
stem epitope in the case of influenza) are recruited into the immune
response, and subsequent GC reactions, and induced to generate
memory B cells is key to successful vaccine development. Moreover,
knowing how GC-dependent memory B cells are recruited again into GC
responses upon boosting with a second immunization is also important.
Hence, one way to induce memory B cells for re-entering GC responses
would be to modify the immunogens, for example by introducing muta-
tions or glycan masking140,141, so that they are recognized by the desired
germ-line or intermediate BCRs, but not by non-neutralizing BCRs.
Given that limited TFH cell help at the T–B border is another bottle­
neck, increasing the number of antigen-specific TFH cells might allow
low-affinity B cells to be recruited into the immune responses and
subsequent GC reactions. Indeed, experiments using an HIV model
showed that higher levels of T cell help allow rare B cells that express
the germ-line BCRs of mature bnAbs to enter the GC reaction142. Hence,
it is likely that with high quantities and qualities of TFH cells, rare B cells
with germ-line BCRs of potential bnAbs could have a better chance of
being recruited into GCs, wherein these BCRs become matured by SHM,
eventually generating high-quality bnAb-expressing memory B cells81.
Finally, as discussed above, particularly during booster vaccina-
tion, and differing from SARS-CoV-2 infection, avoidance of antibody
feedback may make sense for generating memory B cells that are
capable of producing bnAbs.
Outlook
In the past 10 years, the cellular and molecular mechanisms of memory
B cell function in polyclonal settings have been carefully analysed, and
the findings have broad implications for vaccinology and the treatment
of autoimmunity. Although future directions and open questions have
Review article
been discussed throughout this Review, we emphasize the importance
of gaining a better fundamental understanding of the spatiotemporal
aspects of memory B cell generation, maintenance and reactivation,
and how memory B cell heterogeneity (such as conventional versus
atypical memory B cells) can be formed, as well as how other types of
cells, particularly TFH cells and FDCs, participate in these processes.
Recent technical advances in high-throughput single-cell sequencing
to explore both gene expression and immune repertoire profiles will
allow us to uncover novel principles underlying clonal selection and
the acquisition of different differentiation trajectories. The develop-
ment of technologies to investigate immunization-induced memory
B cells in higher primates shifts the studies to the human setting, which,
in turn, will allow us to engineer vaccines optimized for the generation
of memory B cells or to target memory B cells for the treatment of
autoimmune diseases and allergies in humans. In this respect, research
into the functions of memory B cells in disease pathologies should be
a high-priority research area.
Published online: xx xx xxxx
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Acknowledgements
The authors thank P. D. Burrows for critical reading of the manuscript. This work was
supported, in part, by Japan Society for the Promotion of Science KAKENHI (JP21H02749 to
T.I., JP22H00450 to T.K.), the Mochida Memorial Foundation for Medical and Pharmaceutical
Research (to T.I.) and the Chemo-Sero-Therapeutic Research Institute (to T.I.).
Author contributions
T.K. contributed to conceptualization of the article. All authors contributed to writing and
editing of the manuscript.
Competing interests
The authors declare no competing interests.
Additional information
Peer review information Nature Reviews Immunology thanks Jason Cyster and the other,
anonymous, reviewers for their contribution to the peer review of this work.
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