Immunology and Cell Biology (2008) 86, 389–397

& 2008 Australasian Society for Immunology Inc. All rights reserved 0818-9641/08 $30.00
www.nature.com/icb

REVIEW

Determination of T-cell fate by dendritic cells

Sandra S Diebold

Dendritic cells (DC) are professional antigen-presenting cells with a unique T-cell stimulatory aptitude that play a crucial role
in the instruction of adaptive immune responses upon infection. By controlling the initiation of a diverse set of effector
functions, which are suitable for the elimination of a wide range of pathogens, DCs form the pivotal link between the innate and
the adaptive immune system. The innate pattern recognition pathways that trigger DC activation are central for skewing of the
adaptive immune responses that are subsequently induced. Thus innate activation not only precedes adaptive immune
activation, it also controls it and tailors the effector functions to the requirements of the infection. The adaptive immune
response has to match the nature of the infection, but this does not only concern the type of pathogen, it is also affected by the
localization of the infection. Tissue homeostasis has to be ensured and thus tissue-derived environmental factors influence the
functional activity of activated DCs and thereby contribute to shaping of the immune response. Adaptive immune responses are
vital for the elimination of pathogens, have the potential to attack tumor cells and play a detrimental role during transplant
rejection and in a variety of autoimmune diseases. Better understanding of the mechanisms that control the induction of
different T-cell effector functions will enable the development of strategies to manipulate the immune system in the context
of vaccination, tumor immunotherapy, transplantation and autoimmunity.
Immunology and Cell Biology (2008) 86, 389–397; doi:10.1038/icb.2008.26; published online 1 April 2008

Keywords: dendritic cells; innate immunity; pattern recognition receptors; adaptive immunity

Dendritic cells (DCs) act as sentinels in peripheral tissues where
they come into direct contact with invading pathogens in the
course of an infection. A small, but highly conserved set of germ
line-encoded pattern recognition receptors (PRRs), which recognize
general microbial signatures, enables DCs to detect a variety
of different pathogens. The molecular structures triggering activation
of these receptors are indispensable for the life cycle of the microbes
and are either fundamentally different from the molecular structures
found in the host or have access to the PRRs in contrast to
similar molecular structures present in the host. Binding of these
so-called pathogen-associated molecular patterns (PAMPs) to PRRs
on DCs leads to their activation and to the induction of a maturation
process.1
In the course of their maturation, DCs alter the uptake, processing
and presentation of material from their environment.2 Immature DC
constantly take up material from their environment, but are not very
efficient in antigen presentation. Once the cells are activated and
undergo maturation, processing and presentation of antigens from the
ingested material is induced.3 In particular the levels of major
histocompatibility complex (MHC) class II molecules at the cell
surface are increased, since recycling of these molecules and their
passage through endosomal class II-rich compartments ceases upon
DCs activation.4,5 As a consequence of this, DCs display increased
levels of antigen at the cell surface and impart a snapshot of pathogen-
derived antigens, which they have encountered at the site of infection.
Subsequent to PRR-mediated activation, DCs stop taking up and
processing new material from their environment.6–8
In addition, the maturation process entails a change in chemokine
receptor expression from CCR6 to CCR7 and the upregulation of co-
stimulatory molecules by DCs.9 Expression of CCR7 in combination
with inflammatory mediators at the site of infection such as prosta-
glandin E2 enables DCs to leave the inflamed tissue and migrate to the
draining lymph node.10,11 Upon arrival in the draining lymph node,
the activated DCs interact with T cells. The DC-derived signals that
determine the outcome of these interactions are the levels of antigen
presentation (signal 1), the display of co-stimulatory molecules (signal
2) and the presence of immunomodulatory factors such as cytokines
(signal 3).12
While increased levels of antigen presentation and the expression of
co-stimulatory molecules such as CD80 and CD86 on DC are crucial
for the expansion of antigen-specific T cells, they are not sufficient
for the induction of effector functions. The differentiation of expanded
T cells into effector cells is dependent on signal 3, which has to be
provided in cis by the antigen-presenting cell (APC) that interacts with
the antigen-specific T cell.13 Signal 3 is thought to be one of the main
determining factors controlling the induction of particular types of
effector functions in T cells.14
The ability of DCs to induce different effector functions in T cells
enables the immune system to adjust its response to very diverse
classes of pathogens, while in parallel allowing for the regulation of

Peter Gorer Department of Immunobiology, King’s College London, Guy’s Hospital, London, UK
Correspondence: Dr SS Diebold, Peter Gorer Department of Immunobiology, King’s College London, Guy’s Hospital, Second Floor Borough Wing, London SE1 9RT, UK.
E-mail: sandra.diebold@kcl.ac.uk
Received 27 February 2008; accepted 28 February 2008; published online 1 April 2008
 Determination of T-cell fate by dendritic cells
390
responses during the course of infections and in the steady state with a
given set of cells. Since the immune system receives a multitude of
different signals during the course of an infection and due to the
flexibility of the system, the boundaries between the different types of
T-cell responses are not necessarily clear-cut and mixed responses can
be observed. The type of immune response that is required for the
elimination of the infection depends primarily on the type of patho-
gen and, therefore, the pathogen itself is the most important single
factor skewing the adaptive immune response in a particular direction.
The key players that transmit this information are the antigen-
presenting DCs.15,16 In addition to the PAMPs that mediate DC
activation, tissue-derived environmental factors can influence DC
activation and thereby skew the type of adaptive immune response
that is initiated by the APCs.17 Furthermore, DCs can interact with a
variety of cells of the innate immune system that reside in or are
recruited to the inflamed tissue and which either have direct contact
with the pathogen or are activated indirectly by the inflammatory
environment. DCs receive additional signals from these cells, which
have an impact on their activation.15 Similarly, DCs receive feedback
signals from activated T cells with which they interact in the draining
lymph nodes.18 All these different signals are integrated by the DCs
and define their activation mode, which, in turn determines the
effector functions that are induced in T cells upon antigen-specific
interaction. To counteract their elimination by such effector cells
pathogens have evolved a multitude of strategies to interfere with
immune activation, including the expression of immunosuppressive
factors, which impair or alter DC activation and lead to the induction
of effector functions that are beneficial to the pathogen (Figure 1).
DIFFERENT EFFECTOR FUNCTIONS
The adaptive immune response is often crucial for the eradication of
invading organisms and for the induction of immunity. CD4+ T
MHC-peptide complex signal 1
co-stimulatory molecules signal 2
cytokines signal 3
pathogen immunosuppressive
factors
PRR-mediated
activation
DC
tissue-derived
environmental factors
interactions with other
cells of the innate
immune system
periphery
Figure 1 In the periphery dendritic cells (DCs) become activated in the course of infection. Their activation is influenced by pathogen-derived factors such as
the pathogen-associated molecular patterns (PAMPs), which trigger particular pattern recognition receptor (PRR) on the DCs, but also by pathogen-derived
immunosuppressive factors. Tissue-derived environmental factors and interaction with other cell types at the site of infection further influence DC activation.
Once activated tissue-derived DCs reach the draining lymph nodes, they receive further signals from the T cell they interact with. Upon integration of all
these different signals DCs direct the differentiation of the antigen-specific T cells accordingly. Tissue-derived DCs also transfer antigen to lymphoid-resident
DCs with different functional specializations.
Immunology and Cell Biology
SS Diebold
helper (Th) cells play a vital role in the induction of adaptive immune
responses and in steering them toward particular effector phenotypes.
Th cells are equally important for the induction of humoral and
cellular immunity and provide crucial signals for the activation of B
cells and for the induction of cytotoxic T lymphocytes (CTLs).
Depending on the signals transmitted by the activated DCs, naive
CD4+ T cells can differentiate into different types of Th cells, which
can be distinguished by their cytokine secretion. Th1 cells produce
interferon (IFN)-g, while Th2 cells are characterized by the production
of interleukin (IL)-4, IL-5 and IL-13, and the more recently identified
Th17 cells secrete IL-17.
Intracellular pathogens such as viruses demand the induction
of Th1 immune responses, which not only lead to the production
of neutralizing antibodies, but also to the induction of cellular
immunity. Cellular immunity in the course of Th1 responses is
mediated by CTLs that kill infected tissue cells, which present
pathogen-derived antigen. The destruction of infected host cells
prevents intracellular pathogens from forming hidden depots, which
could lead to the recurrence of the infection upon later release of the
microbes from the infected cells.
In contrast to viruses, extracellular pathogens such as most patho-
genic bacteria, fungi and protozoa do not require the immune system
to attack cells of the host. Thus CTL responses are not induced, since
they would not be helpful in eliminating the pathogen. For clearing
infections with extracellular pathogens such as helminths, Th
responses of a Th2 phenotype are beneficial. Th2 cells are crucial
for the induction of antibody class switching in B cells and for
inducing a humoral response. The pathogen-specific antibodies
produced during the course of a Th2 response mediate pathogen
eradication via opsonization aimed at phagocyte activation,
complement induction, toxin neutralization and interference with
pathogen adhesion.
Th1
T cell
feedback
Th2
T cell
migration
activation Th17
DC
Treg
transfer
?
T cell
CTL
DC
lymph node

Differentiation of Th responses into Th1 and Th2 responses has
been the focus of research for many years.19 More recently, a new type
of Th response, characterized by the proinflammatory cytokine IL-17
that mediates neutrophil-driven inflammatory responses, was
described. Th17 responses have been detected upon infection with a
variety of pathogens such as extracellular and intracellular bacteria,
fungi and parasites such as Toxoplasma gondii.20 One current model
for the role of Th17 cells in adaptive immunity is that the induction of
Th17 is short lived and mediates inflammation irrespective of the
pathogen and prior to the induction of Th1 or Th2 cells. It has been
shown that IL-17 is involved in the induction of Th1 and Th2
responses and that Th1- and Th2-derived cytokines suppress the
induction of Th17 cells, thus pointing toward a temporal interrela-
tionship of these different effector cells.21–23 While IL-17 plays a
protective role during infections, Th17 cells have also been shown to
be involved in chronic inflammation and tissue injury and can,
therefore, be detrimental to the host.24
Once the adaptive immune system has been activated, the immune
system has to strike a balance between the elimination of the pathogen
and protection of the host tissue. In the case of unregulated activation
of the adaptive immune system, chronic inflammation and immuno-
pathology are observed. While the main task of natural CD25+
regulatory T cells is probably the suppression of autoreactive immune
responses, gd T cells play a role in the regulation of effector T cells in
inflamed tissue.25,26 While these two regulatory cell populations do
not seem to require instruction by APCs such as DCs, antigen-specific
regulatory T cells can be induced as a consequence of DC–T cell
interactions.27 Two different types of inducible regulatory CD4+ T
cells can be distinguished on the basis of the cytokines that they
secrete. Th3 cells secrete high levels of tumor growth factor (TGF) b,
whereas T regulatory 1 cells produce high levels of IL-10 and no IL-4.25
Experimental evidence points toward a role for Th3 in oral tolerance
induction and in particular in mucosal tolerance to commensal
microflora.28,29 In addition, induction of regulatory T cells in an
antigen-specific context may be important for the regulation of
infection-induced responses to avoid immunopathological changes
in the inflamed tissue and to allow for tissue repair. Thus immunor-
egulation can be seen as a vital part of any adaptive immune response.
Other regulatory mechanisms that prevent the induction of auto-
immune responses in the periphery are deletion of autoreactive T cells
or anergy induction. In both cases, DCs are the crucial APCs
determining the fate of autoimmune T cells.30 Yet, the factors that
control the outcome of interactions between DC and self-reactive
T cells are still not fully understood. It is currently unclear whether
specialized tolerogenic DC subsets exist and are crucial for the deletion
of autoreactive cells or whether all DC subsets that mediate immune
activation in response to infection have tolerogenic properties in the
uninfected host. Similarly it still awaits further clarification as to
whether immature DCs are tolerogenic or whether alternative forms of
maturation are necessary for immature DCs to differentiate into
tolerogenic DCs.31
PATTERN RECOGNITION RECEPTOR-MEDIATED ACTIVATION
CONTROLS DC FUNCTION
Since the adaptive immune response has to ensure the eradication of
the invading pathogen, the pathogen itself is the primary factor
affecting the induction of signal 3 and thereby skewing the type of
adaptive immune response that is induced.32,33 Among the germ line-
encoded PRR that allows cells of the innate immune system to sense
pathogens, Toll-like receptors (TLRs) occupy a prominent role
in controlling the induction of primary immune responses.16,34 The
Determination of T-cell fate by dendritic cells
SS Diebold
391
well-characterized TLR family comprises ten members in humans and
mice with the capacity to detect a wide range of different PAMPs.
TLRs can be grouped into two subfamilies, one expressed at the cell
surface sampling the environment for the presence of bacterial, fungal
and protozoan cell wall components, the other localized to a specia-
lized endosomal compartment detecting the presence of pathogen-
derived nucleic acids.35
The endosomal TLRs are crucial for the detection of virus infection,
since viruses largely lack pathogen-specific PAMPs that are funda-
mentally different from molecular structures found in the host.
Viruses are dependent on the host metabolism to replicate and the
viral petidoglycan, lipoprotein and glycolipid structures therefore
largely resemble the molecular structures of the host. Three classes
of viral nucleic acids can be discriminated with TLR3 recognizing
double-stranded RNA, TLR7 and TLR8 detecting single-stranded
RNA and TLR9 sensing DNA.36–39 Interestingly, the nucleic acid-
sensing TLRs do not rely upon structural differences for discrimina-
tion between viral and nonviral nucleic acids, but rather depend on
differences in their access to the TLR-containing endosomal compart-
ment.40 While viral nucleic acids are shielded from degradation inside
virus particles, nucleic acids released from necrotic cells are quickly
degraded and do not reach the endosomal compartment under
physiological conditions. The system, however, requires specific
uptake mechanisms to deliver virus particles or viral nucleic acids
into the endosome where recognition takes place. This can be achieved
by antibody-mediated uptake of opsonized virus particles via Fcg
receptor or direct binding of surface receptors to the viral capsid or
envelop proteins.41,42 Upon delivery into the endosomal compart-
ment, lysosomal degradation releases the genomic viral nucleic acids
from the virus particles and allows their detection by the endosomal
TLRs. Autophagy is another mechanism by which virus-infected DCs
can mediate the transfer of cytoplasmic replication intermediates into
the nucleic acid-sensing endosomal compartment.43 Since the
endosomal TLRs are unable to discriminate between self- and
pathogen-derived nucleic acids, self nucleic acids can trigger
potent immune activation when they gain access to the compartment
as seen in the course of autoimmune diseases such as systemic lupus
erythematosus.44,45
In contrast to the endosomal TLRs, the TLRs at the cell surface
recognize petidoglycan, lipoprotein, glycolipid and protein structures
that constitute part of bacterial and fungal cell walls or flagella. These
molecular structures are absent from the host and, therefore, represent
a signature of microbial infection. Examples include different forms of
lipopolysaccharides that trigger TLR4 or TLR2, fungal cell wall
components recognized by TLR2, bacterial triacyl and diacyl lipopep-
tides, which are ligands for heterodimers of TLR2 with TLR1 and
TLR6, respectively, and bacterial flagellin detected by TLR5.46–53 Since
recognition of these PAMPs takes place at the cell surface, uptake of
pathogens is not necessary for TLR activation. APCs such as macro-
phages and DCs, however, express scavenger receptors that mediate
the uptake of bacterial and fungal material for antigen processing and
presentation. Upon uptake of pathogen material into antigen-proces-
sing compartments, TLRs such as TLR2 and TLR4 are recruited to the
compartment and induce phagosome autonomous maturation, which
results in efficient MHC class II presentation of antigens associated
with TLR stimuli.54,55
The activation of DCs in response to binding of TLR agonists is
controlled by the signaling pathways that transmit the stimulatory
signal. TLRs harbor a Toll-like/IL-1 receptor (TIR) domain in their
cytoplasmic tail region, which recruits TIR domain-containing adap-
ter molecules upon ligand binding. TIR domain-containing myeloid
Immunology and Cell Biology
 Determination of T-cell fate by dendritic cells
SS Diebold
392
differentiation factor 88 (MyD88) is used as an adapter molecule by all
TLRs except TLR3, which exclusively signals via TIR domain-contain-
ing adapter protein inducing IFN-b (TRIF). While MyD88 is directly
recruited to the TIR domain of TLR7-TLR9, the MyD88-adapter-like
(MAL) adapter is required to recruit MyD88 upon ligand binding to
TLR2 and TL4. Similarly TRIF-related adapter molecule (TRAM) is
crucial for the recruitment of TRIF to TLR4.56 While MyD88 recruit-
ment is required for the induction of nuclear factor-kB, which induces
expression of proinflammatory cytokines such as tumor necrosis
factor (TNF)-a, IL-6 and IL-12, TRIF induces the transcription factor
IFN response factor 3, which leads to the induction of IFN-b.
Plasmacytoid DCs (PDCs) differ from conventional DCs and induce
IRF7 in response to TLR7 and TLR9 ligands. TLR7 is essential for
the expression of high levels of IFN-I by PDCs in response to
viral PAMPs.57
Recognition of viral PAMPs by the endosomal nucleic acid-sensing
TLRs leads to the induction of Th1 responses.58–61 A hallmark of viral
infections is the TLR-induced production of high levels of IFN-I by
PDC.62 IFN-I promotes the induction of CTL responses via cross-
priming, supports antibody class switching in B cells and acts directly
on T cells and is, thereby, actively involved in skewing the Th response
toward a Th1 phenotype.63–65 For TLRs, which do not mediate
activation of PDC and do not consequently lead to high levels of
IFN-I, the induction of IL-12 is crucial for skewing the immune
response toward the Th1 phenotype. TLRs that favor the induction of
Th1 responses in response to nonviral stimuli include TLR4, TLR5,
TLR11 and PRRs recognizing Candida albicans and Aspergillus
fumigatus in form of yeast and conidia, respectively.66–70
The induction of Th2 responses has been described for the several
TLR ligands triggering TLR2 or heterodimers of TLR2 with TLR1 or
TLR6 such as LPS from Porphyromonas gengivalis, Pam3cys, peptido-
glycan and zymosan, and also for schistosome eggs and hyphae from
C. albicans and A. fumigatus, which trigger mutiple and/or undefined
PRRs.66–72 The induction of a Th2 response under these conditions is
assigned to the suppression of IL-12 induction by the transcription
factor c-Fos.67,73 The interaction of DC with helminths also promotes
the development of Th2 cells mediated via the upregulation of Ox40
ligand (OX40L) and the induction of the Notch ligand Jagged by the
DCs in response to helminth stimuli.32,74
In addition to TLRs, some C-type lectin receptors (CLRs) function
as PRRs. CLRs contain a carbohydrate-binding domain and in the
case of PRRs such as dectin-1 the binding of fungal carbohydrate
structures, which are absent from mammalian cells triggers DC
activation. The signaling pathway involved in transmitting dectin-
1-induced activation is fundamentally different from TLR-transmitted
signaling and involves recruitment of Syk to a hemITAM motif in the
cytoplasmic domain of the receptor.75 The signal is then transmitted
via CARD9 and eventually leads to the induction of IL-23. IL-23 is
involved in the differentiation of CD4+ T cells into Th17 cells and
stimuli associated with fungal pathogens, such as C. albicans that
trigger dectin-1, consequently skew the adaptive immune response
toward a Th17 phenotype.76 Induction of IL-17-producing cells is
observed in response to a wide range of pathogens, including bacteria,
fungi, Herpes simplex virus and T. gondii.20
ENVIRONMENTAL FACTORS DIRECT DC FUNCTION
While LPS from Escherichia coli skews the response toward the
induction of the Th1 phenotype when given systemically, bacterial
infections of the gut have a preference for the induction of Th2
responses. The mucosal environment of the gut is in constant contact
with commensal microorganisms, which express the same PAMPs as
Immunology and Cell Biology
the pathogenic species. Thus the gut has to avoid responses against
commensal bacteria and the development of chronic inflammation,
but must be able to react in response to an infection. Gut DCs
accomplish this by showing a preference for the induction of a Th2
phenotype.77,78 Adaptive immune responses in the gut lead to the
production of immunoglobulin (Ig) A antibodies, which play an
important role in gut immunity. To what extent the induction of
IgA-mediated responses by gut DCs is an intrinsic property of these
DC subsets or the result of environmental factors that influence the
activation of gut DCs is currently unclear. However, it has been shown
that epithelial cells, mast cells and basophils release factors such as
thymic stromal lymphopoietin (TSLP), which influence DC activa-
tion. Upon treatment with TSLP, DCs interacting with CD4+ T cells
induce a Th2 phenotype even in the presence of PAMPs that favor a
Th1 response.79 The induction of OX40L on DCs treated with TSLP is
crucial for the Th2-skewing properties of the APCs.80 Interestingly,
deficiencies in this mechanisms seem to be involved with the devel-
opment of Crohn’s disease, an inflammatory bowl disease associated
with a Th1 phenotype.79 It is thought that constitutive expression of
TSLP by intestinal epithelial cells prevents activation induced by the
PAMPs of gut commensals. Additional evidence for a role of TSLP in
skewing the Th response toward a Th2 phenotype comes from studies
into atopic dermatitis and allergic asthma. Both conditions are
associated with a Th2 phenotype and in both cases, TSLP production
has been observed.81,82
Similarly, the type of Th phenotype that is induced in response to
Leishmania major depends on the route of delivery of the pathogen.
When injected subcutaneously or intraperitoneally into mice, the
parasite induces a strong Th1 response. But upon intranasal admini-
stration of L. major the induction of a Th2 response is observed.83
Thus environmental factors play a crucial role in controlling the
phenotype of primary responses to pathogens. Whether this influence
is solely exerted via secreted tissue mediators such as TSLP or is in part
due to intrinsic properties of the DC subsets found in these tissues
remains to be seen.
INTERACTIONS WITH OTHER LEUKOCYTES INFLUENCE DC
FUNCTION
DCs are not the only cells that express PRRs. Other cells of the
immune system and tissue cells express cell type-specific sets of TLRs
and can, therefore, sense pathogens directly. Thus other cells in the
inflamed tissue become directly activated through contact with
invading microbes and are additionally influenced by inflammatory
mediators present at the site of infection. While direct activation of
DC is absolutely crucial for their ability to induce effector functions in
the CD4+ T cells with which they interact, the activation mode of DC
is nevertheless affected by interactions with other cells of the immune
system. The influence of other cells on DC function was first identified
in the form of T-cell feedback. When studying the role of
CD40–CD40L interactions between activated DCs and CD4+ T cells,
it became obvious that the interaction of these two cell types
was not unidirectional with the DCs activating the naive T cells,
but that the activated T cells in return transmitted a signal to the
DCs. This so-called T-cell feedback signal was shown to be crucial for
the ability of activated DCs to induce CTL responses.84–86 This
explained the mechanisms behind the Th cell dependence of CTL
responses and established a two-step model for the induction of
cellular immunity. During the initial interaction of DCs and Th
cells, DCs become licensed by the Th cells and during the subsequent
interaction of licensed DC and naive CD8 T cells CTL priming
takes place.

In addition to the functional implications for their ability to prime
naive CD8+ T cells, CD40 stimulation of DCs also amplifies their
upregulation of co-stimulatory molecules and the induction of cyto-
kines in response to PRR-mediated activation. Feedback signals from
activated CD4+ T cells via molecules such as CD40L, in the absence of
PRR-mediated DC activation lead to the upregulation of co-stimula-
tion, but fail to induce cytokine induction and are, therefore,
qualitatively different from direct activation via PRRs.18 The increases
in co-stimulation and cytokine secretion induced by T-cell feedback in
response to PRR-mediated DC activation are purely quantitative and
these signals are not altered qualitatively.87 Consequently, CD40-
mediated stimulation does not skew the phenotype CD4+ Th
responses induced by activated DCs. Thus, T-cell feedback acts as a
licensing stimulus for the induction of CTL responses and as an
amplifying stimulus enhancing DC activation in response to PAMPs.
A similar form of DC licensing has been identified for interactions
of DCs with invariant natural killer T (iNKT) cells. The invariant
T-cell receptor (TCR) of iNKT cells recognizes lipids presented by
CD1d on DCs. Co-administration of TLR ligands and the iNKT cell
ligand a-galactosylceramide, which is presented on CD1d, greatly
enhances the adaptive immune response.88,89 As with T-cell feedback,
DC licensing by NKT cells is dependent on CD40 signaling and does
not seem to skew the type of immune response that is induced, but
rather acts as an amplifying signal increasing the strength of the
response.90
Another class of innate lymphocytes with the ability to sense altered
self are gd T cells.26 Interactions between gd T cells and DCs can lead
to the maturation of DCs via CD1c- and/or TNF-a-dependent
mechanisms.91,92 Tissue-resident gd T cells become activated upon
recognition of altered self in the absence of infection, yet they receive
additional stimulatory signals in the course of infections. It is likely
that there are qualitative differences in the interaction between DCs
and gd T cells in response to altered self in the presence or absence of
direct activation by PAMPs that influence the functional mode of
these cells, however, this awaits further clarification.
Interactions of DCs with natural killer (NK) cells have been shown
to enhance the induction of Th1 responses and affect the effector
functions of both cell types. PDC-derived IFN-I and DC-derived IL-12
is important for NK cell-derived IFN-g, which is, in turn, important
for driving Th1 responses.93 In the course of antiviral immune
responses, upon activation, NK cells exert potent cytotoxic killer
functions and destroy host cells that express signs of cellular stress
and viral infection. To date a role for NK cells during Th2-driven
immune responses has not been described.
Thus in contrast to DC activation which is induced by PRR
stimulation and manipulated by environmental factors, the interac-
tions of DCs with T, iNKT, gd T and NK cells do not seem to alter DC
function with regard to the induction of particular Th phenotypes.
This could be explained in part by the fact that all cells of an ongoing
immune response receive the same TLR-mediated activation signals
and are influenced by the same environmental mediators. Since these
two factors are crucial in defining which Th response is required for a
given infection, all cells of the immune system are instructed in the
same direction.
FUNCTIONAL SPECIALIZATIONS OF DIFFERENT DC SUBSETS
A variety of DC subsets with distinct phenotypes and different
functional properties can be distinguished.94 The two major classes
of DCs that are discriminated are PDCs and conventional DCs. While
conventional DCs are potent APCs, PDCs are specialized in producing
high levels of IFN-I in response to virus infections and were thus
Determination of T-cell fate by dendritic cells
SS Diebold
393
originally called natural IFN-producing cells.62,95 Upon activation by
viral PAMPs, PDCs undergo maturation and gain T-cell stimulatory
properties, but due to their limited ability to present exogenous
antigens, they only seem to contribute to T-cell priming when infected
by viruses.59,96 In accordance with their role, PDCs do not act as
sentinel DCs in uninflamed tissue, but circulate in blood. PDCs are
specialized in virus recognition via TLR7 and TLR9,60,97,98 however,
their role during infection with other classes of pathogens is not well
defined. During viral infections, PDCs are recruited to inflamed
lymph nodes, where they aid Th1-type immune responses by secreting
IFN-I.99 IFN-I not only promotes cross-priming of CTL responses, it
also acts directly on B and T cells and plays an important role in
antibody class switching.63–65 Due to their functional specialization
PDCs have limited influence on skewing T-cell fate via direct
priming of T cells.
In contrast to PDCs, conventional DCs efficiently process and
present exogenous antigen and represent potent APCs. Conventional
DCs can be further subdivided into a variety of different DC subsets.
The sentinel DCs present in peripheral tissue are distinguished from
lymphoid-resident DCs, which enter lymphoid organs such as spleen
and lymph nodes from blood and where they reside in an immature
stage in the absence of infection.100 Since the classical life cycle of DC
encompasses the detection and uptake of pathogen material in the
periphery, the subsequent activation and migration to the draining
lymph node, followed by priming of antigen-specific T cells, the role
of lymphoid-resident DCs during infections was initially enigmatic.
Yet, it has been demonstrated that these DCs have potent T-cell
stimulatory capacity and participate in T-cell priming. In particular,
murine CD8a+ DCs were shown to be crucial for the initiation of
antiviral CTL responses and transfer of antigen from freshly immi-
grated tissue-derived DCs to lymphoid-resident CD8a+ DCs has been
demonstrated.101–104 The striking role of CD8a+ DCs in priming of
CD8 T cells has to do with their specialization in the cross-presenta-
tion of exogenous antigens on MHC class I.105–108 The underlying
mechanisms of antigen transfer are, however, still largely unknown
and it is also unclear how the cells are activated. CD8a+ DCs are a
potent source of IL-12 in response to infection, yet indirect activation
of the cells by inflammatory cytokines leads to surface marker
upregulation but not to the production of cytokines.109 Since the
induction of cytokines is crucially dependent on direct activation of
DCs via PRRs, the cells require direct contact with PAMPs. How this is
accomplished is currently unclear, but one can hypothesize that not
only antigens, but also PAMPs are transferred from the tissue-derived
sentinel DCs to the lymphoid-resident CD8a+ DCs. While CD8a+
DCs are important for the induction of CTLs in the context of virus
infection, it is unclear to what extent they contribute to the induction
of Th responses particularly in the context of Th2- and Th17-
dominated response against extracellular pathogens. Although the
role of CD8a+ DCs in direct priming of CD4+ T cells is questionable,
IL-12 produced by CD8a+ DCs in response to certain PAMPs is
crucial for the induction of Th1 responses.
In addition to the CD8a+ DCs two further lymphoid-resident
conventional DC subsets can be found in the mouse spleen: the
CD4+ DCs and DC negative for CD4 and CD8a, which are often not
distinguished as single subsets, but referred to as the CD8a! DC
subset. CD8a! DC represent so-called myeloid DC, which are less
efficient than CD8a+ DC in cross-presenting exogenous antigen and
consequently are not crucial for the priming of CD8+ T cells, however,
are potent stimulators of CD4+ T cells.110,111 CD8a! DCs have
been shown to favor Th2 immune responses in contrast to isolated
CD8a+ DCs, which preferentially induce a Th1-type phenotype. This
Immunology and Cell Biology
 Determination of T-cell fate by dendritic cells
SS Diebold
394
dichotomy was observed upon vaccination with antigen-loaded
CD8a! versus CD8a+ DCs in the absence of PRR-mediated immune
activation. In the presence of Th1-promoting PAMPs, which lead to
the induction of cytokines favoring cellular immunity, myeloid DCs
skew the fate of CD4+ T cells toward a Th1 phenotype.112 While there
is a clear role for priming of Th responses by directly activated
lymphoid-resident CD8a! DCs during systemic infections, their
role during infections localized to particular tissues is less clear. This
would require transfer of antigen and activating stimuli from
immigrating tissue-derived DCs similar to what is observed for
CD8a+ DCs.
The sentinel DCs that reside in peripheral tissues are also myeloid in
origin. In the case of these DCs, the PAMPs that are encountered at the
site of infection and environmental factors such as TSLP control the
type of Th response that are induced by these cells upon migration to
the draining lymph node. While direct presentation of antigen on
MHC class II on these cells allows them to prime Th responses,
transfer of antigen to CD8a+ DCs is important for priming of
CD8 T cells.
ROLE OF DCS IN IMMUNOREGULATION AND TOLERANCE
INDUCTION
The TCR repertoire is generated by gene recombination and the
thymic selection process has to ensure that the MHC–TCR interac-
tions are functional while TCRs reactive to self-antigens are deleted.
Thymic tolerance induction is not, however, absolute as not all genes
expressed in the organism are represented in the thymus and since a
low affinity to self-antigen is crucial for the transmission of T-cell
survival signals.113 Due to these constraints, peripheral tolerance
induction and regulation of responses to self-antigens are fundamental
aspects of the immune system.
Peripheral tolerance induction is mediated by DCs in the absence of
infection.30 Yet, the underlying mechanisms of peripheral tolerance
induction still have to be unraveled in detail. Immature DCs from
peripheral tissues constitutively immigrate into draining lymph nodes
at a low rate. In the uninfected host, the tissue-derived and the
lymphoid-resident DCs found in secondary lymphoid tissues present
self-antigens.114 Interactions between immature DCs and self-reactive
T cells are thought to have three potential outcomes: ignorance,
anergy induction or deletion. The factors that control these outcomes
are the affinity of the TCRs, the level of co-stimulation present on the
DCs and the type of DCs that presents the self-antigen. Immature DCs
express low levels of MHC class II molecules at the cell surface, offer
little co-stimulation and produce no proinflammatory cytokines. It is
not entirely clear whether immature DCs are capable of mediating
peripheral tolerance induction or whether some undefined alternative
modes of activation are required for inducing tolerogenic effector
functions in DCs. Stimuli, which lead to the upregulation of signal 1
(antigen presentation) and signal 2 (co-stimulation) in the absence of
signal 3 (for example, cytokines or Ox40L) on DCs may be crucial for
peripheral tolerance induction.115 Various DC subsets have been
implicated in peripheral tolerance induction, including PDCs and
CD8a+ DCs, however, whether these tolerogenic DCs are immature or
have received endogenous signals that mediate alternative maturation
is still a matter of debate.116–118
Interestingly, indirect activation of DCs by inflammatory mediators
such as prostaglandin E2, TNF-a and IFN-I can induce upregulation
of signal 1 and 2, but fails to induce cytokine production.119–121
Consequently, indirect activation of DCs is fundamentally different
from direct PRR-mediated activation of DCs and indirectly activated
DCs are unqualified for the induction of adaptive immunity. It has
Immunology and Cell Biology
been shown that indirectly activated DCs lead to the expansion of
antigen-specific T cells that fail to acquire Th effector functions.13 Yet,
the fate of the expanded T cells is still unknown.
Effector T cells recruited to the inflamed tissue during the course of
an infection will eventually lead to immunopathology if immune
activation is not controlled by regulatory mechanisms. Many different
cell types can execute T-regulatory functions such as gd T cells and
naturally occurring CD4+ CD25+ regulatory T cells.25,26 Naturally
occurring CD4+ CD25+ regulatory T cells are generated in the thymus
and are thought to control the induction of responses against self-
antigens. In addition to naturally occurring CD4+ CD25+ regulatory T
cells, regulatory T cells can be induced by tolerogenic DCs in the
periphery.
It is currently unclear whether tolerogenic DCs are largely induced
upon alternative maturation or exhaustion. Upon activation of DCs
with PAMPs, DCs upregulate signal 1 and 2 and also induce signal 3,
which is necessary for the induction of Th cells. However, the
production of proinflammatory cytokines by activated DCs is tran-
sient and they become refractory to restimulation once cytokine
production has ceased. Interaction between such exhausted DCs and
naive T cells has been shown to favor the induction of Th2 or
nonpolarized T cells.122 The induction of regulatory T cells by
exhausted DCs could be important for the resolution of the immune
response once the pathogen has been eradicated and stimulatory
signals are no longer present to prevent the establishment of an
environment conducive to immunopathology.
Alternative maturation of DCs in the presence of IL-10 or upon
uptake of material from uninfected apoptotic cells have also been
described as pathways for the induction of tolerogenic DCs.115,123
Treatment of DCs with IL-10 induces a tolerogenic phenotype and
it was argued that IL-10 produced by regulatory T cells could generate
a positive feedback loop leading to the induction of more regulatory
T cells.62,124 Factors that have been implicated in driving the induction
of regulatory T cells by alternatively activated DCs include IL-10,
TGFb, inhibitory B7 family members such as B7-H1 and B7-DC and
Ig-like transcript factors such as ILT3 and ILT4.14
CONCLUSIONS
T-cell fate is primarily controlled by the PRRs that mediate DC
activation and the environmental factors that control DC function.
Despite the plasticity in DC activation and in their ability to induce
different effector functions, the various DC subsets are functionally
specialized and take charge of different aspects of T-cell priming. DCs
are also crucial for the induction of peripheral tolerance and for
certain forms of immune regulation. Thus DCs represent the central
decision makers of the immune system orchestrating complex
responses according to the various signals that mediate their activa-
tion. Understanding the mechanisms of their decision-making in
more detail will have profound influence on the design of better
strategies for vaccination, tolerance induction and therapy of auto-
immune diseases.
ACKNOWLEDGEMENTS
SD is funded by a Cancer Research UK Career Development Award. I thank
Amy Lewis for her critical reading of the paper.
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