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Trafficking of B Cell Antigen
in Lymph Nodes
Santiago F. Gonzalez,1 Søren E. Degn,2
Lisa A. Pitcher,1 Matthew Woodruff,1,3
Balthasar A. Heesters,4 and Michael C. Carroll1,3
1
The Immune Disease Institute and Program in Molecular and Cellular Medicine,
Children’s Hospital and Harvard Medical School, Boston, Massachusetts 02115;
email: [email protected]
2
Department of Medical Microbiology and Immunology, Aarhus University Graduate
School of Health Sciences and the Danish Graduate School of Immunology,
Aarhus University, DK-8000 Aarhus C, Denmark
3
Graduate Program in Immunology, Harvard University, Cambridge, Massachusetts 02138
4
Graduate Program of Life Sciences, Utrecht University, 3508 TC Utrecht,
The Netherlands
Annu. Rev. Immunol. 2011. 29:215–33
Keywords
First published online as a Review in Advance on
December 21, 2010
fibroblast reticular cells, follicular dendritic cells, conduits, dendritic
cells, complement receptors CD21 and CD35
The Annual Review of Immunology is online at
immunol.annualreviews.org
This article’s doi:
10.1146/annurev-immunol-031210-101255
c 2011 by Annual Reviews.
Copyright All rights reserved
0732-0582/11/0423-0215$20.00
Abstract
The clonal selection theory first proposed by Macfarlane Burnet is
a cornerstone of immunology (1). At the time, it revolutionized the
thinking of immunologists because it provided a simple explanation
for lymphocyte specificity, immunological memory, and elimination of
self-reactive clones (2). The experimental demonstration by Nossal &
Lederberg (3) that B lymphocytes bear receptors for a single antigen
raised the central question of where B lymphocytes encounter antigen.
This question has remained mostly unanswered until recently. Advances
in techniques such as multiphoton intravital microscopy (4, 5) have provided new insights into the trafficking of B cells and their antigen. In
this review, we summarize these advances in the context of our current
view of B cell circulation and activation.
215
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ROLE OF ANTIGEN IN B CELL
DIFFERENTIATION
(approximately every 24 h) and in the absence
of antigen have a half-life of a few days. They
leave the vascular system and enter lymph
nodes via specialized endothelia termed high
endothelial venules (HEV) (see 19 for review).
Lymph nodes are organized into discrete compartments: B cells localize within the cortical
region near the subcapsular sinus, whereas
T cells localize in the paracortical region
(Figure 1). Until recently, it was held that
migration within the lymph nodes was determined principally by chemokine gradients. B
cells are attracted to the follicles by the release
of CXCL13 by follicular stromal cells [FDCs,
already mentioned, and fibroblastic reticular
cells (FRCs)] (20, 21), whereas T cells migrate
to a gradient of CCL19 and CCL21 (19). More
recent studies using multiphoton intravital microscopy (MP-IVM) have identified migration
of T cells and dendritic cells (DCs) along a
network of reticular fibers (22, 23). Similarly,
B cells were shown to traffic within the follicles
From their birth in the bone marrow to when
they first express a mature B cell receptor
(BCR), B cells’ fate is determined by cognate
antigen (6). Immature B cells go through two
checkpoints, one in the bone marrow (checkpoint 1) and the second in the spleen (checkpoint 2) prior to maturation and migration to
the B cell follicles (7–9). Engagement of antigen
in the bone marrow leads to deletion (10, 11),
anergy (12), or receptor editing (13–16). Cells
surviving negative selection in the bone marrow
migrate to the spleen, where encounter with
self-antigen leads to anergy and death (checkpoint 2) (9, 17). How self-antigen is presented
to immature B cells is unclear, although investigators speculate that they engage antigen
held by stromal cells, possibly follicular dendritic cells (FDCs) (18).
Mature B cells circulate though the secondary lymphoid organs (SLOs) regularly
b
Follicular
FRCs
a
Capsule
FRC
CXCL13
Pc
Path of
antigen
c
Follicular conduit
SCS
Paracortical
conduit
B
Afferent lymphatics
Follicular
conduit
Paracortical
FRCs
Follicle
MΦ
SCS
Fo
FDC
Fo
Fo
FDC
HEV
Efferent Efferent/afferent
lymphatics blood vessels
1 µm
CCL19
FDC
Medulla
CCL21
B
Pc
B
T
DC
T
DC
Figure 1
(a) Lymphocytes enter the lymph node via high endothelial venules (HEV) and are directed to the follicular (Fo) or paracortical (Pc)
areas following chemokine gradients on the FRC reticular fibers. (b) Fibroblastic reticular cells (FRCs) are divided into follicular
conduits or paracortical conduits according to the different chemokines expressed. Follicular conduits transport CXCL13, a
chemoattractant for B cells, and paracortical conduits transport CCL19 and CCL21, which attract T cells and dendritic cells (DCs) to
the paracortical area. (c) Electron micrograph of a FRC and a follicular conduit in the subcapsular sinus area (SCS) of the lymph node.
The black arrow indicates the lumen of the conduit. [Panel c adapted with permission from Current Opinion in Immunology (Reference
104).]
216
Gonzalez et al.
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along the FDC dendritic processes (23). Thus,
lymphocytes are guided within the lymph node
along a complex of reticular fibers or FDC
processes in a nonrandom manner.
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LYMPH NODE STROMAL
CELL RETICULUM
FRCs and their reticular fibers were identified
30 years ago in studies examining the anatomy
of rat lymph nodes (24, 25). The collagen-rich
reticular fibers, which are ensheathed by FRCs,
not only provide an infrastructure, but also act
as conduits for delivery of small proteins within
the draining lymph to the HEV within lymph
nodes (26–30). For example, chemoattractants
such as monocyte chemoattractant protein 1
(MCP-1) (now known as CCL2) draining from
a possible infection in the skin are delivered
to the HEV of local lymph nodes, where they
provide a signal to circulating leukocytes, as
proposed by the “remote control hypothesis”
(31). Reticular fiber conduits have also been described in the spleen, where they appear to deliver small proteins from the blood to the white
pulp areas (32).
As noted above, recent imaging studies indicate that reticular fibers act as highways
for migrating T lymphocytes and DCs and
that this is enhanced by the localization of
T cell chemokines (CCL19 and CCL21) secreted by FRCs. In addition to their secretion
of chemokines, FRCs are an apparent source of
self-antigen that acts to regulate CD8+ T cells
(33, 34).
DC uptake and presentation of peripheral
antigens to T cells appear to occur in two time
frames. Migratory DCs take up antigen from
the tissues and arrive in the lymph node 12–
18 h after injection, whereas small antigens
gain rapid access to lymph node–resident DCs
within minutes after subcutaneous injection
(35). FRC conduits provide pathways for passive delivery of small antigens from the draining
afferent lymph to resident DCs within the paracortical region of lymph nodes. Resident DCs
localize to the T cell area conduits and sample
small lymph-borne antigens for presentation
to cognate T cells migrating along the fibers
(36, 37). Thus, the conduits provide an efficient
network for alerting resident DCs to small foreign antigens, cytokines, or chemokines entering the draining lymph node from a potential
site of infection (36, 37).
The FRC conduits, which have an outer
diameter of 1–2 μm, are composed of a core
of tightly packed type I collagen fibers with
spacing of approximately 5–8 nm (37, 38)
(Figure 2). This structural arrangement would
explain the known size exclusion of proteins
over 60–70 kDa. Although the collagen core
is enveloped by FRCs, our studies indicate
that the contents of the conduits are directly
accessible to B cells and FDCs (M.C. Carroll,
unpublished results; Reference 38).
The B cell area also includes FRC-like
stromal cells and collagen-rich reticular fibers
that are structurally and immunohistochemically similar to those in the T cell area (38).
However, they are less dense than in the
cortical region. Notably, the FRC conduits
are interconnected with the FDC network
(Figure 2). We discuss the potential importance of this intersection in more detail below.
One major difference between FRCs in the T
and B cell areas is that the latter (also referred
to as marginal reticular cells) are a source of B
cell chemokine (CXCL13). Therefore, release
of the chemoattractant into the conduits
would provide a guide or highway for B cells
migrating within the follicles.
The spleen serves as a major component of
SLOs and filters antigens from the circulation.
Although its architecture is different from
that of lymph nodes, the spleen’s overall
organization is similar, and FRC reticular
fibers appear to play a similar role in guiding T cells within the T cell zone (32, 39)
(Figure 2). Therefore, for this review we point
out similarities and differences with lymph
nodes but do not provide detail.
GUARDIANS OF THE LYMPH
NODE: SINUS-LINING
MACROPHAGES
The lymph node sinus is lined with CD169+
CD11clo CD11b+ macrophages that act as
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a
b
c
Co
Co
Co
FRC
2 µm
500 nm
e
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d
Fo
2 µm
500 nm
scs
scs
Figure 2
(a) Transmission electron micrograph showing a longitudinal section of a follicular conduit (Co). (b) High magnification image showing
the space between collagen fibers inside a conduit. (c) Electron micrograph showing a transverse section of a follicular conduit. The double
pointed arrow indicates the conduit diameter. To clarify the electron micrograph, the conduits and the FRC in panels a, b, and c are colored
in blue and green, respectively. (d ) Multiphoton intravital microscopy (MP-IVM) snapshot showing small antigen [turkey egg lysozyme
(TEL), 14 kDa, red] within the follicular conduits, although large antigen (PE-TEL, 240 kDa, green) is restricted to the subcapsular
sinus (SCS) space. Arrowheads indicate cognate MD4 B cells, which rapidly acquire TEL directly from the conduits. (e) Follicular
conduits intersect with FDCs. MP-IVM snapshot showing the intersection of follicular conduits (filled with TEL, green) and FDCs
(blue) in the follicles. Arrows indicate colocalization of TEL and FDC. [Panel d adapted with permission from Immunity (Reference 38).]
guardians to sample and clear microorganisms entering via the afferent lymph
(Figure 3). Two major subsets of macrophages,
i.e., subcapsular sinus macrophages (SSMs)
and medullary macrophages (MMs), have been
identified based on location and expression of
cell surface markers (40). SSMs line the sinus in the region of the afferent lymph vessels and are characterized by expression of the
metallophilic antigen monoclonal antibody1 (MOMA-1) (41). They are similar to the
metallophilic macrophages that line the inner marginal zone sinus in the spleen, and
they are dependent on lymphotoxin cytokines
(LTα/β) for their localization (42). In contrast,
MMs line the medullary sinus, are distinguished
by expression of mannose receptor, SIGN-R1,
and F4/80, and are more similar to the outer
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Gonzalez et al.
marginal zone macrophages in the spleen (38,
42, 43). In general, SSMs are less endocytic
relative to MMs and their lysosomal compartment is less mature (42). This may be an important property in retaining captured lymphborne antigens on their surface, as is discussed
in more detail below. In contrast, MMs are
more typical of mature macrophages and efficiently take up and clear opsonized particles
and antigens from the lymph.
FOLLICULAR DENDRITIC
CELLS AS A DEPOT FOR
B CELL ANTIGEN
The Ig receptor expressed on B cells readily
binds antigen in fluid phase, at least in vitro;
however, it seems unlikely that free antigen is
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a
b
PR8 virus
SCS
SSM
F4/80
MOMA-1
PR8
c
Fo
o
Fo
Fo
MM
PR8
Medulla
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Medulla
Figure 3
(a) A MP-IVM snapshot showing UV-inactivated influenza virus PR8 (red ) at 7 min after footpad injection. The virus is already present
in the subcapsular sinus (SCS) and in the medulla of the lymph node, and it colocalizes with subcapsular sinus macrophages (SSMs)
(MOMA-1+ , green) and medullary macrophages (MMs) (F4/80+ , blue). (b) Schematic drawing showing trafficking of influenza PR8 in
the lymph node. SSMs and MMs capture and internalize influenza virus. (c) Electron micrograph showing influenza virions inside a
SSM at 30 min after footpad injection. [Panel a adapted with permission from Nature Immunology (Reference 72).]
bound efficiently in vivo. A more likely source
of B cell antigen is antigen that is concentrated
on the surface of cells. Model binding studies
in vitro using transgenic B cells and membranebound antigen have identified a reorganization
of the cell surface proteins on both the B cell
and the target cell following antigen engagement (44–46). Thus, the BCR forms a dynamic
synapse within the cell surface, which results in
membrane spreading that facilitates an increase
in signaling and an efficiency in antigen uptake
similar to that described for the T cell synapse
(47). In model systems in vitro, B cell encounter
with membrane antigen results in formation
of microclusters that include components of
the BCR, i.e., IgM and IgD, CD19, and adhesion molecules ICAM-1 (intercellular adhesion
molecule-1) and LFA-1 (lymphocyte function–
associated antigen-1) (48, 49). Although initial
studies suggested that the CD19/CD21/CD81
coreceptor was not required, more recent studies in vivo support a role for complement receptors in acquisition of membrane antigen; we
discuss these studies in more detail below (50).
Early studies tracking radiolabeled protein
antigens injected intravenously into immune
animals identified rapid uptake within the
spleen (51). Closer inspection revealed capture
of the labeled immune complexes (ICs) on
dendritic-shaped cells that were referred to as
FDCs because of their morphology and location within the splenic follicles. Use of cobra
venom factor, which transiently depletes C3,
demonstrated that complement was important
in the localization of ICs to the FDC surface
(52). More recent studies have shown that ICs
are captured on naive FDCs principally by
complement receptors CD21 (CR2) and CD35
(CR1) (53, 54) and by FcRIIb (55). CD21 and
CD35 are expressed on naive FDCs, whereas
FcRIIb is expressed following activation
(Figure 4).
FDCs originate from mesenchymal cells and
depend on LTα/β for their mature phenotype
(for review, see 56). A primary source of LTα/β
for FDC differentiation is derived from circulating naive B cells. For example, reconstitution
of RAG-1−/− mice, which are deficient in mature lymphocytes, with B cells restores FDCs
and the architecture of lymph nodes. FDCs are
a major source of CXCL13, as noted above,
and also provide the B cell survival factor B
cell–activating factor (BAFF). Thus, B cells and
FDCs interact to maintain normal lymph node
architecture.
Initial electron microscopy (EM) images
of spleen sections from mice injected intravenously with 125 I- and 131 I-labeled ICs
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B
B
Expansion
C3d
Ag
B
Plasma cell
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MHC
Fo
T cell
area
B
T
b
Spleen
Bone marrow
Mature B cell
a
B
Memory
B cell
TCR
FcγR
Fo
o
CD21 CD19
BCR
CD81
GC Fo
T cell
area
CD21
FDC
GC
Fo
Cognate
B
B
Medulla
Fo
Ag
C3d
c
MHC
TCR
TFH
GC Fo
Antigen selection
Figure 4
Role of complement receptors CD21 and CD35 in B cell differentiation. (a) Mature B cells are located in the follicle and express
complement receptors CD21/35 (CD21 in figure), which form a coreceptor with CD19 and CD81. (b) Binding of C3d-coated antigen
with the B cell coreceptor lowers the threshold of B cell activation and directs the activated B cells to the T cell–B cell boundary, where
they further differentiate and undergo somatic cell hypermutation and class switch recombination. (c) B cells acquire cognate antigen
deposited on FDCs within the germinal center (GC) and present it to follicular T helper cells (TFH ). Following the encounter of the B
cells with antigen and TFH , B cells differentiate into effector and memory B cells. [Model adapted with permission from the Journal of
Immunology (Reference 105).]
identified deposits on FDCs within the B cell or
follicular zone (57). Subsequent EM histology
using ICs composed of horseradish peroxidase
and substrate provided further support for uptake of ICs along the FDC reticular processes,
and, based on their beaded structure, they were
220
Gonzalez et al.
referred to as IC-coated bodies (iccosomes)
(58). The beaded structures of approximately
0.25–0.38 μm in diameter appeared to be
enveloped by a membrane. Similarly, ex vivo
cultures of FDCs loaded with ICs via FcRIIb
revealed a distinct periodic array of deposits
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along the dendritic processes similar to that
observed in vivo. However, in contrast to the
beaded structures reported earlier, the array of
ICs was located on the outer membrane surface
(59). Recent studies have shown that the FDCs
retain antigens and can activate cognate B cells
for more than one week after antigen administration (50). Together, these data indicate that
FDCs serve as a central depot for long-term
antigen retention in the B cell follicle.
LYMPH NODE
GERMINAL CENTERS
A general feature of a B cell response to T
cell–dependent antigen is formation of germinal centers (GCs) within the follicular region
of SLOs (6, 60, 61) (Figure 4). These are
specialized microenvironments where activated
B cells undergo clonal expansion, class switch
recombination (CSR), somatic hypermutation
(SHM), and affinity maturation (20). They are
critical in host immunity as they are the principal site of B cell differentiation into longterm memory and effector cells. On the basis
of immunohistochemical studies, investigators
have divided GCs into dark and light zones.
The light zone is typically more proximal to
the subcapsular sinus in lymph nodes and to
the marginal zone in spleens. This orientation
may enhance entrance of naive B cells and/or
antigen. In the traditional GC model (60), the
dark zone serves primarily as the region where
B cells undergo rapid cellular division, CSR,
and SHM. Subsequently, they migrate into the
light zone within the FDC network and undergo antigen selection in the presence of follicular helper T cells (TFH ) (62) (Figure 4c).
This traditional view of GC function was recently revised based on studies using MP-IVM
(63–66). Tracking GC B cells in real time revealed that B cells within the two zones are
more similar than previously proposed and that
migration between the two regions in both directions is common. Importantly, B cells undergo cellular division and antigen selection in
both zones, and it is unlikely that CSR and
SHM are limited to the dark zone only. Thus,
the real-time imaging provides a view of a dynamic movement in both regions and migration between them. However, certain features
distinguish the two regions and favor separate functions consistent with the traditional
model. For example, B cells in the dark zone
express the chemokine receptor CXCR4 and
are attracted to this region based on expression
of stromal cell–derived factor (SDF) ligand by
stromal cells (67). Downregulation of CXCR4
by dark zone B cells leads to migration into the
light zone because the GC B cell is attracted
to the FDC network by CXCL13. In addition
to the presence of the FDC, the light zone is
further distinguished by an enrichment of TFH
(CD4+ CXCR5+ ).
A hallmark of the GC is selection of B cells
after undergoing CSR and SHM for antigen reactivity (6, 68). Thus, GC B cells are selected for
both BCR recognition of antigen and presentation to TFH cells (62). These events would be
expected to occur more efficiently in the light
zone that is enriched with antigen retained on
the FDC and in the presence of TFH cells. GC
B cells that fail to obtain a signal via the BCR
and CD40 undergo apoptosis and are cleared
by tingible body macrophages.
One striking observation from the real-time
imaging studies is that the morphology of the
GC B cell appears different from that of naive
B cells (64). GC B cells appear more irregular in shape, with extended filopodia apparently
probing the surrounding FDCs. In some images, GC B cells were tethered to the FDC by
long, thin extensions. This distinct morphology could enhance GC B cell interaction with
cognate antigen bound to the surface of FDCs.
B CELLS ACQUIRE ANTIGEN
FROM FOLLICULAR
DENDRITIC CELLS
Direct evidence of B cell acquisition of
antigen from the FDC surface in vivo was
recently reported (50). To track the uptake
of antigen, passively immune mice were
injected subcutaneously with labeled lysozyme
that binds to MD4 Ig transgenic B cells at
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either high, i.e., hen egg lysozyme (HEL)
(Kd ≈ 1 × 109 ), or intermediate, i.e., duck
egg lysozyme (DEL) (Kd ≈ 1 × 107 ) affinity.
Nine days later the mice were administered
fluorescent-labeled antigen-specific (MD4) B
cells. MP-IVM imaging of B cells within the
follicles identified acquisition of the labeled
antigen. In some examples, the antigen was
removed along with a fragment of the FDC
membrane. Notably, efficient capture of intermediate affinity DEL antigen was dependent
on CD21/CD19/CD81 coreceptor, given
that MD4 B cells deficient in CD21 acquired
significantly less labeled antigen than did
Cr2+/+ control B cells. One explanation for
the requirement of the coreceptor in antigen
uptake is that BCR and coreceptor coligation
of C3d-DEL complexes on the FDC surface
enhances signaling in microsignalosomes and
in turn increases the efficiency of acquisition
of membrane antigen.
In summary, FDCs not only provide a critical source of antigen for clonal selection of B
cells within the GC, but also provide a potential
source of antigen for naive B cells in a primary
response.
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LYMPH NODE SINUS
MACROPHAGES CAPTURE
PARTICULATE ANTIGENS
The recent use of MP-IVM to track the
movement of fluorescent-labeled antigen into
draining lymph nodes has provided an insight
otherwise unattainable into the uptake and
accessibility of antigen by B cells (40). Multiple
pathways are apparently used to transport
antigen into the follicles. The pathway(s)
involved is determined by factors such as
antigen size, presence of preexisting antibody,
and activation of the complement system, as
well as by whether migratory DCs transport
antigen into the lymph node (Figure 5).
Particulate antigens draining via afferent
lymph such as vesicular stomatitis virus (VSV)
(69), protein-coated beads (70), and ICs composed of large proteins and IgG (71) are captured and displayed on the surface of SSMs.
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Gonzalez et al.
Strikingly, cognate B cells within the underlying follicles were observed to acquire antigen
directly from the SSM surface and to migrate
to the T-B cell border, where antigen is presented to T cells. Elimination of sinus-lining
macrophages by pretreatment with clodronateloaded liposomes (CLLs) reduces the frequency
of antigen-specific B cells that acquire virus
within the first few hours of immunization (69).
MP-IVM imaging identifies antigen-specific B
cells in direct contact with antigen bound to
the surface of the SSM and shows a reduction
in their velocity, suggesting the formation of a
synapse (70). In one study, fluorescent-labeled
beads draining into the peripheral lymph node
were observed to accumulate on FDCs over
24 h. How the beads were transported in the
absence of specific B cells was not determined;
however, it was proposed that naive B cells or
low-affinity B cells participated in their transport (70). Whether SSMs provide a long-term
source of antigen was not examined, but it seems
unlikely in this dynamic environment given that
SSMs are constantly bathed in afferent lymph.
In the Junt et al. (69) study using VSV as
the antigen, SSMs not only provided a source
of antigen to B cells, but also limited systemic
spread of the virus entering lymph nodes via the
lymph. Elimination of SSMs and MMs using
CLLs led to systemic spread of the virus, confirming the importance of the sinus-lining cells
as guardians against microbial infections. How
VSV is captured by SSMs was not addressed;
however, binding of virus by SSMs and MMs
was observed in C3−/− mice, suggesting that
complement was not required, although direct
opsonic effects of C1q, mannan-binding lectin
(MBL), and/or ficolins cannot be ruled out.
OPSONIZATION OF INFLUENZA
BY MANNAN-BINDING LECTIN
Not all lymph-borne particulate antigens are
retained on the surface of SSMs for relay to
B cells. In a recent study using a fluorescentlabeled UV-inactivated form of influenza A
virus (A/Puerto Rico/8/34; PR8; H1N1) injected in the footpad, Gonzalez et al. (72) found
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SCS
Immune
Ag complex
CR3
1
IgG
SSM
Afferent
lymphatics
Small
antigen
Conduit
SSM
C3d
Mφ
CD81
2
SSM
4
B
Cognate
Follicular
FRCs
B
Fo
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Fo
SLC
Fo
B cell follicle
FDC
B
CD21
Medulla
3
FcγR
Cognate
B
5
Figure 5
Pathways for the transport and recognition of B cell antigen in the lymph node. (1) Immune complexes (ICs), formed by the deposition
of complement proteins (in this illustration, C3d) and IgG on the surface of antigen, bind to complement receptor 3 (CR3) on the
surface of subcapsular sinus macrophages (M). (2) Naive B cells transport complement-coated ICs from the subcapsular sinus to
FDCs. (3) The ICs are transferred in a complement receptor 2 (CD21)-mediated mechanism from the surface of the B cell to the FDC.
(4) Cognate B cells capture small antigen directly from the follicular conduits or large antigen complexes from the surface of FDCs (5),
associated with FcγR or CD21 receptors.
that the inactivated PR8 virus was rapidly captured and internalized by SSMs and MMs. In
contrast to the earlier models, the inactive virus
was not transferred to naive B cells but rather
was transported by a novel pathway. We discuss
this in more detail below.
The envelope of influenza A virus particles
bears two surface glycoproteins, the hemagglutinin and the neuraminidase. Both are critical to the ability of the virus to replicate
in susceptible target cells, and the oligosaccharides attached to the viral glycoproteins
play a number of important biological roles.
The mannose-rich glycoproteins provide a
PAMP (pathogen-associated molecular pattern) for recognition by C-type lectins, Ca2+
-dependent carbohydrate-binding proteins that
share primary and secondary structural homology in their carbohydrate-recognition domains
(CRDs) (73). The members of one subgroup
of C-type lectins, the collectins, appear to be
especially important for host defense against
influenza. The collectins contain a collagenlike domain and usually assemble into large
oligomeric complexes, allowing high-avidity
binding based on multiple low-affinity interactions of their CRDs (74). This enables collectins
to discriminate not only specific carbohydrate
moieties but also specific patterns of these
present on pathogens. Most collectins, including MBL (75), are present in serum and body
fluids. In addition to the collectins, a number of
cell surface–associated C-type lectins appear to
play a role in innate defense toward influenza,
such as the macrophage mannose receptor (76),
the macrophage galactose-type C-type lectin 1
(MGL1) (77), the human DC-specific intercellular adhesion molecule (DC-SIGN) (78),
and the related mouse DC-specific ICAM-3grabbing nonintegrin homolog, SIGN-related
1 (SIGN-R1) (79). The latter receptor
(SIGN-R1) is discussed in more detail below.
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Influenza virus strain PR8, which has very
little glycosylation on its envelope proteins,
is poorly recognized by the C-type lectin activity of either the macrophage mannose receptor or the MGL1 and is only very weakly
bound by surfactant protein D (80). Thus, it
is taken up poorly by macrophages (81). Notably, binding of PR8 by MBL in a solid-phase
binding assay (72) led to lectin pathway activation and C4 and C3 deposition in vitro (S.E.
Degn and M.C. Carroll, unpublished results).
Importantly, virus was opsonized by MBL in
lymph and was rapidly endocytosed by SSMs
and MMs. Because activation of the lectin pathway via MBL activates complement C3, binding
of the virus is likely mediated by the CR3 receptor, a scenario that is similar to that observed
for C3-coated ICs (discussed below). However,
MBL is also thought to bind to specific receptors on macrophages, so it will be important to
understand the specific pathway.
In the study with UV-inactivated PR8 virus,
macrophages were not required for an effective
humoral response, but on the contrary seemed
to dampen the ensuing response. Indeed, MBL
has previously been reported to modify the humoral response of mice toward viral antigens,
dependent on their background (82, 83). This
effect may mechanistically be explained with the
increased clearance and degradation of antigen,
as is also indicated above regarding viral infection of macrophages. Although this effect is
detrimental in the scenario of an influenza vaccine, it may obviously be crucial in the control of infection with live virus. Presumably,
the MBL-mediated opsonization in the blood
and subsequent uptake by macrophages serves
an important barrier function restricting spread
of virus, as has been previously suggested concerning the spread of influenza virus into the
bloodstream from the lungs (84).
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COMPLEMENT-DEPENDENT
CAPTURE OF IMMUNE
COMPLEXES
Soluble proteins in the afferent lymph gain entry into the B cell follicles via several routes de224
Gonzalez et al.
pending on size, presence of specific antibody,
or recognition by innate immunity leading to
opsonization or direct binding to macrophage
surface receptors. For example, proteins larger
than approximately 60 kDa injected into passively immune mice form ICs that activate complement, resulting in covalent attachment of
C3 (C3-IC). The C3-coated complexes are captured by SSMs and made available to B cells in
the underlying follicles, as observed with particulate antigens (71) (Figure 5). Notably, C3coated ICs are taken up by SSMs and are relayed in a unidirectional manner to naive B cells
(42). Because SSMs express the CR3 receptor,
this receptor is likely involved in the binding
and shuttling process. Strikingly, C3-ICs are
off-loaded onto noncognate (naive) B cells that
take up the complexes via CD21 and CD35 and
possibly FcRIIb receptors (38, 71). This is an efficient process, given that a relatively high frequency of follicular B cells acquire ICs within
a few hours after administration of antigen in
preimmune mice. FcRIIb is known to internalize Ig complexes on DCs into a nondegradative
compartment and then return ICs to the cell
surface for presentation to B cells (85). Whether
this pathway occurs in the case of C3-IC uptake
and relay is not clear, but this could help explain
the relatively high efficiency of transfer of C3ICs to naive B cells.
In a model in which preexisting antibody is
not present in the lymph, it seems likely that innate recognition proteins such as natural IgM;
C-type lectins such as MBL and ficolins; pentraxins, including C-reactive protein; and other
complement activators could effectively bind
the foreign protein and activate complement,
resulting in uptake via CR3.
Noncognate B cells loaded with C3-ICs migrate to FDCs, where the complexes are transferred. Again, this process is apparently efficient
given that, within a few hours after antigen administration, FDCs bear complexes on their
surface (38, 71). The mechanism for transfer
of C3-ICs from B cells to FDCs is not clear
because both employ CD21 and CD35 receptors in binding. One possible explanation is
that the relatively high density of CD21 and
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CD35 on the surface of FDCs mediates the
directional transfer. However, further studies
are needed to understand this important process. A similar transport pathway was predicted
almost a decade ago based on studies of the uptake of labeled ICs from circulation by marginal
zone B cells in the spleen (86–88). More recent studies demonstrate a constitutive pathway
in which marginal zone B cells cycle between
the marginal zone and the B cell follicles by a
process dependent on CXCR5 for migration to
the follicles and sphingosine 1-phosphate receptors (S1P1 and S1P3) for retention within
the marginal zone (89). Marginal zone B cells
that express relatively high levels of CD21 and
CD35 pick up C3-ICs from the sinus and deliver the complexes to FDCs as they migrate
though the follicles. As discussed above, the
mechanism by which C3-ICs are stripped from
the B cell and captured by FDCs is not known.
ENTRY OF SMALL
ANTIGENS INTO LYMPH
NODES VIA FRC CONDUITS
Small proteins gain direct access to the B
cell follicles in a manner similar to that described above for chemokines, cytokines, and
small T cell antigens, i.e., via FRC conduits
(Figures 2, 5). Although the distribution and
density of follicular conduits is different from
that of the paracortical area, they provide a
passive entry for small molecules to the B cell
area. Follicular conduits intersect with FDCs,
providing a direct connection for C3-coated
antigens to bind to the FDC surface, where they
can be taken up via complement and Fc receptors (38, 90). Confirmation that small antigen
directly enters the follicles via the conduits was
obtained using MP-IVM (Figure 2). In one
study, small (turkey egg lysozyme; TEL) and
large (TEL-coupled phycoerythrin) antigens
were mixed and injected in the footpad of anesthetized mice, and the popliteal lymph node was
then imaged in real time. The results showed
rapid draining of the small antigen through
the conduits and access to the FDC processes;
antigen that was too large to enter the conduits
remained adjacent to the subcapsular sinus floor
(38) (Figure 2). In another intravital imaging
study, Germain and colleagues (90) tracked
various small lymph-borne antigens, i.e.,
wheat germ agglutinin, ovalbumin, and HEL,
draining from subcutaneous ear tissue into
the B cell follicles of the ear-draining lymph
nodes and binding to FDCs. Interestingly,
cognate B cells appear to efficiently access small
antigens within the FRC conduits as observed
by MP-IVM (38). On acquisition of antigen,
the movement of the cognate B cells (but
not noncognate cells) slows, suggesting that
the antigen-specific B cells become activated.
High-resolution EM images of the follicles of
popliteal lymph nodes identify B cell filopodia, displacing the FRC sheath and directly
accessing the conduits (38). Therefore, B cells
migrating along the conduits survey the reticular fibers for cognate antigen, although this is
more likely only a transient source of antigen
because the FDCs would provide a long-term
and more efficient site for display of C3-ICs.
The size exclusion of conduits presents
somewhat of a dilemma for understanding how
antibody complexes composed of small antigens access the follicles. One explanation is that
antibodies bind small antigens within the follicles as they exit the conduits and that activation of complement provides a ligand for
uptake on CD21 and CD35 receptors. Alternatively, ICs form in the tissues or draining lymph
and activate complement, resulting in tagging
of the antigen with C3d ligand, which is approximately 30 kDa. Although IgG is too large to enter the conduits, it is transported across the subcapsular sinus by the neonatal Fc receptor (91).
An alternative pathway for small antigens
to enter the follicles independent of conduits
was proposed by Pape et al. (92). Using
conventional confocal imaging of cryosections of lymph nodes from mice injected
subcutaneously with HEL antigen, they
identified HEL antigen bound to cognate B
cells throughout the B cell area within minutes
of subcutaneous injection. Elimination of
sinus-lining macrophages with CLLs prior to
injection of antigen did not block acquisition of
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antigen by cognate B cells. Their interpretation
of the results was that the HEL antigen entered
the follicles through gaps in the sinus floor.
DENDRITIC CELLS TRANSPORT
B CELL ANTIGEN
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A third major pathway for entry of foreign
antigens into lymph nodes is active transport by
migratory DCs. This pathway is best described
for delivery of antigens into the T cell compartment (93). For example, during lung infection
with influenza, at least two distinct populations
of respiratory dendritic cells (RDCs)—
CD103+ and CD103− CD11chi CD11bint —are
known to transport influenza into the draining
mediastinal lymph nodes (mLNs) (94, 95).
Migratory DCs enter lymph nodes via either
HEV or lymph vessels. In the example of
lung infection with influenza, RDCs enter
the draining mLNs via the lymphatics by a
pathway that is CCR7 dependent.
In addition to antigen presentation by
the migratory DCs, a resident population of
CD11chi CD8α+ DCs within the mLN also
take up the viral antigen and present it to CD8
T cells (95, 96). This opens the interesting possibility that migratory DCs transfer or hand
off antigens to resident populations within the
mLN. Whether the antigen is processed before
delivery or is transferred intact is not clear. It
seems reasonable to speculate that migratory
DCs enter the subcapsular sinus via the afferent lymph and migrate along the FRC reticular
network, where they encounter resident DCs.
A similar pathway was proposed for skin migratory DC transfer of herpes simplex virus to
resident CD11c+ CD8α+ DCs (97). This pathway suggests that the viral antigen is transferred
from the migratory skin DCs to the resident
DCs.
To test whether B cell antigens are also
transported via migratory DCs, Germain and
colleagues (98) adoptively transferred DCs
loaded in vitro with labeled HEL into mice
seeded with lysozyme-specific B cells. Using
MP-IVM, they tracked labeled DCs into the
HEV of draining lymph nodes, where the HEL
226
Gonzalez et al.
antigen was acquired by the cognate B cells.
This was an important observation because it
not only supported a clear role for migratory
DCs to transport B cell antigen into local lymph
nodes via the circulation, but it also suggested
that the antigen is maintained intact. It will be
important to learn whether migratory DCs that
take up antigen at peripheral sites such as the
lung also transport B cell antigen into the local
lymph node via the lymphatics and present it
directly to B cells or hand off the intact antigen
to a resident population of DCs.
RESIDENT DENDRITIC CELLS
CAPTURE LYMPH-BORNE
ANTIGENS DIRECTLY
Sinus-lining macrophages are not the only
cell type within the lymph node to filter
particulate antigen; DCs residing in the
lymph node medulla also sample particulates.
Recent studies have identified a novel role
for this relatively uncharacterized population
of CD11chi CD11bhi DCs. Using a UVinactivated PR8 strain of influenza A as a model
vaccine, Gonzalez et al. (72) found that the virus
was captured by the lymph node–resident DC
population via SIGN-R1 (Figure 6). As noted
above, the inactive virus is also bound by both
SSMs and MMs, but binding is not required
for humoral immunity. Instead, blocking of
SIGN-R1 and MBL impairs the local humoral
response. Moreover, elimination of CD11chi
DCs in CD11c-DTR bone marrow chimeric
mice treated with diptheria toxin blocks
both the T-dependent (as expected) and the
T-independent humoral responses to UV
influenza (72). Notably, binding of the virus by
lymph node–resident DCs induced a significant
increase in velocity in a nonrandom manner
and a net directional movement toward the
FDC region. By contrast, neighboring resident
DCs that did not take up the inactive virus
failed to increase motility or gain a nonrandom
movement. The combined results support a
model in which the resident DCs transport the
virus to the B cell follicles, where it is handed
off either directly to FDCs or to other DCs.
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14 February 2011
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a
c
b
B cell follicle
FDC
Afferent lymphatics
CD21
SSM
Fo
Fo
o
Fo
SIGN-R1
DC
MM
Efferent
lymphatics
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Medulla
C3d
Medulla
PR8
virus
DC
Figure 6
(a) A MP-IVM snapshot showing the capture of influenza (PR8, red ) by medullar resident dendritic cells (DCs) ( green, white arrows) at
46 min after injection of the virus in the footpad. The lymph node capsule and the medullary conduits are shown in blue. (b) Schematic
drawing showing the cells involved in the capture of lymph-borne UV inactive influenza virus in the lymph node (SSM, subcapsular
sinus macrophage; MM, medullary macrophage). (c) DCs capture influenza virus in a SIGN-R1-dependent manner. This model
speculates that C1q is activated by SIGN-R1 (not illustrated) and leads to C3 deposition on the surface of the virus. After binding to the
virus, SIGN-R1 receptors could cluster on the surface of the cell, and the resident DCs could then transport the C3-coated virus to the
follicles, where it could be transferred to the FDCs. (Panel a adapted with permission from Nature Immunology (Reference 72).]
Unlike the observations with C3-ICs, B cells
did not appear to participate in viral transport.
Whether the resident DCs also transport the
virus to the paracortical T cell area was not
examined, but it seems reasonable that they
might also be involved in T cell priming or
handing off the antigen to other subsets such
as CD11c+ CD8α+ DCs.
SIGN-R1 is one of several homologs of
human DC-SIGN and is expressed by marginal
zone macrophages in the spleen and MMs in the
pLNs (79). Although SIGN-R1 shares many
ligands with DC-SIGN (99), such as glycans
rich in mannan, it contains an altered intracellular domain that signals via SRC family kinases
through a JNK-dependent pathway rather
than the canonical ERK pathway attributed to
DC-SIGN (100). Although much of the literature describes SIGN-R1 as a phagocytic receptor, zymosan binding data have indicated that
the receptor may actually be poorly phagocytic
in the absence of other phagocytic receptors
such as dectin-1 (101). This finding may be important in understanding antigen transfer in the
lymph node, as DCs would have to retain antigen on their surface or recycle in a nonlysomal
compartment, as discussed above for FcRIIb
(85). Interestingly, DC-SIGN can retain
specific antigens without digestion through
the use of low-pH, recycling, nonlysosomal
compartments (102), suggesting a potential
mechanism for SIGN-R1-dependent retention
of viral antigens on lymph node–resident DCs.
A novel function of SIGN-R1 is that binding of Streptococcus pneumoniae activates complement C3 via C1q through the classical pathway
(103). In their study, Kang et al. (103) found
that blocking of SIGN-R1 binding or absence
of C3 resulted in impaired humoral immunity
to the bacteria. They proposed that C3 deposition was essential for uptake of S. pneumoniae on
FDC. However, the mechanism of transport of
opsonized bacteria to FDC was not explored.
Based on the observations of Gonzalez et al.
(72) with inactive influenza, one might speculate that S. pneumoniae is captured by resident DCs as well as by MMs and transported to
the FDC by a mechanism similar to that proposed above for influenza (Figure 6). Thus,
one could envision that binding of S. pneumoniae to SIGN-R1 leads to C3 deposition on
the pathogen surface that provides a ligand
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for the CD21 and CD35 receptors on FDCs.
Thus, resident DCs might transport the C3opsonized bacteria to the B cell follicles and
hand off the complex to FDCs (Figure 6).
SUMMARY
Annu. Rev. Immunol. 2011.29:215-233. Downloaded from www.annualreviews.org
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A long-standing enigma in immunology has
been how and where B lymphocytes acquire
their cognate antigen. The use of MP-IVM has
allowed fresh insight into trafficking of leukocytes and the fate of lymph-borne antigens
and their entry into the B cell follicles. In this
review, we discussed three major pathways in
which B cell antigens are captured and delivered to the B cell compartment and deposited
on FDCs. In the first pathway, macrophages
lining the lymph node subcapsular sinus are
critical not only to limiting the spread of
pathogens but also to capturing and relaying
particulate antigens and ICs to naive and
cognate B cells in the underlying follicles. B
cells play a major role in the transport of ICs
via complement receptors in this pathway. In a
second pathway, small antigens in the afferent
lymph drain passively into the follicles through
collagen-rich conduits. The conduits, which
are secreted by FRCs, intersect with a network
of FDCs, providing a direct connection for capture and retention of antigens via complement
and Ig Fc receptors. In a third major pathway,
DCs residing along the medullary sinus sample
lymph-borne antigens either directly or in
conjunction with MMs. One model system
suggests, for example, that capture of a viral
antigen via SIGN-R1 leads to activation of the
DC and migration in the direction of the B cell
compartment.
Future challenges lie in characterizing the
innate receptors and recognition proteins such
as C-type lectins that participate in opsonization of various microorganisms and in determining how they alter antigen retention on the
macrophage surface. Similarly, we must understand the signals involved in induction of
resident DC migration to either the B cell or
T cell compartments and whether they deliver antigens directly to FDCs or hand off
the antigens to either B cells or other resident
DCs.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
We thank the members of the Carroll laboratory for suggestions and especially Ms. Alex
Gillmore for help in assembly and submission of the manuscript and figures. We also thank
Drs. Shannon Turley and Veronika Lukacs-Kornek for sharing experimental results and helpful
discussions related to dendritic cell trafficking and differentiation. Research was supported by U.S.
National Institutes of Health (NIH) grants (5 RO1 AI039246, 1 PO1 AI078897, 5 RO1 AI067706)
(M.C.C.); Marie Curie International Outgoing Fellowship Career Development award (220044)
(S.F.G.); NIH Transfusion Biology and Medicine training grant (5T32HL066987-09) (L.A.P.);
NIH T32 AI07498, PhD Program in Immunobiology (M.W.); Lundbeck A/S scholarship through
the Denmark-America Foundation (S.E.D.).
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Annual Review of
Immunology
Contents
Volume 29, 2011
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Innate Antifungal Immunity: The Key Role of Phagocytes
Gordon D. Brown p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Stromal Cell–Immune Cell Interactions
Ramon Roozendaal and Reina E. Mebius p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p23
Nonredundant Roles of Basophils in Immunity
Hajime Karasuyama, Kaori Mukai, Kazushige Obata, Yusuke Tsujimura,
and Takeshi Wada p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p45
Regulation and Functions of IL-10 Family of Cytokines
in Inflammation and Disease
Wenjun Ouyang, Sascha Rutz, Natasha K. Crellin, Patricia A. Valdez,
and Sarah G. Hymowitz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p71
Prevention and Treatment of Papillomavirus-Related Cancers
Through Immunization
Ian H. Frazer, Graham R. Leggatt, and Stephen R. Mattarollo p p p p p p p p p p p p p p p p p p p p p p p p 111
HMGB1 Is a Therapeutic Target for Sterile Inflammation and Infection
Ulf Andersson and Kevin J. Tracey p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 139
Plasmacytoid Dendritic Cells: Recent Progress and Open Questions
Boris Reizis, Anna Bunin, Hiyaa S. Ghosh, Kanako L. Lewis, and Vanja Sisirak p p p p p 163
Nucleic Acid Recognition by the Innate Immune System
Roman Barbalat, Sarah E. Ewald, Maria L. Mouchess, and Gregory M. Barton p p p p p p 185
Trafficking of B Cell Antigen in Lymph Nodes
Santiago F. Gonzalez, Søren E. Degn, Lisa A. Pitcher, Matthew Woodruff,
Balthasar A. Heesters, and Michael C. Carroll p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 215
Natural Innate and Adaptive Immunity to Cancer
Matthew D. Vesely, Michael H. Kershaw, Robert D. Schreiber,
and Mark J. Smyth p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 235
Immunoglobulin Responses at the Mucosal Interface
Andrea Cerutti, Kang Chen, and Alejo Chorny p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 273
HLA/KIR Restraint of HIV: Surviving the Fittest
Arman A. Bashirova, Rasmi Thomas, and Mary Carrington p p p p p p p p p p p p p p p p p p p p p p p p p p p 295
v
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Mechanisms that Promote and Suppress Chromosomal Translocations
in Lymphocytes
Monica Gostissa, Frederick W. Alt, and Roberto Chiarle p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 319
Pathogenesis and Host Control of Gammaherpesviruses: Lessons from
the Mouse
Erik Barton, Pratyusha Mandal, and Samuel H. Speck p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 351
Genetic Defects in Severe Congenital Neutropenia: Emerging Insights into
Life and Death of Human Neutrophil Granulocytes
Christoph Klein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 399
Annu. Rev. Immunol. 2011.29:215-233. Downloaded from www.annualreviews.org
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Inflammatory Mechanisms in Obesity
Margaret F. Gregor and Gökhan S. Hotamisligil p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 415
Human TLRs and IL-1Rs in Host Defense: Natural Insights
from Evolutionary, Epidemiological, and Clinical Genetics
Jean-Laurent Casanova, Laurent Abel, and Lluis Quintana-Murci p p p p p p p p p p p p p p p p p p p p 447
Integration of Genetic and Immunological Insights into a Model of Celiac
Disease Pathogenesis
Valérie Abadie, Ludvig M. Sollid, Luis B. Barreiro, and Bana Jabri p p p p p p p p p p p p p p p p p p p 493
Systems Biology in Immunology: A Computational Modeling Perspective
Ronald N. Germain, Martin Meier-Schellersheim, Aleksandra Nita-Lazar,
and Iain D.C. Fraser p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 527
Immune Response to Dengue Virus and Prospects for a Vaccine
Brian R. Murphy and Stephen S. Whitehead p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 587
Follicular Helper CD4 T Cells (TFH )
Shane Crotty p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 621
SLAM Family Receptors and SAP Adaptors in Immunity
Jennifer L. Cannons, Stuart G. Tangye, and Pamela L. Schwartzberg p p p p p p p p p p p p p p p p p 665
The Inflammasome NLRs in Immunity, Inflammation,
and Associated Diseases
Beckley K. Davis, Haitao Wen, and Jenny P.-Y. Ting p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 707
Indexes
Cumulative Index of Contributing Authors, Volumes 19–29 p p p p p p p p p p p p p p p p p p p p p p p p p p p 737
Cumulative Index of Chapter Titles, Volumes 19–29 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 744
Errata
An online log of corrections to Annual Review of Immunology articles may be found at
http://immunol.annualreviews.org/errata.shtml
vi
Contents