The Journal of Immunology
Different Bacterial Pathogens, Different Strategies, Yet the
Aim Is the Same: Evasion of Intestinal Dendritic
Sammy Bedoui,* Andreas Kupz,* Odilia L. Wijburg,* Anna K. Walduck,*
Maria Rescigno,†and Richard A. Strugnell*
Given the central role of intestinal dendritic cells (DCs)
in the regulation of gut immune responses, it is not sur-
prising that several bacterial pathogens have evolved
strategies to prevent or bypass recognition by DCs.
In this article, we will review recent findings on the in-
teraction between intestinal DCs and prototypical bac-
terial pathogens, such as Salmonella, Yersinia, or
Helicobacter. We will discuss the different approaches
with which these pathogens seek to evade DC recogni-
tion and subsequent T cell activation. These diverse
strategies span to include mounting irrelevant immune
responses, inhibition of Ag presentation by DCs, and
stretch as far as to manipulate the Th1/Th2 balance of
CD4+T cells in the bacteria’s favor.
Immunology, 2010, 184: 2237–2242.
food-derived nutrients, this permeability also creates gateways
for entry by incompletely degraded immunogens and patho-
genic microbes. Accordingly, the intestinal immune system has
evolved multiple strategies to protect the epithelia involving
innate and adaptive immune mechanisms (1–4).
Evolution, largely through horizontal gene transfer, has
yielded pathogenic bacteria that can overcome the barrier
properties of the gut epithelia and the protection by the in-
testinal immune system (5). Virulence factors injected by
bacteria into or near epithelial cells are responsible for directed
uptake and transcytosis, paracellular entry, and local damage
that result in epithelial or lamina propria and sometimes
deeper, systemic infections. Although the interaction between
different pathogenic intestinal bacteria, such as Salmonella,
Yersinia, or Helicobacter and the innate immune system has
been the subject of many studies, much less is known about
how the bacteria interact with intestinal dendritic cells (DCs).
Given the critical role of DCs in inducing, priming, and
regulating antibacterial immunity, it is not surprising that
The Journal of
he gastrointestinal epithelia perform essential roles in
the degradation and absorption of food. Although the
primary function of the intestine is the uptake of
pathogenic bacteria have developed distinct strategies to cir-
cumvent immune recognition by DCs. In this review, we will
outline recent findings on the interaction between intestinal
bacteria and DCs and discuss how some of these interactions
can be regarded as sophisticated evasion strategies promoting
bacterial colonization and/or dissemination.
Intestinal DC subtypes
DCs make up a heterogeneous group of cells, which differ
significantly in phenotype and function (6, 7). A useful way of
classifying different subsets is to divide them into tissue-resi-
dent DCs and those that reside primarily in lymphatic organs
such as the spleen or the lymph nodes (LNs). Tissue-resident
DCs are strategically positioned in the periphery where they
sample a variety of Ags, including those of self- and microbial
origin. Upon successful ingestion of Ag, DCs will undergo
maturation and migrate to the local draining LNs (8).
Through upregulation of MHC and costimulatory molecules,
matured DCs convert into highly efficient APCs (9). Suc-
cessful Ag presentation to CD4+T cells requires recognition
of cognate peptide in the context of MHC class II molecules,
whereas epitopes presented on MHC class I molecules stim-
ulate Ag-specific CD8+T cells. It was long held that T cells
specific for tissue-derived Ags were only primed by migratory
DCs. However, it is now clear that migratory DC can also
transfer their Ag to resident DCs for T cell stimulation,
a process that most likely involves cross-presentation (10, 11).
Even though the transfer of Ag from migratory DCs to those
DCs residing only in the lymphatic tissues represents an in-
teresting function, resident DCs are best known for their
ability to capture and present Ags that are either present
within the local microenvironment or, in terms of the spleen,
are blood borne (8). The diverse nature of Ags (i.e., self-de-
rived, food, commensals, and pathogenic microbes) requires
that Ag presentation by DCs is very strictly regulated. To
avoid activation of self-reactive T cells and to limit un-
necessary responses, such as those against commensal flora,
DCs can imprint tolerance onto T cells (12). Even though we
have only a limited understanding of the precise mechanisms
*Department of Microbiology and Immunology, University of Melbourne, Parkville,
Victoria, Australia; and†Department of Experimental Oncology, European Institute of
Oncology, Milan, Italy
Received for publication December 1, 2009. Accepted for publication January 7, 2010.
Address correspondence and reprint requests to Dr. Sammy Bedoui, Department of
Microbiology and Immunology, University of Melbourne, Gate 11, Royal Parade, Park-
ville 3010, Victoria, Australia. E-mail address: firstname.lastname@example.org
Abbreviations used in this paper: DC, dendritic cell; LLO, listeriolysin O; LN, lymph
node; M cell, microfold cell; S. Typhimurium, Salmonella enterica serovar Typhimu-
rium; SPI, Salmonella pathogenicity island; TTSS, type III secretion system; Yop, Yersi-
nia outer protein.
Copyright ? 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00
and the events that govern whether immunity or tolerance is
induced, tolerance induction appears to depend on local
factors (13, 14), the presence of regulatory cells (15, 16), and
importantly, on which DC subset presents the Ag (11, 14).
With only a single layer of epithelial cells separating the
external from the internal world amid the constant need for
particle exchange, intestinal DC play a key role in maintaining
intestinal homeostasis as well as governing protective immune
responses against invading pathogens. To complete this com-
plex task, intestinal DCs differ significantly with respect to
subset composition, function, and location from other DC
subsets (11, 13, 15, 17, 18). Traditionally, intestinal DCs have
been differentiated based on the expression of CD11b and
CD8a (CD11b2CD8a2, CD11b+CD8a2, and CD11b2
CD8a+). More recent studies indicate that the expression of
aE-integrin (CD103) defines two functionally distinct subsets
(14, 19–21). Whereas CD1032DCs are thought to initiate
proinflammatory T cell immunity (22), CD103+DCs have the
potential to induce FOXP3+regulatory T cell responses
through the production of TGF-b and retinoic acid (14, 23,
24). However, it remains to be determined whether the re-
cently observed dichotomy in CD11b expression (25) on
CD103+DCs (CD11b+versus CD11b2) further divides this
DC subset functionally and where CD103-expressing mesen-
teric LN-resident CD8a+DCs fit into the picture (26).
One interesting observation concerning DC engagement
with intestinal bacteria comes from studies showing that DCs
extend protrusions between epithelial cells, enabling direct
sampling of luminal Ags (27). Whereas this unique function
was directly attributed to the expression of CX3CR1(28),
others have suggested that the signals required for the delivery
of these protrusions extended into the lumen involve CCL20
secretion from a parenchymal, radioresistant cell type (29).
These studies revealed that the development of protrusions
depended on TLR2 and TLR4 expression and that the pro-
trusions markedly decreased after broad-spectrum antibiotic
treatment (29). From these observations, it was concluded that
the radioresistant cells probably represent epithelial cells that
are sensing luminal, microbe-derived pathogen-associated
molecular patterns and, in response, release CCL20 into the
lamina propria. The expression of E-cadherin on intestinal
epithelial cells suggested that CD103 might play an important
role in guiding lamina propria DCs close to the epithelial
surface (25). However, more recent evidence indicates that
CX3CR1is expressed by CD1032DCs rather than CD103+
DCs in the lamina propria (25). This observation questions
whether both DC subsets are equally efficient at sampling the
intestinal lumen, whether this is a subset-specific function, or
whether this unique function is exclusive to CX3CR1+CD1032
DCs. Finally, on the basis of a study, which showed that
lamina propria DCs can also be found in the intestinal lumen
(30), it was recently suggested that sending out protrusions
into the lumen might only be a first step toward entering the
intestinal lumen. However, whether there is a sequential re-
lationship between DCs sending out their protrusions and
migration into the lumen remains to be elucidated.
Salmonella Typhimurium deceives and inhibits DCs
Salmonella enterica serovar Typhi is the causative agent of ty-
phoid fever in humans. Similarly, S. enterica serovar Typhi-
murium (S. Typhimurium) causes a systemic salmonellosis in
mice, an infection that is widely used to model typhoid fever
(31). Following ingestion, bacterial invasion occurs either di-
microfold cells (M cells), a specialized cell type interspersed
between epithelial cells lining the intestinal surface (32). Once
translocated to the lamina propria, the bacteria replicate ex-
tracellularly and eventually gain access to Peyer’s patches. One
of the major virulence determinants of Salmonellae are host cell
modulating effector proteins that can be injected directly into
host cells through one of two types of type III secretion systems
(TTSS). Salmonella pathogenicity island (SPI)-1– and SPI-2–
encoded TTSS of S. Typhimurium play an important role in
determining how the bacteria invade the host (33). Whereas
SPI-1–encoded genes initiate extracellular Salmonella invasion
via M cells and epithelial cells, SPI-2–dependent genes direct
Salmonella invasion via DCs (34). In the absence of fully
functional SPI-2, S. Typhimurium infection in mice occurs
through direct invasion into epithelial cells, a SPI-1–encoded
phenomenon that is termed “the classical pathway.” Under
these circumstances, Salmonellae are taken up by M cells and
intestinal epithelial cells (35), causing these cells to die very
rapidly. This in turn promotes bacterial escape into the sub-
epithelial compartment (36) and dissemination of the bacteria
both locally and systemically. Surprisingly, the SPI-1–de-
pendent pathway of invasion appears to be less important, be-
cause SPI-1–deficient Salmonellae still infect mice and cause
colitis (34), although mucosal IgA responses are reduced (37).
This observation raises the question as to what the biological
relevance of the SPI-1–dependent invasion pathway might be.
To address this question, it is worth having a closer look at the
events that occur during the extracellular lifespan of the bac-
teria. To directionally navigate in the extracellular space, Sal-
monellae use a flagellin-based propulsion system (38). Flagellae
are composed of numerous subunits that are attached to the
bacterial surface via a “hook-system” and a basal body, which
acts as a “motor” to drive flagella rotation (39). Of the major
interest to immunologists, because it is the prototypical ligand
for TLR5 (40). Recognition of FliC by TLR5 expressed on
epithelial cells and monocytes, for example, results in the se-
cretion of proinflammatory mediators, such as IL-6, TNF-a,
IL-1b, as well as the anti-inflammatory cytokine IL-10 (41).
However, flagellin is not only a TLR agonist, but it is also at-
tractive “bait” for DCs. Upon ingestion and processing within
the DC, a peptide derived from its FliC subunit is presented in
the contextofMHC classII moleculestoCD4+Tcells (42). In
studies that were greatly facilitated by the generation of a TCR
transgenic mouse line in which all CD4+T cells are specific for
FliC (43), analysis of FliC-specific CD4+T cell responses
during Salmonella infection has yielded some remarkable
findings. Although FliC-specific CD4+T cells rapidly upre-
gulate the early activation marker CD69, undergo clonal pro-
liferation, and gain effector function, these fully armed CD4+
T cells fail to protect the host (43). With flagellin being one of
the most abundant bacterial proteins present in the infected
host tissues, it is quite surprising that flagellin-specific CD4+
T cells are so remarkably inefficient. Elegant work by Cookson
and colleagues (44) provides a simple yet striking explanation
for this puzzling observation. Once Salmonella has reached the
inside of a cell, the bacteria change their gene transcription
profile substantially, and among these changes, the production
2238 BRIEF REVIEWS: EVASION OF INTESTINAL DCs BY BACTERIAL PATHOGENS
of FliC is dramatically reduced. This makes biological sense,
because the bacteria no longer require motility when residing
immediate T cell response to Salmonella (45), the shutdown of
FliC production and therefore elimination of the their cognate
T cell response functionally irrelevant. Thus, by directing DCs
to induce T cell responses against Salmonella Ags that rapidly
become irrelevant, Salmonella uses an intriguing strategy of
deception and diversion (Fig. 1).
The interaction of S. Typhimurium with DCs is not limited
to the regulation of key epitopes and their presentation to
T cells. As with macrophages and monocytes (46, 47), it has
been suggested that infected DCs can act as vehicles for Sal-
monella invasion and dissemination (48). Seminal work by
Hapfelmeier et al. (34) has recently demonstrated that caecal
inflammation following SPI-1–deficient Salmonella infection
was entirely abrogated in DC-depleted mice, indicating that
SPI-2–mediated entry of the host occurs exclusively via DCs.
This, of course, creates a situation in which large quantities of
Salmonella Ags are present within cells that are specialized to
activate T cells to foreign Ags. One obvious approach at pre-
cell activation is to trigger apoptosis in infected DCs. Indeed,
Salmonella is quite effective at inducing apoptosis of DCs (49).
However, bearing in mind that Salmonella also uses DCs to
facilitate its dissemination (48), it would be evolutionarily
unwise to kill off all infected DCs. Remarkably, Salmonella
responds to this challenge by inhibiting Ag presentation by
infected DCs. van der Velden and others (50–52) have shown
to stimulate Ag-specific CD4+and CD8+T cells. This in-
hibitory action not only accounts for presentation of bacterial-
derived Ags (52) but also extends to T cell proliferation fol-
lowing pulsing of DCs with cognate peptides (51, 52). This
effect is dependent on bacterial protein synthesis, suggesting
within infected DCs (51). The precise mechanisms by which
trafficking of MHC molecules along actin polymers (53), or
their ubiquitination (54). Thus, by inhibiting Ag presentation
disguise its presence in the most potent APCs. Taken together,
these findings indicate that Salmonella has developed distinct
strategies to circumvent DC-mediated immune recognition.
Considering the functional heterogeneity among the different
DC subsets, it is tempting to speculate that distinct evasion
strategies target different DC subsets. However, to date, the
precise role different DC subsets play in response to Salmonella
infection is largely unknown, and many questions remain un-
answered. Clearly, future studies need to shed light into this
exciting area of research.
Yersinia enterocolitica inhibits Ag presentation by DCs
Salmonellae are not the only intestinal pathogen that has de-
veloped means to prevent priming of bacteria-specific T cells
by interfering with Ag presentation by DCs. Yersinia
Salmonella invasion involves bacteria breaching the intestinal
barrier either directly through the epithelium or via M cells.
Once translocated into the lamina propria, bacteria are in-
Upon migration into the Peyer’s patches, these DCs present
FliC-derived peptides to specific CD4+T cells. Considering
the rapid downregulation of FliC upon successful invasion of
irrelevant, because their cognate Ag is no longer present.
A strategy of deception used by Salmonella.
The Journal of Immunology2239
enterocolitica is a Gram-negative bacterium that causes food-
borne acute and chronic gastrointestinal diseases (55). In-
gested Y. enterocolitica are taken up by M cells, colonize
Peyer’s patches, and disseminate to liver and spleen (56).
Despite its predominantly extracellular lifestyle, the bacteria
have a TTSS, allowing them to inject a number of effector
proteins, including Yersinia outer proteins (Yops) into host
cells. Notably, DCs are also targeted by Yops in vivo and
injection of these bacterial effector molecules has been shown
to inhibit Ag presentation by DCs (57). By interacting di-
rectly with the actin cytoskeleton, Yops inhibit the phagocytic
activity of DCs (58) and, as proof of principle, transfection of
DC with YopP has been shown to reduce uptake of OVA
(59). Direct evidence that YopP can inhibit the ability of DCs
to present Ag to CD8+T cells in vivo was provided by
Tru ¨lzsch et al. (60), who tracked the induction of CD8+T cell
responses to Yersinia encoding for the Listeria-derived Ag lis-
teriolysin O (LLO). Upon infection of mice with wild-type Y.
enterocolitica encoding LLO, they found that the frequency of
IFN-g–producing LLO-specific CD8+T cells was greatly re-
duced when compared with mice challenged with Listeria
monocytogenes. Importantly, priming of LLO-specific CD8+
T cells was reinstated when mice were infected with a mutant
of Y. enterocolitica that lacks YopP. Given that similar amounts
of LLO were transferred by the YopP mutants, these findings
indicate the potent ability of Y. enterocolitica to actively inhibit
the induction of Ag-specific T cells via injection of YopP. Even
though the mechanisms involved in the inhibition of Ag pre-
sentation by Y. enterocolitica remain unresolved, it has been
suggested that the transfer of Yops induces apoptosis of DCs,
stimulation (60, 61). Of note, other members of the Yersinia
genus also appear to have developed special strategies to in-
teract with DCs. For example, Y. pestis, the infamous causative
agent of the plague, has been shown to infect DCs (62),
whereas Y. pseudotuberculosis uses YopE to circumvent
phagocytosis by DCs (63). Thus, direct inhibition of the
ability of DCs to present Ag represents another interesting
evasion strategy used by intestinal bacterial pathogens (Fig. 2).
Helicobacter pylori modulates CD4+T cell differentiation
by Helicobacterpylori.This Gram-negative bacterium is unique
among the intestinal pathogens, because it inhabits the gastric
mucosa (64). Infections with H. pylori almost always lead to
chronic infection, and in some patients, this chronic infection
can lead to gastritis, ulcers, or gastric cancer (65). Despite its
bacterium and DCs. First, DCs are recruited into the gastric
mucosa very early on postinfection of mice with H. pylori (66).
Second, H.pylori can productively infect bone marrow-derived
DCs in vitro (67), and third, DCs in the gastric mucosa of H.
pylori-infected individuals can send protrusions into the lumen
with which they make direct contacts with H. pylori (67). Even
though there is still an ongoing debate as to the exact role of
CD4+T cells during H. pylori infection, these cells are clearly
current concept stipulates that a strong bias of CD4+T cells
toward a Th1 phenotype is associated with attenuated H. pylori
colonization (70, 71). Consistent with this notion, it appears
that H. pylori has evolved strategies with which to prevent the
induction of Th1-biased CD4+T cells. Direct evidence for this
comes from a study that compared H. pylori-induced IL-12
secretion by monocyte-derived DCs following short-term and
sustained stimulation with fixed H. pylori. Whereas short-term
stimulation induced DC maturation and strong IL-12 re-
sponses, sustained stimulation significantly impaired DC
function and reduced the secretion of IL-12 (72). Lending
further support to the notion that H. pylori skews the Th1/Th2
balance by reducing IL-12 secretion, Kao et al. (66) recently
identified a nonproteinaceous factor in sonicates of H. pylori
that has the ability to prevent IL-12 secretion by DC in vitro,
opposed to causing exhaustion through chronic stimulation.
Although the precise nature of this factor remains enigmatic,
this process likely involves the C-type lectin DC-SIGN, which
is expressed by DCs. Fucose-motifs present in H. pylori inhibit
IL-12 secretion by means of modulating DC-SIGN signal-
osome plasticity (73). Furthermore, interaction between DC-
SIGN and Lewis Ags expressed in certain phase variants of
response (74). Even though much remains to be examined, the
above-mentioned observations suggest that H. pylori manages
to regulate Th1 immunity in its favor, by skewing DCs toward
thus representing yet another strategy with which an intestinal
pathogen evades DC recognition and the subsequent T cell
The above-discussed observations and findings clearly indicate
that different bacterial pathogens have evolved sophisticated
only target certain functional aspects that are relevant to the
subsets. Given the functional heterogeneity among the subsets,
the presentation of relevant Ags, or alternatively, modulating
their TTSS, Y. enterocolitica manipulates DC function. YopP interacts not
only with the actin skeleton but also inhibits phagocytosis and Ag pre-
sentation on MHC class I molecules to CD8+T cells.
By injecting effector molecules, such as YopP, into DCs via
2240 BRIEF REVIEWS: EVASION OF INTESTINAL DCs BY BACTERIAL PATHOGENS
rather than the priming of T cells would result in little evolu-
tionary advantage. Thus, future research should revisit pre-
We apologize to all researchers whose work could not be discussed here due to
space limitations.The critical review of the manuscript by Kirsty Short is grate-
The authors have no financial conflicts of interest.
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2242BRIEF REVIEWS: EVASION OF INTESTINAL DCs BY BACTERIAL PATHOGENS