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Eur. J. Immunol. 2007. 37: 3304–3310
Mini-Review:
Innate responses of B cells
David Gray1, Mohini Gray2 and Tom Barr1
1
2
Institute of Immunology and Infection Research, University of Edinburgh, Ashworth
Labs, Edinburgh, UK
MRC Centre for Inflammation Research, The Queen's Medical Research Institute,
University of Edinburgh, Edinburgh, UK
In this review, we describe the non-antibody-mediated functions of B cells within the
immune system. In addition to antibody production, B cells also present antigen to
T cells, programme T cell differentiation and regulate effector T cell responses and much
of this is mediated by the cytokines they make. We focus on the potential of B cells to
perform these functions simply as a result of activation via 'innate' receptors (e.g. Tolllike receptors) and often independently of BCR ligation. We feel an appreciation of
these broad and often antigen-nonspecific functions is important at a time when there is
an increasing use of B cell depletion as a therapy for autoimmune disease.
Introduction
B cells are best known as antibody producing cells.
Antibodies are a first line defence against infection and
most vaccines work because they elicit a protective
antibody response. However, there is darker side to
antibody production if the B cells have a BCR specificity
that reacts with components of self. The autoantibodies
they make can then precipitate the panoply of
inflammatory responses leading to the whole range of
autoimmune diseases. It is perhaps not surprising,
therefore, that clinicians wishing to alleviate symptoms
and possibly treat the cause of autoimmune diseases in
man should identify B cell depletion as an attractive
therapy. The biological reagent (e.g. Rituximab), binding to the B cell-specific molecule CD20, already existed
Correspondence: Dr. David Gray, Institute of Immunology &
Infection Research, University of Edinburgh, Ashworth Labs,
King's Buildings, West Mains Road, Edinburgh, EH9 3JT, UK
Fax: +44-131-650-7322
e-mail: [email protected]
Abbreviations: CIA: collagen-induced arthritis PRR: pattern
recognition receptors
f 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Received 6/8/07
Revised 10/9/07
Accepted 16/10/07
[DOI 10.1002/eji.200737728]
Key words:
Antigen presenting
cells B lymphocytes
Cytokines Innate
immunity Toll-like
receptors
and was tried and tested in the treatment of nonHodgkins lymphomas [1]. The results of B cell depletion
in treating a number of diseases have been more than
promising [2–4] and so far the predicted drawbacks
have not materialised. The most obvious potential side
effect is that the patient becomes immuno-compromised
and, therefore, susceptible to infection. The audit of
B cell-depleted patients does not indicate any increased
rate of infection, however, it is early days and much of
the data derive from lymphoma patients. Still, it may be
that the observed maintenance of circulating antibodies
specific for previous infections or vaccinations provides
sufficient protection [5]. However, if we are to deplete
B cells from people over long periods, we should be
aware of the many non-antibody related functions of
B cells and the potential ensuing effects if the B cell
compartment is ablated. In this short review, we will
demonstrate that B cell function in vivo is much more
complex and diverse than simply making antibodies.
B cells present antigen to T cells and then via
mechanisms that involve both co-stimulation and
cytokine production, they influence T cell differentiation
and then, finally regulate the T cell response.
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Eur. J. Immunol. 2007. 37: 3304–3310
B cell activation
As part of the adaptive immune system B cells carry
somatically re-arranged receptors (BCR) that they use to
recognise, bind and internalise specific antigen. In most
B cells this means that they have a single specificity for
antigen and can respond only to that antigen by
initiating a signal transduced into the cell via BCRassociated molecules such as CD79a and b. However,
B cells can also be activated by a range of stimuli,
independently of the BCR. For mouse B cells the classic
mitogenic stimulus is lipopolysaccharide (LPS) [6], that
we now know activates cells via a complex binding to
LPS-binding protein (LBP), CD14 and Toll-like receptor
(TLR) 4 [7]. Thus, LPS activation is a paradigm for the
non-antigen-specific activation of B cells via innate
receptors. Recently, it has become clear that B cells
express most TLR and can respond to a variety of TLR
ligands [8, 9], such as TLR2, TLR3, TLR5, TLR7 and
TLR9. Their response to these stimuli can be to
proliferate, to differentiate into antibody secreting cells,
to become more efficient antigen-presenting cells
(APC), or to secrete cytokines. Clearly, the responses
of B cells to antigens in their environment are not solely
mediated through the BCR. Crucially, B cells, as with all
other APC, can respond to broad classes of antigen
(pathogen) via innate, pattern recognition receptors
(PRR) and as a result influence immune activation in the
vicinity. This means that the response of the one of the
major lymphocyte populations in secondary lymphoid
tissues (up to 50% of cells) to pathogens expressing
combinations of PRR ligands is initially driven, not by
Ag-specific stimuli, but rather by the activation of PRR.
TLR activation of B cells and antibody
secretion
The idea, mentioned above, that B cells when activated
via TLR differentiate to become antibody-producing
plasma cells (T-independent responses) is not a
controversial one. However, in the last year or two,
studies have been published, indicating that T-dependent antibody responses also require TLR activation of
B cells [10, 11]. The prevailing view prior to this had
been that antigen-specific signals, through the BCR, in
conjunction with help from T cells (CD40 ligand +
cytokines) were sufficient for B cells to make antibodies
to T-dependent antigens. The fact that T-dependent
antibody responses are impaired in mice deficient in
MyD88 (a TLR signalling adaptor protein) was thought
to be due to a failure of T cell priming in association with
dendritic cells (DC). Now, Pasare and Medzhitov [10]
have suggested that MyD88-signalling is required also in
B cells. This conclusion has not been met with universal
f 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Highlights
approval. Nemazee and colleagues [12] have produced
equally puzzling data to indicate that T-dependent
antibody responses proceed quite normally in MyD88/
TRIF double knockout mice that cannot transduce any
TLR signal. They propose that PRR stimuli other than
TLR are at work. The truth may lie somewhere in
between, with particular subclasses of antibody being
more or less dependent on TLR signals to B cells. For
instance, several papers show that switching to the
IgG2a isotype (IgG2c in C57BL/6 mice) is determined by
and may require TLR9 signalling [13–15]. Our own data
on this from chimeras in which the B cell compartment is
MyD88-deficient, also show that the IgG2a response to a
variety of antigens is severely impaired and interestingly
so is the IgM response (TB and DG, unpublished data),
while all other IgG subclass responses are normal. TLRmediated IL-6 production may be a significant driver of
the IgM response [16].
TLR have been proposed to sustain long-lived serum
antibody responses by stimulating (intermittently)
differentiation of memory B cells into the long-lived
bone marrow plasma cell pool [17]. Again, this is
controversial as it circumvents the need for T cell help for
antibody secretion, with the attendant check on
production of autoantibodies by somatically mutated,
self-reactive memory cells. An alternative explanation
may be provided by the observation of Drner,
Radbruch and colleagues [18, 19] that the antigennonspecific plasma cells seen on boosting are the result
of mobilization of plasma cells from the bone marrow
and not the bystander activation of memory cells. The
absolute need for T cell help in the initiation of
autoantibody production has also been called into
question by Marshak-Rothstein [20] and Shlomchik
[21] who have shown that co-ligation of BCR and TLR by
autoantigen (e.g. DNA or RNA containing complexes)
can cause autoantibody to be made, which in turn
enhances delivery of Ab-autoAg complexes to TLRcontaining processing compartment in plasmacytoid DC
[22]. This will initiate autoreactive T cell activation and
so amplify the autoantibody response. Interestingly, the
development of autoimmunity (lupus), including autoantibodies in BAFF-transgenic mice proceeds in the
absence of any T cells [23].
B cells as APC in vivo
The dogma that most B cells possess just a single antigenspecificity has led to the notion that B cells are only
effective APC for the antigen to which their BCR binds.
This is largely true in vitro when B cells are given a
protein antigen for which they have no BCR specificity;
they present it very poorly, especially in comparison to
DC [24]. On the other hand they are just as efficient as
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DC when their BCR recognises the antigen [24]. This has
led to the perception that B cells do not contribute as
APC in primary responses, as there are too few antigenspecific B cells available. The role of B cells in priming
T cells has long been controversial with data from B celldeficient mice both for [25–27] and against [28, 29].
Recently, data have appeared suggesting that B cells may
contribute surprisingly early. First, bone marrow
chimeric mice, in which the B cell compartment lacks
MHC class II, exhibit an impairment of T cell activation
that can be seen at very early time points (day 3)
following immunization [30]. Secondly, in studies using
an mAb to detect specific peptide-MHC class II complex
on the surface of APC, the appearance of presumably
immunogenic material on B cells is within hours [31] or
even minutes [32] after intradermal injection of the
antigen. Pape et al. [32] go on to show that follicular
B cells acquire soluble antigen diffusing from the
subcapsular sinus in lymph nodes draining sites of
immunization, in a process that does not require
intermediary DC. This stimulates them to move to the
follicular-T zone border where cognate interaction with
T cells occurs [32]. The groups of Batista [33] and Cyster
[34] have since shown that particulate (bacterial)
antigens [33] and immune complexes [34] are also
picked up by B cells in the region of the subcapsular
sinus. In the spleen, marginal zone B cells have long
been implicated in this process [35–37]; there are B cells
in lymph nodes that resemble marginal zone B cells [38].
It may also be significant that marginal zone B cells are
demonstrably the most efficient B cell APC [39]. None of
this usurps the role of DC in initial priming of T cells;
naive B cells are still generally thought of as tolerogenic
in their interaction with naive T cells [40, 41]. However,
it does suggest that very soon after infection/immunization (within hours, not days), B cells are actively
contributing to the antigen-presenting/T cell programming activity.
How can this be if frequencies of antigen-specific
B cells are so low? Several possibilities spring to mind.
(i) Antigen-specific or cross-reactive B cells exist at
higher frequencies than we currently appreciate. (ii) The
lymphoid organs (especially the lymph nodes) are
designed to allow the antigen-specific cellular interactions at very low frequency for the production of
antibody responses (proposed by Jenkins and colleagues
[32]). (iii) B cells can take up and present antigen via
receptors other than the BCR. Thus, antigens that carry
PRR (e.g. TLR) may be more effectively taken up by
B cells. Antigen-nonspecific B cells have been shown, in
vivo, to acquire soluble protein, process and present it
[42]. Furthermore, TLR ligands on the same particle and
in the same endocytic compartment of APC enable
efficient presentation to and activation of CD4 T cells
[43]. This evidence does not address whether this is
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Eur. J. Immunol. 2007. 37: 3304–3310
related to enhanced Ag uptake, however, TLR11 and/or
associated molecules do seem to be involved in the
uptake of the Toxoplasma gondii antigen, profilin [44].
Interestingly, the recent demonstration of antigen
capture by B cells in the subcapsule of lymph nodes
and subsequent transport to the follicle is an antigennonspecific process, requiring the B cells to express
complement receptor 2 (CR2); however, there is no
indication that the antigen is taken up, processed and
presented to T cells [34]. The basis in physiological
reality of these possibilities needs much more investigation. We have not considered here B cell presentation in
the establishment and perpetuation of autoimmune
disease; unfortunately it is beyond the scope of this brief
review; see the reviews [5, 45] for a proper treatment of
the topic.
B cell cytokines and T cell programming
B cells, like other APC, have a programming function in
T cell differentiation and this is mediated by the
secretion of cytokines. B cells are known to make a
wide range of cytokines [46, 47]. Lund and colleagues
[46] have characterised cytokine-secreting B cells into
subsets similar to Th1 and Th2, so-called Be1 (making
IFN-c and IL-12) and Be2 (making IL-4) (Be = B
effector); both subsets make IL-2, IL-6 and IL-10 [46].
The cytokine production by B cells, however, needs to be
distinguished as either “primary” or “secondary”.
Primary production is elicited by primary stimuli, such
as TLR, while secondary production requires the
interaction of activated B cells with activated helper
T cells. For instance, we can find no primary stimuli that
elicit IL-4 production by B cells; however, if they are
allowed to interact with IL-4-secreting, activated Th2
cells, they too will begin to make IL-4 [48]. In vivo this
may be important for the establishment of Th2
immunity during infection [49]. We have found that
TLR ligands are the most potent stimuli for production of
cytokine by B cells and that this can be augmented by
T cell-derived costimuli such as CD40L [8]. Although
B cells do make cytokines when both BCR and CD40 are
stimulated, we find that the cross-linking of BCR on TLRactivated B cells is often an inhibitor of cytokine
production [8].
Several models have provided evidence for the
programming role of B cells in the development of
Th2 responses [50, 51]. The basis of this might be related
to IL-4 production [48], to delivery of co-stimuli such as
OX40L [26, 52] or ICOSL [53, 54] or their production of
IL-10 (down-regulating Th1 responses) [47]. The role of
B cells in the induction of other types of response has
received less attention. In relation to Th1 differentiation,
B cells make very little IL-12; on a per cell basis, they
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Eur. J. Immunol. 2007. 37: 3304–3310
make 1000-fold less than DC [8], although one could
argue that this might be important if large numbers of
B cells are making it after polyclonal activation. B cells
also make IFN-c in response to combinations of TLR
ligands (e.g. TLR2, 4 and 9), but not to single stimuli [8].
It has been noted by Mastroeni and colleagues [55] that
B cell-deficient mice do not mount protective Th1
responses to Salmonella typhimurium. Th1 development
is also impaired in chimeras in which B cells do not
express MyD88 and so is related to the TLR-mediated
activation of B cells; however, it does not require them to
make IFN-c (TB and DG, unpublished observations).
B cells make significant amounts of IL-6 in response to a
variety of stimuli and exhibit TGFb message, although
the stimuli required for secretion of active TGFb have not
been defined. Any role for B cells delivering these two
cytokines in Th17 generation [56] remains to be
investigated.
B cells are not homogenous and there are differences
in the propensity of different subsets to make cytokines.
In relation to subsets, IL-10 has been most intensively
studied. B1 B cells were the first to be recognised as IL-10
producers [57] and this is reflected in the role of
neonatal CD5+ B cells in dampening acute inflammation
in new born mice, by producing IL-10 [58, 59]. In adult
mice, we find that marginal zone (MZ) B cells and B1
cells produce most IL-10 in response to TLR ligands
(TLR2, 4 and 9), while, in comparison, follicular cells
make very little [8], an observation supported by other
labs [60]. Other workers have suggested that transitional T2 B cells are the main IL-10 producers [61],
although how this fits with their transient, differentiating nature is unclear. Interestingly, in our hands, a
dichotomy in cytokine production exists as MZ B cells
make IL-10 and no IFN-c, while follicular B cells make
IFN-c but no IL-10 [8].
B cells and regulation
B cells make both IL-10 and TGFb and thus could
conceivably be involved in the development of one of the
regulatory T cell subsets. Dealing first with CD25+
FoxP3+ Tregs: the data in this area are limited,
fragmentary and often contradictory; for instance in
B cell–deficient mice there is no alteration in the
numbers or function of CD25+ FoxP3+ Treg [62], while
in Rituximab/B cell-depleted patients the numbers of
these cells rise [63]. In some disease models evidence
points to a positive role for B cells in the Treg control of
colitis [64] and of EAE [65], in anterior chamber (of the
eye) immune deviation (ACAID) [66] and in transplant
tolerance [67]. In this last example, the authors raise the
possibility that B cells render T cells (potential effectors)
unresponsive and so, receptive to suppression by donorf 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Highlights
specific Tregs. Thus, the involvement of B cells in Treg
function is not necessarily an inductive one, but might
involve a collaboration bringing about regulation or,
recruitment of Treg to sites of inflammation, e.g. CNS
[65]. It should be remembered that each model has its
own idiosyncrasies; for instance, in the NOD thyroiditis
model, B cell-deficient mice are resistant to disease
induction and the role of B cells in Treg function seems
to be negative. It is proposed that B cells sustain a
persistent presentation of autoantigen (in B cell-sufficient NOD mice) that renders effector T cells resistant to
suppression by Tregs [62].
As discussed above the presentation of antigen by
naive/resting B cells is thought to render naive T cells
tolerant [40, 41]. Recent data suggest that this tolerance
may result from the generation of Tregs [68, 69] with an
unusual phenotype, (CD25+, CD62L+ and FoxP3–) [69].
During the in vitro culture with naive T cells, the B cells
make IL-10 although this is not required for the
development of this Treg population [69]. It will be
interesting to know if TGFb is involved as small resting
B cells express this cytokine [47]. In contrast, several
slightly older studies, showed that B cell-derived IL-10
was crucial for the resolution of EAE [70], the delayed
progression of inflammatory bowel disease [71], and
the prevention of induction of collagen-induced arthritis
(CIA) [72]. In all these cases the B cells involved were
activated and consequently produced IL-10. How this
B cell-derived IL-10 production mediates these effects
has not been determined but the induction of a Treg
population seems most likely.
In relation to this, Gray et al. [73] have recently
linked the immune suppressive activity of apoptotic cells
on the development of CIA, with IL-10 production by
B cells. The injection of apoptotic cells prevented
development of CIA, a protection that was dependent
on both B cells and on IL-10 [73]. A dissection of the cell
interactions indicated that apoptotic cells had a direct
effect on B cells, which augmented their IL-10 production, which in turn caused the differentiation of a
population of IL-10-producing T cells. B cells it seems
induce Tr1 cells. It is worth noting that in these
experiments the amount of IL-10 made by B cells
(stimulated via TLR + apoptotic cells) is of a similar
magnitude to that made by the effector T cells and thus
the B cell-derived IL-10 is also likely to have effects
independent of Tr1 cells. The unexpected link between
B cell regulation and apoptotic cells raises the question
of whether the recognition of apoptosis during inflammation is a common feature in triggering a resolving
B cell cytokine response.
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Eur. J. Immunol. 2007. 37: 3304–3310
3 Leandro, M. J., Edwards, J. C., Cambridge, G., Ehrenstein, M. R. and
Isenberg, D. A., An open study of B lymphocyte depletion in systemic lupus
erythematosus. Arthritis Rheum. 2002. 46: 2673–2677.
4 Pitashny, M. and Shoenfeld, Y., B cell depletion in autoimmune rheumatic
diseases. Autoimmun. Rev. 2005. 4: 436–441.
5 Martin, F. and Chan, A. C., B cell immunobiology in disease: evolving
concepts from the clinic. Annu. Rev. Immunol. 2006. 24: 467–496.
6 Quintans, J. and Lefkovits, I., Clonal expansion of lipopolysaccharidestimulated B lymphocytes. J. Immunol. 1974. 113: 1373–1376.
7 Akira, S. and Takeda, K., Toll-like receptor signalling. Nat. Rev. Immunol.
2004. 4: 499–511.
8 Barr, T., Brown, S., Ryan, G., Zhao, J. and Gray, D., TLR-mediated
stimulation of APCs: Distinct cytokine responses of B cells and dendritic
cells. Eur. J. Immunol. 2007. 37: 3040–3053.
Figure 1. Roles of TLR in B cell responses. TLR activation alone
can lead to antigen/BCR-independent antibody production, but
most meaningful T-independent antibody responses in vivo
involve Ag recognition by BCR. Note also that while cytokine
production by B cells can be BCR independent, it may be
enhanced by CD40 or modulated/altered by BCR signals.
9 Genestier, L., Taillardet, M., Mondiere, P., Gheit, H., Bella, C. and
Defrance, T., TLR agonists selectively promote terminal plasma cell
differentiation of B cell subsets specialized in thymus-independent
responses. J. Immunol. 2007. 178: 7779–7786.
10 Pasare, C. and Medzhitov, R., Control of B-cell responses by Toll-like
receptors. Nature 2005. 438: 364–368.
11 Ruprecht, C. R. and Lanzavecchia, A., Toll-like receptor stimulation as a
third signal required for activation of human naive B cells. Eur. J. Immunol.
2006. 36: 810–816.
Concluding remarks
We are only beginning to understand the mechanisms by
which B cells modulate T cell responses. At one extreme
we may come to accept that innate (TLR?), non-BCRmediated activation of B cells gives them the potential to
be a dominant APC population following infection with
organisms that carry TLR ligands. At the very least we
can be certain that TLR-mediated cytokine production
by B cells both drives T cell differentiation and regulates
its excesses (inflammation). We have highlighted here
the many non-antibody-mediated functions of B cells
and have focused mainly on their positive roles (see
summary in Fig. 1). In the light of these lessons, one
might be reluctant to ablate B cells from patients, but in
autoimmune disease the balance is dramatically tipped
towards the very deleterious effects of B cell autoantibody production and/or autoantigen presentation and,
therefore, such drastic action is certainly warranted.
However, these patients need to be followed carefully as
they may well tell us a more complete story of the way
that B cells contribute in the round to immune responses
and their modulation.
Conflict of interest: The authors declare no financial or
commercial conflicts of interest.
References
1 Grillo-Lopez, A. J., White, C. A., Varns, C., Shen, D., Wei, A., McClure, A.
and Dallaire, B. K., Overview of the clinical development of rituximab: first
monoclonal antibody approved for the treatment of lymphoma. Semin.
Oncol. 1999. 26: 66–73.
2 Edwards, J. C. and Cambridge, G., Sustained improvement in rheumatoid
arthritis following a protocol designed to deplete B lymphocytes.
Rheumatology (Oxford) 2001. 40: 205–211.
f 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
12 Gavin, A. L., Hoebe, K., Duong, B., Ota, T., Martin, C., Beutler, B. and
Nemazee, D., Adjuvant-enhanced antibody responses in the absence of Tolllike receptor signaling. Science 2006. 314: 1936–1938.
13 Ehlers, M., Fukuyama, H., McGaha, T. L., Aderem, A. and Ravetch, J. V.,
TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a
and 2b autoantibodies in SLE. J. Exp. Med. 2006. 203: 553–561.
14 Jegerlehner, A., Maurer, P., Bessa, J., Hinton, H. J., Kopf, M. and
Bachmann, M. F., TLR9 signaling in B cells determines class switch
recombination to IgG2a. J. Immunol. 2007. 178: 2415–2420.
15 Liu, N., Ohnishi, N., Ni, L., Akira, S. and Bacon, K. B., CpG directly induces
T-bet expression and inhibits IgG1 and IgE switching in B cells. Nat.
Immunol. 2003. 4: 687–693.
16 Yi, A. K., Klinman, D. M., Martin, T. L., Matson, S. and Krieg, A. M., Rapid
immune activation by CpG motifs in bacterial DNA. Systemic induction of
IL-6 transcription through an antioxidant-sensitive pathway. J. Immunol.
1996. 157: 5394–5402.
17 Bernasconi, N. L., Traggiai, E. and Lanzavecchia, A., Maintenance of
serological memory by polyclonal activation of human memory B cells.
Science 2002. 298: 2199–2202.
18 Odendahl, M., Mei, H., Hoyer, B. F., Jacobi, A. M., Hansen, A.,
Muehlinghaus, G., Berek, C. et al., Generation of migratory antigenspecific plasma blasts and mobilization of resident plasma cells in a
secondary immune response. Blood 2005. 105: 1614–1621.
19 Radbruch, A., Muehlinghaus, G., Luger, E. O., Inamine, A., Smith, K. G.,
Dorner, T. and Hiepe, F., Competence and competition: the challenge of
becoming a long-lived plasma cell. Nat. Rev. Immunol. 2006. 6: 741–750.
20 Leadbetter, E. A., Rifkin, I. R., Hohlbaum, A. M., Beaudette, B. C.,
Shlomchik, M. J. and Marshak-Rothstein, A., Chromatin-IgG complexes
activate B cells by dual engagement of IgM and Toll-like receptors. Nature
2002. 416: 603–607.
21 Lau, C. M., Broughton, C., Tabor, A. S., Akira, S., Flavell, R. A., Mamula,
M. J., Christensen, S. R. et al., RNA-associated autoantigens activate B cells
by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp.
Med. 2005. 202: 1171–1177.
22 Marshak-Rothstein, A., Toll-like receptors in systemic autoimmune disease.
Nat. Rev. Immunol. 2006. 6: 823–835.
23 Groom, J. R., Fletcher, C. A., Walters, S. N., Grey, S. T., Watt, S. V., Sweet,
M. J., Smyth, M. J., Mackay, C. R. and Mackay, F., BAFF and MyD88 signals
promote a lupuslike disease independent of T cells. J. Exp. Med. 2007. 204:
1959–1971.
24 Sallusto, F. and Lanzavecchia, A., Efficient presentation of soluble antigen
by cultured human dendritic cells is maintained by granulocyte/macrophage
www.eji-journal.eu
Eur. J. Immunol. 2007. 37: 3304–3310
colony-stimulating factor plus interleukin 4 and downregulated by tumor
necrosis factor alpha. J. Exp. Med. 1994. 179: 1109–1118.
25 Kurt-Jones, E. A., Liano, D., HayGlass, K. A., Benacerraf, B., Sy, M. S. and
Abbas, A. K., The role of antigen-presenting B cells in T cell priming in vivo.
Studies of B cell-deficient mice. J. Immunol. 1988. 140: 3773–3778.
26 Linton, P. J., Bautista, B., Biederman, E., Bradley, E. S., Harbertson, J.,
Kondrack, R. M., Padrick, R. C. and Bradley, L. M., Costimulation via
OX40L expressed by B cells is sufficient to determine the extent of primary
CD4 cell expansion and Th2 cytokine secretion in vivo. J. Exp. Med. 2003.
197: 875–883.
Highlights
45 Shlomchik, M. J., Craft, J. E. and Mamula, M. J., From T to B and back
again: positive feedback in systemic autoimmune disease. Nat. Rev.
Immunol. 2001. 1: 147–153.
46 Harris, D. P., Haynes, L., Sayles, P. C., Duso, D. K., Eaton, S. M., Lepak, N.
M., Johnson, L. L. et al., Reciprocal regulation of polarized cytokine
production by effector B and T cells. Nat. Immunol. 2000. 1: 475–482.
47 Skok, J., Poudrier, J. and Gray, D., Dendritic cell-derived IL-12 promotes
B cell induction of Th2 differentiation: a feedback regulation of Th1
development. J. Immunol. 1999. 163: 4284–4291.
27 Liu, Y., Wu, Y., Ramarathinam, L., Guo, Y., Huszar, D., Trounstine, M.
and Zhao, M., Gene-targeted B-deficient mice reveal a critical role for B cells
in the CD4 T cell response. Int. Immunol. 1995. 7: 1353–1362.
48 Harris, D. P., Goodrich, S., Mohrs, K., Mohrs, M. and Lund, F. E., Cutting
edge: the development of IL-4-producing B cells (B effector 2 cells) is
controlled by IL-4, IL-4 receptor alpha, and Th2 cells. J. Immunol. 2005. 175:
7103–7107.
28 Epstein, M. M., Di Rosa, F., Jankovic, D., Sher, A. and Matzinger, P.,
Successful T cell priming in B cell-deficient mice. J. Exp. Med. 1995. 182:
915–922.
49 Lund, F. E., Schuer, K., Hollifield, M., Randall, T. D. and Garvy, B. A.,
Clearance of Pneumocystis carinii in mice is dependent on B cells but not on P.
carinii-specific antibody. J. Immunol. 2003. 171: 1423–1430.
29 Topham, D. J., Tripp, R. A., Hamilton-Easton, A. M., Sarawar, S. R. and
Doherty, P. C., Quantitative analysis of the influenza virus-specific CD4+
T cell memory in the absence of B cells and Ig. J. Immunol. 1996. 157:
2947–2952.
50 Macaulay, A. E., DeKruyff, R. H., Goodnow, C. C. and Umetsu, D. T.,
Antigen-specific B cells preferentially induce CD4+ T cells to produce IL-4. J.
Immunol. 1997. 158: 4171–4179.
30 Crawford, A., Macleod, M., Schumacher, T., Corlett, L. and Gray, D.,
Primary T cell expansion and differentiation in vivo requires antigen
presentation by B cells. J. Immunol. 2006. 176: 3498–3506.
31 Catron, D. M., Itano, A. A., Pape, K. A., Mueller, D. L. and Jenkins, M. K.,
Visualizing the first 50 hr of the primary immune response to a soluble
antigen. Immunity 2004. 21: 341–347.
32 Pape, K. A., Catron, D. M., Itano, A. A. and Jenkins, M. K., The humoral
immune response is initiated in lymph nodes by B cells that acquire soluble
antigen directly in the follicles. Immunity 2007. 26: 491–502.
33 Carrasco, Y. R. and Batista, F. D., B cells acquire particulate antigen in a
macrophage-rich area at the boundary between the follicle and the
subcapsular sinus of the lymph node. Immunity 2007. 27: 160–171.
34 Phan, T. G., Grigorova, I., Okada, T. and Cyster, J. G., Subcapsular
encounter and complement-dependent transport of immune complexes by
lymph node B cells. Nat. Immunol. 2007. 8: 992–1000.
35 Ferguson, A. R., Youd, M. E. and Corley, R. B., Marginal zone B cells
transport and deposit IgM-containing immune complexes onto follicular
dendritic cells. Int. Immunol. 2004. 16: 1411–1422.
51 Stockinger, B., Zal, T., Zal, A. and Gray, D., B cells solicit their own help
from T cells. J. Exp. Med. 1996. 183: 891–899.
52 Flynn, S., Toellner, K. M., Raykundalia, C., Goodall, M. and Lane, P.,
CD4 T cell cytokine differentiation: the B cell activation molecule, OX40
ligand, instructs CD4 T cells to express interleukin 4 and upregulates
expression of the chemokine receptor, Blr-1. J. Exp. Med. 1998. 188:
297–304.
53 Dong, C., Juedes, A. E., Temann, U. A., Shresta, S., Allison, J. P., Ruddle,
N. H. and Flavell, R. A., ICOS co-stimulatory receptor is essential for T-cell
activation and function. Nature 2001. 409: 97–101.
54 Tafuri, A., Shahinian, A., Bladt, F., Yoshinaga, S. K., Jordana, M.,
Wakeham, A., Boucher, L. M. et al., ICOS is essential for effective T-helpercell responses. Nature 2001. 409: 105–109.
55 Mastroeni, P., Simmons, C., Fowler, R., Hormaeche, C. E. and Dougan,
G., Igh-6(-/-) (B-cell-deficient) mice fail to mount solid acquired resistance
to oral challenge with virulent Salmonella enterica serovar typhimurium and
show impaired Th1 T-cell responses to Salmonella antigens. Infect. Immun.
2000. 68: 46–53.
56 Stockinger, B. and Veldhoen, M., Differentiation and function of Th17
T cells. Curr. Opin. Immunol. 2007. 19: 281–286.
36 Gray, D., Kumararatne, D. S., Lortan, J., Khan, M. and MacLennan, I. C.,
Relation of intra-splenic migration of marginal zone B cells to antigen
localization on follicular dendritic cells. Immunology 1984. 52: 659–669.
57 O'Garra, A., Stapleton, G., Dhar, V., Pearce, M., Schumacher, J., Rugo,
H., Barbis, D. et al., Production of cytokines by mouse B cells: B lymphomas
and normal B cells produce interleukin 10. Int. Immunol. 1990. 2: 821–832.
37 Whipple, E. C., Shanahan, R. S., Ditto, A. H., Taylor, R. P. and Lindorfer,
M. A., Analyses of the in vivo trafficking of stoichiometric doses of an anticomplement receptor 1/2 monoclonal antibody infused intravenously in
mice. J. Immunol. 2004. 173: 2297–2306.
58 Sun, C. M., Deriaud, E., Leclerc, C. and Lo-Man, R., Upon TLR9 signaling,
CD5+ B cells control the IL-12-dependent Th1-priming capacity of neonatal
DCs. Immunity 2005. 22: 467–477.
38 Stein, H., Bonk, A., Tolksdorf, G., Lennert, K., Rodt, H. and Gerdes, J.,
Immunohistologic analysis of the organization of normal lymphoid tissue
and non-Hodgkin's lymphomas. J. Histochem. Cytochem. 1980. 28: 746–760.
39 Attanavanich, K. and Kearney, J. F., Marginal zone, but not follicular
B cells, are potent activators of naive CD4 T cells. J. Immunol. 2004. 172:
803–811.
40 Eynon, E. E. and Parker, D. C., Small B cells as antigen-presenting cells in
the induction of tolerance to soluble protein antigens. J. Exp. Med. 1992.
175: 131–138.
41 Fuchs, E. J. and Matzinger, P., B cells turn off virgin but not memory T cells.
Science 1992. 258: 1156–1159.
42 Zhong, G., Reis e Sousa, C. and Germain, R. N., Antigen-unspecific B cells
and lymphoid dendritic cells both show extensive surface expression of
processed antigen-major histocompatibility complex class II complexes after
soluble protein exposure in vivo or in vitro. J. Exp. Med. 1997. 186: 673–682.
43 Blander, J. M. and Medzhitov, R., On regulation of phagosome maturation
and antigen presentation. Nat. Immunol. 2006. 7: 1029–1035.
44 Yarovinsky, F., Kanzler, H., Hieny, S., Coffman, R. L. and Sher, A., Tolllike receptor recognition regulates immunodominance in an antimicrobial
CD4+ T cell response. Immunity 2006. 25: 655–664.
f 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
59 Zhang, X., Deriaud, E., Jiao, X., Braun, D., Leclerc, C. and Lo-Man, R.,
Type I interferons protect neonates from acute inflammation through
interleukin 10-producing B cells. J. Exp. Med. 2007. 204: 1107–1118.
60 Lenert, P., Brummel, R., Field, E. H. and Ashman, R. F., TLR-9 activation
of marginal zone B cells in lupus mice regulates immunity through increased
IL-10 production. J. Clin. Immunol. 2005. 25: 29–40.
61 Evans, J. G., Chavez-Rueda, K. A., Eddaoudi, A., Meyer-Bahlburg, A.,
Rawlings, D. J., Ehrenstein, M. R. and Mauri, C., Novel suppressive
function of transitional 2 B cells in experimental arthritis. J. Immunol. 2007.
178: 7868–7878.
62 Yu, S., Maiti, P. K., Dyson, M., Jain, R. and Braley-Mullen, H., B celldeficient NOD.H-2h4 mice have CD4+CD25+ T regulatory cells that inhibit
the development of spontaneous autoimmune thyroiditis. J. Exp. Med. 2006.
203: 349–358.
63 Vallerskog, T., Gunnarsson, I., Widhe, M., Risselada, A., Klareskog, L.,
van Vollenhoven, R., Malmstrom, V. and Trollmo, C., Treatment with
rituximab affects both the cellular and the humoral arm of the immune
system in patients with SLE. Clin. Immunol. 2007. 122: 62–74.
64 Wei, B., Velazquez, P., Turovskaya, O., Spricher, K., Aranda, R.,
Kronenberg, M., Birnbaumer, L. and Braun, J., Mesenteric B cells
centrally inhibit CD4+ T cell colitis through interaction with regulatory T cell
subsets. Proc. Natl. Acad. Sci. USA 2005. 102: 2010–2015.
www.eji-journal.eu
3309
3310
David Gray et al.
65 Mann, M. K., Maresz, K., Shriver, L. P., Tan, Y. and Dittel, B. N., B cell
regulation of CD4+CD25+ T regulatory cells and IL-10 via B7 is essential for
recovery from experimental autoimmune encephalomyelitis. J. Immunol.
2007. 178: 3447–3456.
66 Ashour, H. M. and Niederkorn, J. Y., Peripheral tolerance via the anterior
chamber of the eye: role of B cells in MHC class I and II antigen presentation.
J. Immunol. 2006. 176: 5950–5957.
67 Deng, S., Moore, D. J., Huang, X., Lian, M. M., Mohiuddin, M.,
Velededeoglu, E., Lee, M. K. t. et al., Cutting edge: transplant tolerance
induced by anti-CD45RB requires B lymphocytes. J. Immunol. 2007. 178:
6028–6032.
68 Chen, X. and Jensen, P. E., Cutting edge: primary B lymphocytes
preferentially expand allogeneic FoxP3+ CD4 T cells. J. Immunol. 2007.
179: 2046–2050.
f 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Immunol. 2007. 37: 3304–3310
69 Reichardt, P., Dornbach, B., Rong, S., Beissert, S., Gueler, F., Loser, K.
and Gunzer, M., Naive B cells generate regulatory T cells in the presence of a
mature immunologic synapse. Blood 2007. 110: 1519–1529.
70 Fillatreau, S., Sweenie, C. H., McGeachy, M. J., Gray, D. and Anderton, S.
M., B cells regulate autoimmunity by provision of IL-10. Nat. Immunol. 2002.
3: 944–950.
71 Mizoguchi, A., Mizoguchi, E., Takedatsu, H., Blumberg, R. S. and Bhan,
A. K., Chronic intestinal inflammatory condition generates IL-10-producing
regulatory B cell subset characterized by CD1d upregulation. Immunity
2002. 16: 219–230.
72 Mauri, C., Gray, D., Mushtaq, N. and Londei, M., Prevention of arthritis by
interleukin 10-producing B cells. J. Exp. Med. 2003. 197: 489–501.
73 Gray, M., Miles, K., Salter, D., Gray, D. and Savill, J., Apoptotic cells
protect mice from autoimmune inflammation by the induction of regulatory
B cells. Proc. Nat. Acad. Sci. USA 2007. 104: 14081–14085.
www.eji-journal.eu