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Infectious Disorders – Drug Targets, 2012, 12, 232-240
232
Primary and Secondary B-Cell Responses to Pulmonary Virus Infection
Yoshimasa Takahashi1,*, Taishi Onodera1, Kazuo Kobayashi1 and Tomohiro Kurosaki2,3
1
Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo 162-8640,
Japan; 2Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, and Graduate School of
Frontier Biosciences, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; 3Laboratory for Lymphocyte
Differentiation, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa 230-0045,
Japan
Abstract: Viruses form particulate structures possessing high-density B-cell epitopes and viral RNA/DNA, which are
ligands for multiple Toll-like receptors (TLRs). B cells are able to sense these viral antigenic signatures through B-cell antigen receptors (BCRs) and TLRs, both of which synergistically shape the magnitude and quality of virus-specific B-cell
responses. In many viruses, B-cell recognition of these virus signatures is often hampered by tissue tropisms toward nonlymphoid organs. However, ectopic localizations of B cells at virus replication sites facilitate the efficient recognition of
intact virus particles. Following pulmonary infection by influenza virus, virus-specific B-cell responses occur in the tertiary lymphoid organs of lungs near the sites of virus replication as well as in the draining lymph nodes. Lungs then begin
to support the germinal center response and the formation of niches for plasma cells and memory B cells, thus potentiating
B-cell intrinsic recognition of virus particles at these sites. In this review, we discuss how the anatomical location and virus-sensing properties of B cells coordinate protective B-cell responses against pulmonary virus infection.
Keywords: Affinity maturation, germinal center, influenza virus, lung, memory B cell, plasma cell, toll-like receptor.
INTRODUCTION
One hallmark of the adaptive immune response is the
long-term memorization - many times lasting up to several
decades - of an encounter with a pathogen. A phenomenon
called “immunological memory,” by which a primed host
can promptly and vigorously eliminate invading pathogens,
is the basis of the protective immunity provided by vaccinations or previous infections [1]. Immunological memory is
composed of two distinct types of adaptive immune responses: Antibody (Ab)-mediated humoral responses and T
cell-mediated cellular responses. Ab-mediated humoral
memory plays considerably important roles in protection
against many pathogens, as demonstrated by evidence that
most of licensed vaccines depend on neutralizing Abs for
efficacy [2]. B-cell memory is equipped with two cellular
arms: long-lived plasma cells and memory B cells, both of
which mainly develop in germinal centers (GCs) [3, 4].
Long-lived plasma cells are primarily present in bone marrow (BM) and maintain long-lasting neutralizing Abs in serum that confer immediate protection at a time of reinfection
as the first line of defense [3]. Memory B cells mediate the
recall response by robustly generating plasma cells in response to antigen challenges [4]. Although memory B cells
do not prevent initial infection, they do play a role in preventing the spread of pathogens, allowing faster resolution of
infection.
Viruses comprise organized structures of proteins, lipids,
sugars and nucleic acids but differ from protein antigens or
adjuvant immunogens in several aspects. First, several (but
*Address correspondence to this author at the Department of Immunology,
National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo
162-8640, Japan; Tel: 81-3-4582-2714; Fax: 81-3-5285-1156;
E-mail: [email protected]
2212-3989/12 $58.00+.00
not all) viruses (e.g. rhabdo-, parvo-, picorna-, toga-, and
influenza viruses) form particulate structures with envelope
proteins that display B-cell epitopes in a highly repetitive
manner [5]. Second, they include several types of nucleic
acids that are sensed by pattern recognition receptors (PRRs)
in innate and acquired immune systems [6]. B cells are
unique in their capacity to sense highly repetitive envelope
proteins and endosomal/cytosolic nucleic acids through Bcell antigen receptors (BCRs) and PRRs, respectively, in a
consecutive way [5, 7]. Recently, accumulated evidence has
begun to reveal the impact of B-cell intrinsic recognition of
these viral signatures on the magnitude and fate-decisions of
B-cell development against invading viruses.
B cell locations that are closer to virus replication sites
are thought to facilitate direct recognition of virus signatures.
For instance, following pulmonary infection by influenza
virus, the viruses replicate in respiratory tracts but not in the
secondary lymphoid organs, where the initial priming of B
and T cells typically takes place [8-12]. Therefore, initial B
cell priming is primarily conducted by viral antigens transported by dendritic cells (DCs), which potentially lowers the
chance of sensing the highly organized structure of the virus
particles themselves [13]. However, infected lungs then begin to support the GC response and the formation of cellular
niches for plasma cells and memory B cells [14-18], thus
facilitating B-cell intrinsic sensing of virus signatures following secondary pulmonary infection. Here, we review
current understanding of virus-specific B-cell responses that
take place in the lungs and the draining lymph nodes following primary and secondary pulmonary infection and discuss
the possible functional compartmentalization in each organ
for orchestrating these protective B-cell responses.
© 2012 Bentham Science Publishers
B Cell Responses Against Virus Infection
TWO ANATOMICAL SITES REQUIRED FOR THE
PRIMARY B-CELL RESPONSES FOLLOWING
PULMONARY VIRUS INFECTION
Because individual viruses have distinct entry routes and
cellular tropisms, it is difficult to depict a generalized view
of initial B-cell priming and subsequent differentiation of
primed B cells following infection by all virus types. Here,
we will focus on B cell responses in the mice infected with
influenza virus for which we have substantial information
regarding virus entry routes, initial cellular targets, and innate and acquired immune responses following pulmonary
infection.
The mouse is not a natural host for influenza viruses, but
the adaptation process increases tissue tropism toward the
lower respiratory tract (RT) [19, 20], allowing viruses to
infect ciliated epithelial cells, macrophages, DCs, and several other hematopoietic cells in lung tissues [10, 12]. This
process ultimately causes lethal influenza pneumonia in
cases of highly pathogenic viruses. However, under nonlethal infectious conditions, virus replication is largely restricted to the RT region and does not usually spread into
other tissues, such as the draining lymph nodes (LNs), since
the enzyme required for the cleavage of hemagglutinin is not
present in other tissues [21]. Therefore, viral antigens first
need to be transported to the draining mediastinal lymph
nodes (MLNs), where initial priming of B and T cells takes
place. DCs are situated in immediate proximity to respiratory
epithelial cells [13], and infected DCs start to migrate from
the lungs to MLNs, a process that peaks at 18 hours after
infection [22]. Infected DCs deliver viral antigen to naive B
cells presumably as integral membrane components on their
surface, which likely constitutes poorly organized form
compared to intact virus particles [23]. Infected DCs also
prime helper T cells which deliver cognate help to B cells at
the border of T-cell zone and B-cell follicle [24]. After proliferating in perifollicular region, primed B cells proceed into
either the extrafollicular pathway, which generates shortlived plasma cells, or to intrafollicular GC/memory pathways
[24]. While fully developed, long-lasting GC formation requires cognate interaction of B cells and helper T cells, an
extrafollicular pathway following virus infection can be
taken in both a T-dependent (TD) and a T-independent (TI)
manner. The contribution of TI pathway in MLNs varies
among experimental conditions but is consistent in that the
generation of IgA+ plasma cells is less dependent on cognate
interaction with helper T cells [25, 26]: class II-deficient B
cells are able to generate IgA-secreting plasma cells in the
MLNs following influenza virus infection [25]. In the absence of cognately interacting T cells, DCs may provide
costimulatory signals for IgA responses during B-DC interaction, as RT DCs express B-cell activating factor of the
tumor necrosis factor family (BAFF) and a proliferationinducing ligand (APRIL) [27], which are potent IgAstimulatory molecules [28-30]. Moreover, RT DCs may be
able to secrete IgA-promoting cytokines (e.g. IL-5, IL-6, IL10 and TGF-beta) similar to those in gut-associated lymphoid tissues [31]. While the TD response is more effective
for clearing viruses, the TI response also confers protection
by reducing both morbidity and mortality of lethally infected
mice in the absence of TD response, revealing its early containment role in protection [26, 32].
Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 3
233
While MLNs serve as major priming sites of naive B and
T cells and provide anatomical niches for developed plasma
cells and GCs, recently available data indicates that lung
tissue also provides cellular niches for both plasma cells and
GCs against pulmonary virus infection. In mice maintained
under specific-pathogen free conditions, B and T cells constitute around 30% of lung cells and are largely scattered in
several regions of lung tissue [27, 33]. Following viral pulmonary infection, CD11c+ DC cells first accumulate in peribronchiolar or perivascular space, and both B and T cells
gather in CD11c+ cell-rich areas [34]. B cells then start to
form aggregates in those areas, where they finally develop
into tertiary lymphoid structures containing B- and T-cell
rich areas around high endothelial venules (HEVs) by day 10
after infection [16]. This tertiary lymphoid structure, the socalled “induced bronchus-associated lymphoid tissue”
(iBALT), develops in mice lacking all secondary lymphoid
organs, demonstrating that the cellular recruitment from secondary lymphoid tissues is not an absolute prerequisite for
its formation [16, 35]. Both plasma cells and GC structure
start to emerge concomitantly with iBALT development, and
iBALT supports the lung localization of GCs within follicles
and plasma cells at the periphery of follicles or in the T-cell
zone [27, 36]. Of note, diphtheria toxin (DT)-induced deletion of local DCs after virus clearance has revealed the
unique cellular requirement of iBALT for its maintenance
[27]. When a low dose of DT was intratracheally administered into mice expressing DT receptor on CD11c+ cells after
virus clearance (day 17 after infection), CD11c+ cells in the
lungs were depleted. Unexpectedly, however, the deletion of
CD11c+ cells in the RT area resulted in the gradual reduction
of preexisting iBALT in the lungs. This treatment accompanied the disappearance of preexisting IgA+ plasma cells in
the lungs, suggesting that iBALT includes the cellular niches
for lung plasma cells at this time point. Intriguingly, the specific reduction of plasma cells in the lungs, but not in MLNs,
resulted in a significant drop of IgA titer in bronchusalveolar lymphoid fluid (BALF), indicating that lung plasma
cells contribute to the production of IgA titer in the RT to a
larger extent than do those in MLNs. Lung CD11c+ DCs
increased the expression of several homeostatic chemokines,
such as CXCL12, CXCL13, CCL19, and CCL21, with time
after infection, implying that lung DCs maintain iBALT
structure and plasma niches through the secretion of homeostatic chemokines [27, 37].
What is the functional compartmentalization of the MLN
and iBALT as sites for initial B-cell priming and maintenance of primary B-cell responses? It is conceivable that
following pulmonary infection, MLNs play a more important
role in the early supply of plasma cells, as their preprogrammed lymphoid structure allows rapid generation of
plasma cells immediately after priming. When the first wave
of MLN-derived Ab response is not sufficient for the eradication of invading viruses, and viral replication and an inflammatory environment continues in the lungs, then iBALT
formation is promoted by the presence of TLR agonists and
the inflammatory cytokines, TNF-alpha and IL-6 [38-40].
The developed iBALT provides additional priming sites for
B and T cells that recognize not only the original antigens
but also unrelated antigens or viruses [34, 38, 41]. More importantly, iBALT sustains the cellular niches for plasma cells
234 Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 3
Takahashi et al.
and GCs for long-lasting Ab responses in the lungs in
preparation for secondary infection [27]. Indeed, while MLN
plasma cells develop transiently, peaking in number at day 7
after infection, lung plasma cells gradually emerge thereafter
and persist over the lifetime of the mouse [14, 18]. Thus,
these data support the hypothesis that MLNs are specialized
for the prompt generation of plasma cells that constitute the
first wave of Ab responses while iBALT in the lungs plays a
more important role in sustaining the GC response and the
formation of cellular niches for plasma cells and possibly
memory B cells for a long period at the site of virus entry
Fig. (1).
PERSISTENT
GC
RESPONSE
PULMONARY VIRUS INFECTION
gen on FDC and helper signals from Tfh cells determine
which variants are selected to develop into either long-lived
plasma cells or memory B cells [46, 47]. Therefore, GCs
provide key cellular and molecular interactions for affinity
maturation and specificity of Abs produced via memory Bcell responses, as well as the generation of long-lived plasma
cells and memory B cells with improved affinity and specificity [48].
Following pulmonary infection with influenza virus, GCs
start to appear in MLNs by day 7 and peak in number around
day 20; thereafter, their numbers decline with time. Intriguingly, however, GCs persist for a long period after virus
clearance and are detectable even at 140 days after infection
in a manner resembling the long persistence of splenic GC
response after systemic infection with vesicular stomatitis
virus (VSV) [18, 49]. After influenza virus infection, virus
replication and viral antigens persist in irradiation-resistant
lung cells for more than 1 month after infection [50], with
residual viral antigen continuously transported by lung DCs
to MLNs, as revealed by the cell division of transferred naive T cells in MLNs [50-52]. Moreover, a longer persistence
of GC response was found after immunization with replication-defective, virus-like particles (VLP) or nanoparticles
FOLLOWING
GCs are well-organized, microanatomical structure that
include rapidly dividing B cells and follicular helper T (Tfh)
cells within networks of follicular-dendritic cells (FDCs)
[42]. GC B cells highly express activation-induced cytidine
deaminase (AID), which is a master regulator of somatic
hypermutation and isotype switching [43]. Somatic hypermutation can diversify the affinity and specificity of BCR
expressed on GC B cells [44, 45] while accessibility to anti-
iBALT
Dendritic
cells
Plasma cells
Mesenchymal
sheath
Epithelium
Influenza virus
FDCs
Airway
mucosa
B cells
T cells
GC
HEV
Memory
B cells
HEV
Late response
Mediastinal
lymph node
Early response (< 1 week)
Migrate to
lymph node
(peak at 18 hr)
GC
GC
Memory
B cells
Short-lived
plasma cells
Memory Long-lived
B cells plasma cells
Fig. (1). Primary B cell responses in lungs and MLNs following pulmonary influenza virus infection. Infected dendritic cells (DCs) deliver
viral antigen to MLNs where initial priming of B and T cells and prompt supply of plasma cells takes place. MLNs also support the formation of GCs which persist for a long period. One week after infection, iBALTs begin to develop in inflamed lungs and support cellular niches
for plasma cells and formation of GCs at the sites near virus replication.
B Cell Responses Against Virus Infection
including TLR agonists, indicating that viral replication is
not an absolute requisite for this longer persistence [53, 54].
Collectively, these data indicates that the GC response in
MLNs develops rapidly and persists for a long period, possibly through the combination of continual antigen deposit
after virus clearance and the B-cell stimulatory effect of viral
antigens.
One important functional consequences of the GC response is the continuous introduction of somatic hypermutations and subsequent affinity maturation of Abs [44, 45, 55].
While Ab responses without affinity maturation substantially
contribute to protection against VSV and influenza virus [56,
57], maturation of Ab affinity indeed improves the efficiency
of virus neutralization [58-61]. For example, the biological
importance of Ab affinity becomes evident in mice infected
with respiratory syncytial virus (RSV). It is well known that
immunization with a formalin-inactivated RSV vaccine cannot elicit protective Abs against RSV infection [62], but the
mechanisms underlying this process have not been explored
until recently. Delgado et al. analyzed the affinity of Abs
against the major neutralizing epitopes (F protein) of RSV
after vaccination or natural infection and found that the affinity in vaccinated mice was significantly lower than that in
infected mice [63]. Moreover, they observed that the simultaneous administration of TLR agonists improved affinity
maturation and conferred the protection, concluding that lack
of affinity maturation results in the defect of protection by a
formalin-inactivated RSV vaccine. These RSV data provide
the best example of the significant contribution of affinity
maturation during a neutralizing Ab response against virus
infection. Nevertheless, the relative contribution of affinity
maturation is likely influenced by the balance of at least two
factors: initial affinity of virus-binding Ab before affinity
maturation and the strength of the molecular interaction that
neutralizing Abs need to block.
In addition to their possible contribution to affinity maturation following virus infection, persistent GCs may provide
two additional advantages for protective immunity against
virus infection. Data from human LNs suggest that memory
B cells can be recruited into a preexisting GC structure [64],
implying that memory B cells have a repeated chance to be
subjected to selection as long as preexisting GCs are present.
The additional clonal selection is beneficial for the prompt
adjustment of affinity and specificity of BCR, especially
when the escaped mutants are easily generated during the
replication process. Another functional role for persistent
GCs has recently been depicted in TD B-cell responses elicited by hapten-protein immunization. The study revealed
after extensive immunohistochemical analysis and a fatemapping strategy that allowed genetic labeling of antigenexperienced B cells that IgG+ memory B cells are preferentially located at the periphery of persistent GCs [65]. These
data suggest an intriguing model in which the localization of
IgG+ memory B cells near persistent GCs is beneficial for
their prompt TD reactivation, as GC structures keep antigenspecific memory B cells and Tfh cells close to each other
[65].
iBALTs also support GCs, which contain rapidly dividing B cells together with T cells and FDCs [16, 36]. IgV sequence analysis of BALT from patients with chronic ob-
Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 3
235
structive pulmonary disease (COPD) provide evidence of
ongoing somatic hypermutations at these sites [66]. Important clues regarding the functional roles of iBALT in Ab
responses have been provided by DT-induced deletion studies as mentioned above [27]. DT-mediated deletion of lung
DCs reduced virus-binding serum Ab titer and the number of
BM plasma cells concomitantly with disruption of the
iBALT structure. Moreover, the same treatment resulted in
reduced IgA titer in BALF and in hemagglutinin inhibiting
activity of serum Abs following secondary infection. Considering that a similar treatment retained intact DC function
in MLNs [50], these results suggest that GCs inside iBALT
are functionally competent to provide long-lived plasma
cells and memory B cells in both local and systemic Ab responses. However, further studies are required to reveal the
direct involvement of iBALT GCs in these processes. Furthermore, we need to clarify the nature of iBALT GCs in
their cellular composition, persistence and rate of somatic
hypermutations in order to reveal their similarities to and
differences from canonical GCs in secondary lymphoid organs.
LUNG LOCALIZATION OF MEMORY B CELLS
FOLLOWING PULMONARY VIRUS INFECTION
The location of memory B cells and the cellular and molecular factors surrounding them would logically have a significant influence on the promptness and magnitude of
memory B-cell responses after virus infection. These properties of memory B-cell responses are crucial to the outcome
of disease, especially in cases when rapidly replicating,
acutely infectious cytopathic pathogens invade.
In contrast to recent advances in understanding of memory B-cell localization during systemic immune responses
after protein immunization [65, 67, 68], the lodging sites of
memory B cells against virus infection are poorly defined.
As an initial step, it is important to reveal the tissue distribution of memory B cells after pulmonary virus infection.
Many groups have shown that following infection, memory
T cells reside not only in secondary lymphoid organs but
also in the nonlymphoid organs, contributing to protection
through prompt expression of their effector functions [69,
70]. While both CD4 and CD8 memory T cells reside in the
lungs following respiratory virus infection [71, 72], there is
only limited data regarding the presence of memory B cells
at these sites. In order to count virus-specific memory B
cells, various tissue-derived cells were stimulated with inactivated viruses in vitro under limiting diluted conditions, and
virus-specific memory B cells were enumerated by counting
the numbers of plasma cells induced after in vitro stimulation [15, 17]. While correlation of such numbers with counts
of virus-specific memory B cells that are functionally competent in vivo needs to be addressed, the stimulated lung
cells generated considerable numbers of virus-specific
plasma cells of IgG and IgA isotypes, supporting the idea
that virus-specific, class-switched memory B cells reside in
the infected lungs. IgA+ plasma cells were detected at higher
frequencies in lungs after in vitro stimulation whereas IgG +
plasma cells were equally dispersed in draining MLNs and
lungs. Enhanced detection of IgA+ plasma cells from lung
possibly reflects not only the higher frequencies of IgA+
memory B cells in the lungs but also increased IgA switch-
236 Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 3
ing from IgM/IgG+ memory B cells during in vitro stimulation with virus particles, as TLR signals enhance IgA switching of B cells directly and indirectly through the upregulation of DC-derived BAFF/APRIL [28-30, 73]. In BM, research has failed to detect sufficient numbers of virusspecific B cells, similar to previous studies, but different
from one study [74-76]. Thus, localization of memory B
cells in BM could be affected by several unknown factors
that may depend on entry routes, replication rates, and cellular tropisms of viruses. Although it remains to be clarified
whether virus-specific B cells in the lungs meet the criteria
of memory B cells in their phenotype and function, these
data suggest that memory B cells persist in nonlymphoid
organs and respond to repeated infections. It is tempting to
speculate that, similar to memory T cells, memory B cells in
the lungs may have unique phenotypes and functions that
differ from those in secondary lymphoid organs.
At least three distinct anatomical sites have been identified as lodging sites of splenic memory B cells after immunization with TD antigens: the marginal zone, B-cell follicles, and the periphery of GCs [65, 67, 68]. Lung tissues
comprise several distinct regions that are specialized for gas
exchange but do not possess a representative marginal zone
structure. On the other hand, inflamed lungs after acute virus
infection support B cell follicles within iBALT in the peribronchioles, concomitantly with the formation of GL-7+ GCs
and emergence of virus-specific plasma cells [16, 18, 34].
Thus, B-cell follicles and GCs within iBALT could serve as
the possible lodging sites of memory B cells. Supporting
this, CD27+ memory phenotype B cells are located in iBALT
of COPD patients [66]. Moreover, DT-mediated deletion of
lung DCs and preexisting iBALT structure partially impaired
Ab responses following secondary infection [27]. These results support that memory B cell locate within iBALT, but it
cannot exclude the possibility that memory B cells reside in
other area of inflamed lung. The localization of memory B
cells needs to be addressed separately on individual isotype
(IgM, IgG, IgA) in light of differential localization of IgM+
and IgG+ memory B cells in spleens [65].
Takahashi et al.
lung B cells have greater accessibility to the highly organized structure of virus particles while cells in other tissues
have limited access to them. Indeed, recent study using green
fluorescent protein (GFP)-reporter influenza viruses demonstrated that about 5% of naive lung B cells become positive
for GFP after primary virus infection [12]. This strongly
suggests that the lung localization of B cells facilitates direct
access to infecting virus having intact particles and that lung
memory B cells receive stimulatory signals derived from
high-density epitopes and TLR agonists through direct sensing of virus particles. Several lines of evidence support the
idea that memory B cells can be reactivated in the absence of
DC and T cells when they are stimulated with intact virus
particles. First, in vitro stimulation with virus particles reactivates virus-specific B cells in the absence of CD4 T cells
[77]. Second, administration of virus particles stimulates
donor-derived, virus-specific memory B cells in recipient
mice lacking both T cells and DCs [75, 78, 79]. These results
strongly support the model that virus-specific memory B
cells are rapidly reactivated without the help of DCs and T
cells when they capture intact virus particles in the lung
Fig. (2).
Importantly, the mechanisms underlying reactivation of
memory B cells in the absence of DC and helper T cells remain to be addressed; however, both the presence of highdensity epitopes on virus particles and inclusion of TLR
agonists appear to play synergistic roles in these processes
[5, 7]. TI reactivation of memory B cells is observed in virus-specific memory B cells generated after systemic priming with VSV. The study revealed that reactivation of memory B cells after boosting with highly organized VSV particles was independent of T cells, but that such T-cell independence was largely lost in the response to a poorly organized form of VSV envelope that was displayed on infected
cells [78], suggesting that a highly organized structure is a
key determinant of memory B cell TI reactivation.
After initial respiratory infection, virus-specific plasma
cells persist not only in BM, but also in lung [14, 18]. Thereafter, preexisting Abs in the lung prevent the initial steps of
virus infection and constitute the first line of defense against
secondary infection with homologous virus. However, when
viruses reinvade at a higher dose that exceeds the level of
preexisting Abs, the recall memory response is promptly
initiated to robustly supply plasma cells for elimination of
the virus. In such situations, rapid production of Abs is a
crucial factor, as time delay could significantly worsen the
outcome of disease after infection with a virus having a short
incubation period.
Accumulating evidence has clearly shown that TLR agonists included in virus particles affect the magnitude and
quality of the primary B cell response against viral antigens.
Indeed, deficient TLR signals in all types of cells in vivo led
to impaired Ab responses against polyomavirus, influenza
virus, and H5N1 influenza vaccines [80-83]. Furthermore,
Hou et al. utilized conditional MyD88-deficient mice selectively lacking this molecule on B cells [84]. They found that
B cell-intrinsic MyD88 was required for the primary Ab
response and for GC formation against virus-like structures
that expressed high-density antigens on their surfaces with
inclusion of TLR ligands inside them. These results clearly
demonstrated that during the primary response, the optimal
activation of B cells requires TLR-mediated signals in addition to BCR cross-linking through high-density antigen on
virus particles. Therefore, it is interesting to analyze the possible role of TLR signals during the activation of memory B
cells in the presence or absence of helper T cells.
Compared to primary B cell responses in RT, the mechanisms underlying virus-specific memory B cells in RT are
less well understood. However it is important to consider
several advantage derived from the lung localization of virus-specific memory B cells at a time of reinfection. Due to
their closer localization to virus entry and replication sites,
Recent data suggest that memory B cells may have additional effector functions other than the simple supply of
plasma cells [85, 86]. In response to in vitro stimuli, human
memory B cells are able to secrete a distinct set of cytokines
that are different from that of naive B cells [87], although the
cytokine secretion of murine memory B cells remains elu-
SECONDARY
AB
RESPONSES
RECURRENT INFECTION
FOLLOWING
B Cell Responses Against Virus Infection
Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 3
237
Mesenchymal
sheath
Epithelium
Influenza virus
iBALT
FDCs
Airway
mucosa
B cells
GC
T cells
HEV
Memory
B cells
GC
Mediastinal
lymph node
Plasma cells
Memory
B cells
Plasma cells
Fig. (2). Models of memory B cell reactivation in lungs and MLNs following pulmonary influenza virus infection. When invaded viruses
exceed the level of preexisting Abs, virus particles are directly sensed by memory B cells in lungs which promptly generate plasma cells
without the need of interaction with DCs and T cells. On the other hand, the reactivation of memory B cells in MLNs largely depend on the
interaction with DCs and/or T cells, since an accessibility to intact virus particles is limited in MLNs.
sive. Of note, TLR triggering of B cells led to the induction
of IL-10-producing B cells following Salmonella typhimurium infection [88], indicating the significant contribution
of TLR signals in cytokine secretion by antigen-stimulated B
cells. This topic is discussed elsewhere in this journal, and
we will not provide further details here, but it is reasonable
to speculate that B-cell intrinsic TLR triggering by viruses
may also modulate the secretion of inflammatory/antiinflammatory cytokines for clearance of virus and recovery
of tissue damage.
Localization of memory B cells in the lung may facilitate
their function as antigen-presenting cells or antigentransporting cells to other sites and/or organs, as they are
capable of capturing infected viruses efficiently through
high-affinity BCR and of presenting antigens to T cells along
with expression of costimulatory molecules [89]. Therefore,
it is worthwhile to trace the in vivo dynamics and function of
lung memory B cells after secondary infection.
CONCLUSIONS
We are threatened by enormous numbers and kinds of
viruses possessing a variety of entry routes, replication rates,
and antigen compositions. Many viruses commonly display a
particulate structure with high-density envelopes on their
surfaces with TLR agonists. B cells may have acquired the
238 Infectious Disorders – Drug Targets, 2012, Vol. 12, No. 3
intrinsic ability to recognize these virus signatures through
BCRs and TLRs for the prompt activation and appropriate
fate-decision of subsequent pathways. After infection with
viruses that replicate in nonlymphoid organs, B cells lose
their opportunity to directly sense virus structure during the
primary responses; however, ectopic development of cellular
niches appears to promote the localization of memory B cells
and long-lived plasma cells at the sites of virus replication in
preparation for reinfection. At a time of reinfection, these
memory B cells are more likely to directly sense the structural signatures of replicated viruses and to promptly supply
plasma cells without help from DCs and T cells at the site of
virus replication. Therefore, both the anatomical factors and
the intrinsic ability of B cells to sense virus structure shape
the magnitude and quality of virus-specific memory B cell
response, making our further understanding of these processes clearly important for the development of effective vaccines.
Takahashi et al.
[13]
[14]
[15]
[16]
[17]
[18]
[19]
CONFLICT OF INTEREST
None declared.
[20]
[21]
ACKNOWLEDGEMENTS
This work was supported by grants to Y.T. and T.K. from
Ministry of Education, Culture, Sports, Science and Technology in Japan, by a grant to Y.T. and T.K. from JST,
CREST, and by grants to Y.T. and K.K. from the Emerging
and Re-emerging Infectious Diseases and Regulatory Science of Pharmaceuticals and Medical Devices of the Ministry of Health, Labour and Welfare in Japan.
[22]
[23]
[24]
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