Chapter 10

Innate and Adaptive

Immunity in the Skin
Robert L. Modlin, Lloyd S. Miller,
Christine Bangert, & Georg Stingl

INNATE IMMUNE RESPONSE

Molecules of the
Innate Immune System
Neuropeptides
The skin is a rich source of neuropeptides, including neurotransmitters [e.g., calcitonin gene-related
peptide (CGRP), substance P, somatostatin] and
neurohormones (see Chapter 102). The inhibitory
effects of CGRP and substance P on Langerhans cell
(LC) antigen presentation function are discussed
later. The neurohormone proopiomelanocortin
(POMC) is produced by the pituitary gland as well
as by a number of cell types, including keratinocytes.
OTHER MEDIATORS.
Other secreted protein mediators that can be synthesized and released from keratinocytes and that
may play a role in host defense are the complement
components C3 and factor B. Keratinocytes are
among the cells that synthesize eicosanoids, an ensemble of lipid mediators regulating inflammatory
and immunologic reactions. They can produce and
release the cyclooxygenase product prostaglandin
E2, which has both proinflammatory and immunosuppressive properties and, when acting on DCs,
promotes the development of IL-4-dominated type
2 T-cell responses.28 Other keratinocyte-derived
eicosanoids include the neutrophil chemoattractant leukotriene B4, the proinflammatory 12-lipoxygenase product 12(s)-hydroxyeicosatetraenoic acid,
and 15-hydroxyeicosatetraenoic acid, an anti-inflammatory and immunosuppressive metabolite of
the 15-lipoxygenase pathway.
Another group of biologic response modifiers
originating in keratinocytes and other epidermal cells is free radical molecules, now generally
referred to as reactive oxygen species. These include
the superoxide radical (O2), hydrogen peroxide
(H2O2), the hydroxyl radical (OH), nitric oxide (NO),

and others. These radicals are generally viewed

as dangerously reactive entities threatening the
integrity of many tissues. The skin is particularly
at risk because it is exposed to oxygen from both
inside and outside and because of the activation
of oxygen by light (see Chapters 88 and 89). Free
radicals probably contribute to solar damage and
photoaging of the skin. However, certain reactive
oxygen species have potent inflammation-inducing
properties (e.g., free oxygen radicals) as well as
immunomodulatory properties (e.g., NO), and thus
provide an important host defense mechanism
against microbial invasion. For discussion of these
molecules, the reader is referred to the review by
Bickers and Athar.29

Detailed Studies of TLR

Nucleotide-binding Oligomerization
Domain Proteins (NOD1 and NOD2)
In contrast to TLRs, nucleotide-binding oligomerization domain proteins (NOD1 and NOD2) are
found free in the cytosol and detect breakdown
products of peptidoglycan.72,73 NOD1 recognizes
breakdown products of Gram-negative peptidoglycan whereas NOD2 recognizes muramyl dipeptide
(MDP), which is a breakdown product of peptidoglycan from both Gram-positive and Gram-negative
bacteria. After ligand detection, NODs activate a
signaling pathway that results in NF- activation,
through the adapter molecule RIP2, and transcription of host genes involved in innate and acquired
immune responses. In addition, NOD2 can also
activate the inflammasome leading to the proteolytic cleavage and activation of IL-1.74,75 NOD1
and NOD2 are thought to be primarily important
in recognizing intracellular pathogens. However,
extracellular bacteria can invade the cytoplasm of
cells and lead to activation of NOD2. This has been
demonstrated in the case of S. aureus skin infection.76 Further studies are needed to determine
the role of NOD1 and NOD2 against other skin
pathogens. Interestingly, mutations in NOD2 are
associated with Crohns disease, sarcoidosis, and
Blaus syndrome, which is a disease consisting of
early-onset granulomatous inflammation (arthritis,
uveitis, skin), visceral involvement, and camptodactyly.7779 In addition, polymorphisms in NOD2 and
the NOD2 signaling pathway have been associated
with leprosy, suggesting that all these diseases may
be mechanistically linked.80 Furthermore, NOD1
polymorphisms have been associated with atopic
dermatitis and asthma.81

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Chapter 10:

Innate and Adaptive Immunity in the Skin

Cells of Innate Immune System

Eosinophils
(See Chapter 31). Eosinophils are a distinct class of
bone marrow-derived granulocytes that normally
constitute only a small fraction of peripheral blood
leukocytes and occur in even smaller numbers in
peripheral tissues. The cytokines granulocytemacrophage colony-stimulating factor (GM-CSF), IL-3
and, most importantly, IL-5 are critical for their
development and maturation.

ADAPTIVE IMMUNE RESPONSE

Lymphocytes
Accessory Molecules.122,123
During their maturation in the thymus thymocytes
start to express the molecules that allow T cells to
display their unique functional capacity, which is to
specifically recognize antigen in an MHC-restricted
fashion (see Section General Principles of Antigen
Presentation). These are the TCR and the accessory molecules CD4 and CD8. The latter stabilize
the interaction of the TCR with the MHC-linked
peptide antigen. Whereas CD4 binds to MHC class
II molecules, CD8 acts as an adhesive by binding
to MHC class I molecules. Thymocyte development
follows a strict selection process. First, lymphoid
progenitor cells enter the thymus and develop into
CD25+CD4CD8 (double-negative, DN) thymocytes.
Upon successful generation of functional TCR-b
and pre-TCR- receptors, further development to
CD4+CD8+ (double-positive, DP) thymocytes with
fully functional TCR- chains is initiated. Following low-avidity TCR recognition of self-peptide/
MHC molecules, DP thymocytes receive signals
for survival and further differentiate into single
positive (SP) thymocytes. These positively selected
mature thymocytes constitute only 3%5% of all
thymocytes and are either CD4+CD8 MHC class II
restricted cells or CD8+CD4 MHC class I-restricted
cells. Subsequently, they leave the thymus and
migrate to the peripheral lymphoid tissues (lymph
nodes, spleen, Peyers patches, etc.). On the contrary, thymocytes that show self-reactivity undergo
apoptosis in order to avoid autoimmunity (negative
selection), and DP thymocytes that do not receive
TCR signals die due to neglect. This process is most
active in early infancy and childhood but continues
with decreasing output well into adult life.

Cytotoxic T-Cell Subsets

Two distinct subsets of cytotoxic T cells have
been identified and can be differentiated by the
mechanism by which they kill targets124; the end
result being the induction of a programed cell
death known as apoptosis.125,126 The first mechanism
of cytotoxicity involves the interaction of two cell
surface proteins, FasL (CD95L) on the T cells and Fas
(CD95) on the target. Ligation of these molecules
delivers a signal through Fas that induces the apoptosis cascade in the target. The second mechanism
involves the release of cytoplasmic granules present in such T cells. These granules contain perforin,
which induces a pore in the target, and granzymes,
serine esterases that, when injected into cells,
trigger the apoptotic pathway. Such granules also
contain granulysin, a protein with a broad spectrum
of antimicrobial activity against bacteria, fungi, and
parasites.124,127 In this manner, cytotoxic T cells can
directly kill microbial invaders. Besides contributing to host defense against infection and tumors,
cytotoxic T cells can also contribute to tissue injury.
For example, cytotoxic T cells exist which recognize
self-antigens of melanocytes and thus may contribute to the pathogenesis of vitiligo.128
CD4CD8 T CELLS.
Double-negative (DN) T cells comprise only 1%5%
of the peripheral T-cell population of mice and men.
DN T cells can be detected in lymphoid and nonlymphoid tissues. Their developmental origin is still
under investigation, but several results suggest that
both intra- and extrathymical maturation pathways
may exist.129,130 Early findings already described a
non-MHC restricted-natural suppressor activity of
murine DN T-cell lines,131 although cytokine analysis
revealed a marked IFN- and TNF-., but no IL-2, IL-4,
IL-10, or IL-13 production.132,133 Meanwhile there is
ample evidence of the regulatory function of DN T
cells in vitro and in vivo.132134 In contrast to naturally
occurring CD4+CD25+ regulatory T cells (see Section Functionality), human DN T reg cells seem
to exert their suppressive function in an antigenspecific fashion.133 Interestingly, the capacity of DN
T reg cells to suppress syngeneic CD8+ and CD4+
effector cells arises from their Fas/Fas L-mediated
cytotoxicity.134 DN T cells use their TCR complex to
acquire allo-MHC peptides from APC via trogocytosis (acquisition of membrane-bound proteins)
and then kill CD8+ T cells that recognize the same
allo-MHC peptides.135 In vivo experiments in murine
transplantation models confirmed a cell-to-cell

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Chapter 10:

contact-dependent, antigen-specific killing of CD8+

effectors by DN T cells that effectively prolonged
skin allograft survival132 and, in addition, plays a role
in preventing graft-versus-host disease.136 Similarly,
a protective role of DN T cells has been proposed for
autoimmune diseases137 and cancer development.136
Cd4+/Cd8+ T Cells.
A low percentage (1%3%) of mature CD4+CD8+
double-positive (DP) T cells can be detected in
peripheral mammalian blood. They can further be
distinguished based on the extent of CD4 and CD8
expression, respectively, into CD4high CD8low and
CD4low CD8high T-cell subsets.138 Experiments performed in adult rats showed that DP cells represent
30%40% of yet not fully functional T lymphocytes
in peripheral lymphoid organs during fetal life with
gradually decreasing numbers until reaching the
low percentage seen in adulthood.139 This finding
has been explained by a premature release from
the thymus in the peripheral blood, where their
maturation into immunocompetent single positive T cells continues. In human, it is still unclear
whether the small fraction of DP T cells found in
adulthood represents fully immunocompetent T
cells. The fact that these cells are increased to 20%
of peripheral lymphocytes in chronic viral diseases
such as HIV and EBV infections points in this direction.140,141 In addition, several studies demonstrated
that these cells function as antigen-specific effector memory cells that contribute to the adaptive
immune response during viral infections.138,142
Recently, the occurrence of effector/memory DP
T cells was also described within tumors of breast
cancer143 and solid metastases of human melanoma
patients.144 Analysis of their cytokine profile showed
the production of Th1 and Th2 cytokines including
IL-13, IL-4, TNF-, GM-CSF, Il-2, IFN-, and IL-5, indicating a potential role in tumor immunity.

Virginity
Naive T Cells
Recent studies identified fibroblastic reticular cells
in secondary lymphoid organs as essential source
of IL-7 and the CCR7 ligand CCL19.146 High expression of CCR7 and CD62L on naive T cells ensures
their homing to LN and, at the same time, enables
their IL-7-mediated survival. Under homeostatic
conditions, a stable population size of naive T cells
can thereby be maintained. The transcription factor
FoxO1 has been identified as important regulator
for the expression of CCR7, CD62L, and the chain

Innate and Adaptive Immunity in the Skin 11

of the IL-7 receptor (CD127) on naive T cells. FoxO1deficient mice fail to home to secondary lymphoid
organs and show only very low levels of CD127,
which, in turn, leads to a decrease of naive T cells in
these mice.147 On robust activation, naive T cells undergo a process of expansion and differentiate into
effector cells with potent pathogen-eliminating
functions.148 A great proportion of effector cells dies
off within a few weeks, but few cells are selected to
enter the memory pool according to their capacity
to access and use of survival signals.
Memory T Cells.
Two types of CD45RO+ memory T cells can be generated: central memory and effector memory T cells.
(Central and effector memory T cells are discussed
in detail in the online edition.)
Central Memory T Cells.
Similar to naive T cells, long-lived central memory
T cells express the lymph node homing receptors
CD62L and CCR7, which allow their circulation
through peripheral blood and secondary lymphoid
organs. They are responsible for secondary or longterm responses to antigen and might be involved in
long-term maintenance of effector memory cells.149
The pool of memory T cells increases gradually with
age at the expense of their naive counterparts. In
contrast to naive T cells, memory T cells undergo
cell division within an interval of 23 weeks, which
is balanced by an almost equivalent number of cell
death.150 The homeostatic expansion and survival of
central memory T cells crucially depend on the responsiveness to IL-7 and IL-15, mediated via surface
expression of CD127 (IL7R) and CD122 (IL-15R),
respectively.151 Central memory T cells exhibit only
modest effector functions, but, upon rechallenge
with a given antigen, they can develop into effector
T cells.152
It appears that the strength of the antigenic signal
determines the ultimate fate of a naive T cell, as
robust TCR signaling may result in the generation
of effector memory T cells.149 Contrary to central
memory T cells, effector memory cells are excluded
from secondary lymphoid organs, but home to peripheral tissues and are responsible for immediate
protection against challenge. Following the peak of
the immune response, most of these cells disappear
from the blood and central memory T cells appear
instead. It seems that effector memory cells represent a transitory population rather than a distinct
cell type, ending with the development of central
memory T cells.153 Conversely, central memory T

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Chapter 10:

Innate and Adaptive Immunity in the Skin

cells convert into effector cells and subsequently

into effector memory T cells in the presence of
antigen.153 Recent studies in mice demonstrated
the importance of IL-2 signaling for the survival and
differentiation of long-term effector memory cells,
as IL-2R-deficient T cells maintain the phenotype
of central memory T cells and do not differentiate into effector memory T cells upon secondary
antigen challenge.154 In contrast, IL-15 seems to play
a negligible role in promoting effector memory differentiation during primary immune responses, but
it is apparently essential for the survival of effector
memory T cells after pathogen clearance.154

host responses (see Section CD1-Dependent Antigen Presentation). On antigenic stimulation, NKT
cells produce large quantities of cytokines, particularly IL-4 and IL-10, and can use them to suppress
Th1 responses. The biologic relevance of these in vitro data can be deduced from the observation that
depletion of NKT cells can aggravate and accelerate
Th1-mediated autoimmune diseases in mice, such
as insulin-dependent diabetes, multiple sclerosis,
and inflammatory bowel disease.180

Very recently, two new T-cell subsets have been

described: Th22 (T22) cells and Th9 (T9) cells.156,157
Th22 cells were identified in human peripheral
blood as skin-homing CCR6+ CCR4+ CCR10+ CLA+
memory T cells that produce IL-22, but no IL-17 or
IFN-.156 That somehow came as a surprise, as IL-22
has so far been associated with Th17 cells only. In
vivo, Th22 cells could be isolated from the epidermis of inflammatory skin diseases such as psoriasis,
atopic eczema, and allergic contact dermatitis.158
In vitro, their generation from naive T cells was
reported to be dependent on IL-6 and TNF-.., but
independent from the Th17-specific transcription
factor RORgt.156 Th9 cells produce IL-9 upon stimulation with TGF- and IL-4 and do not express any
of the established transcription factors for T-cell differentiation, suggesting a new lineage of T cells. IL-9,
originally associated with Th2-dominated responses, is known to be involved in immune responses to
helminths and to contribute to the pathogenesis of
asthma. Lately, is has also been described that T-cell
derived IL-9 may mediate immune suppression, as
it is functionally important for allograft survival.159
Future experiments will tell whether Th22 and Th9
T cells truly represent distinct T-cell subsets with
lineage-specific transcription factors.

Further Studies of DDCs.

Investigation of C-type lectin expression on DDCs
demonstrated that CD209 (DC-specific intercellular
adhesion molecule 3 grabbing nonintegrin molecule/DC-SIGN) and CD206 (macrophagemannose
receptor/MMR), both previously associated with
DDCs, are expressed by macrophages in human leprosy lesions and tonsils as well as in TLR-activated
peripheral monocytes in vitro.36 Supporting these
results, recent data obtained from in situ immunofluorescence of DCs in the dermis of normal human
skin (NS) imposed the idea that resident DDCs in
NS are comprised of two phenotypically distinct
subsets: CD209 (DC-SIGN)+/CD163+/CD206+/CD68+
dermal dendritic-appearing macrophages and
CD1c+/CD11c+/CD208+ true DCs.310 Additional
evidence exists that FXIIIa is upregulated on DCs in
culture and rather reflects a specific marker for macrophages than for DCs.311,312 On the basis of these
findings careful revisions of the current literature
will be necessary in order to reevaluate the presence of CD209+FXIIIa+ dermal DCs.

Natural Killer T (NKT) Cells179

NKT cells are a distinctive T-cell population with
low frequency ranging from 0.01% to 1% of T cells
in peripheral blood. They have properties of NK
cells but, at the same time, express TCR / that,
in human beings, consists of an invariant a chain
(V24-J18) preferentially paired with a Vb11 chain.
Phenotypically, NKT cells are also defined by the
expression of CD45RO and CD161, indicating their
effector/memory function. These cells specifically
recognize certain tumor-cell-associated or bacterial
glycolipids in the context of CD1 molecules and are
therefore implicated in tumoricidal and bactericidal

Antigen Presenting Cells

Another DDC subset of normal human skin can be

defined by its CD141 (blood dendritic cell antigen 3/BDCA-3) expression. These DCs constitute
approximately 10% of all CD11c+ dermal DCs and
do not coexpress CD1c (BDCA-1).312 They express
TLR3, produce IL12p70 and IFN-, and excel CD1c+
DCs in their T-cell stimulatory capacity. Recent data
obtained from peripheral blood demonstrate their
capacity of cross-presenting Ag to cytotoxic T cells
after TLR3 ligation and, thus, suggest an important
role in activating cytotoxic T-cell responses.313
DDCs are derived from a common myeloid
precursor cell. Notably, it has been discovered that
DDCs proliferate constitutively in situ in murine
and human quiescent dermis,314 which indicates
that homeostatic cell division contributes to the
maintenance of this skin DC population. Interestingly, UV-induced cutaneous inflammation leads

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Chapter 10:

to a circulating dermal DC precursor replacement

of locally proliferating DDCs, which in contrast to
that of LCs, relies only on CCR2, but not on CCR6dependent cell migration.314 Studies on the ontogeny of human APCs in embryonic foreskin revealed
that at 9 week EGA MHCII+ DCs can already be
distinguished from MHCII+ macrophages by their
expression of the DC marker CD1c. These MHCIIhigh
DCs already exhibit the capacity of antigen uptake,
upregulate costimulatory molecules, and stimulate
T-cell proliferation.286 Under homeostatic conditions,
a predominant proportion of CD1c+/CD11c+ DDCs
is in an immature state and, accordingly, shows only
weak T-cell stimulatory capacity.312 However, their
immunostimulatory potential increases upon maturation/activation. Migration to the draining lymph
nodes (LN) is facilitated, as CD1c+/CD1a+ dermal
DCs from NS express CCR7 and egress the skin in
response to CCL19.315
Models for LC-Depleted Mice.
Two main models were constructed: (a) knockin
mice linking the diphtheria toxin receptor (DTR) to
the Langerin gene locus in order to induce transient LC ablation by administration of diphtheria
toxin276,316 and (b) transgenic mice that coordinately
express the diphtheria toxin subunit A (DTA) with
Langerin resulting in a constitutive and permanent
absence of LC.277 Using DTR mice, one group of
investigators316 demonstrated a diminished CHS
response in LC-free mice, supporting the long-prevailing concept317 that LCs are needed for optimal
contact sensitization. These findings are also inline
with the demonstration of cross-presentation of
keratinocyte antigens (also tumor-associated antigens) by LCs to T cells221 and underscore the role of
LCs in cutaneous immunosurveillance. In sharp contrast to these findings, the other researchers found
that the lack of LCs affects neither the sensitization
nor the elicitation phase of CHS276 or even demonstrated an amplification of the CHS response.277
Together with the observation that DDCs, before
LCs, leave the skin following sensitization, migrate
to the lymph nodes and populate separate areas
than LCs do,276 these results led to the hypothesis
that LCs are primarily concerned with downregulatory functions, whereas DDCs are mainly acting
as inducers of productive immune responses. The
validity of this concept gains support by studies
in mice with graft-versus-host disease318 and by
the finding that LCs are critical for the induction of
regulatory T cells by ultraviolet radiation (UVR).319

Innate and Adaptive Immunity in the Skin 13

The discrepancies in results obtained with the

different LC-depleted mouse models of CHS have
not been fully clarified, but may be due to the different timing of LC depletion in relation to hapten
treatment. The situation became further complicated by the identification of a Langerin+ cell
within the murine dermis. These cells can prime T
cells for hapten sensitization280 and display distinct
features as compared to LCs concerning anti-CCR2
reactivity, radiosensitivity, and the potential for
self-renewal.280282 But then again: mice are not men
and the exact roles of the various DC populations
in healthy and diseased human skin have yet to be
fully unraveled.
Plasmacytoid Dendritic Cells
pDCs develop in the bone marrow and are then
released into the blood stream. Recent experiments
in mice even suggest that pDCs and mDCs might
share a common DC precursor cell.232 Lately, an
important regulator of pDC development has been
identified, namely the transcription factor E2-2.
This E protein is involved in the pDC evolutional
pathway not only by controlling the synthesis of
other pDC transcription factors like SpiB, but also
by regulating genes that induce the production of
IFN, for example, IFN- regulatory factor 7 (IRF7).340
Under homeostatic conditions, pDCs are found in
peripheral blood (0.2%0.8% of peripheral blood
cells) and T cell-rich areas of secondary lymphatic
tissue. Originally characterized as CD4+CD123+ cells,
they lack surface expression of lineage markers for
B cells, T cells, NK cells and myeloid cells. Over the
last decade, pDC-specific markers such as BDCA-2
(CD303), BDCA-4 (Neuropilin-1) and ILT-7 (Ig-like
transcript 7) have been identified and are now
commonly used for their isolation from peripheral
blood or other tissues. While almost absent in
healthy tissue, large numbers of pDCs have been
identified in certain types of skin inflammation
such as viral infections,341 lupus erythematosus,342
psoriasis, allergic contact dermatitis, lichen planus,
and atopic dermatitis.343,344 Whereas pDCs enter
lymphoid organs from the blood stream through
high endothelial venules (HEV) using CD62L and
CCR7, their migration into inflamed skin has been
linked to different chemokine receptors, such as
ChemR23, CXCR3, and CXCR4, and their corresponding chemokines (Chemerin, CXCL9, CXCL10, CXCL11,
CXCL12).345348 Once within the skin, pDCs localize in
perivascular clusters with T cells and, depending on
their activation/maturation status, they upregulate
MHCII, acquire a dendritic cell morphology and
prime distinct T-cell responses.337,349

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Chapter 10:

Innate and Adaptive Immunity in the Skin

Immature pDCs lack surface expression of classical

costimulatory molecules such as CD80 and CD86
and are therefore incapable of inducing T-cell proliferation. Recently, it has been demonstrated that
pDCs constitutively express the inducible costimulator ligand (ICOS-L; B7-H2), which binds to ICOS on
T cells and, similar to CD28, generally has costimulatory impact on T-cell effector function. However,
ligation of ICOS-L on pDCs leads to the generation
of ICOS+FoxP3+ T reg cells.350 Further evidence for
a role of nonactivated pDCs in peripheral immune
tolerance comes from the observation that pDCs
have the capacity to prevent asthmatic reactions to
inhaled allergens by induction of T reg cells, which
in turn suppress antigen-specific effector T-cell
responses.351
Upon maturation, pDCs upregulate MHCII and
costimulatory molecules (CD80, CD86) and acquire
dendritic cell morphology. They selectively express
TLR7/8 and TLR9 and, upon endosomal ligation
of these receptors, acquire the capacity to mount
different immune responses through production
of a robust amount of type I IFN. Early experiments
already demonstrated that pDC-derived IFN-
promotes IFN--dominated Th1 cell responses,349
thereby linking innate and adaptive immunity. This
includes activation of mDCs, NK cells, and B cells,
which are converted into antibody-secreting plasma cells. In addition, IFN promotes the differentiation of monocytes into mDCs, which again induce
a strong CD4+ T-cell-mediated immune response,
and increases their ability to cross-present antigen
to CD8+ T cells. Recent findings demonstrate that
pDCs are prone to detect self-DNA through endosomal TLR9 when complexed with the antimicrobial
peptide LL37, which is overexpressed in psoriatic
skin lesions. Thus activated, pDCs produce type I
interferon and stimulate mDCs which may then
trigger a T-cell-mediated autoimmune response
and, consequently, may contribute to the development of psoriasis.19 Likewise, pDC-derived IFN-
plays a major role in the maintenance of diseasespecific symptoms of systemic lupus erythematosus.
Self-nucleic acids form complexes with autoantibodies against nucleic acids and are subsequently
transported to endosomal TLR7 and TLR9 in pDCs,
which again leads to continuous production of
IFN-.352 As a result, pDC-derived IFN-. initiates an
autoreactive T-cell response primed by activated
and matured mDCs. In addition, autoreactive B cells
are prompted to differentiate into autoantibody-secreting plasma cells.353 pDCs also have the capacity
to acquire effector functions upon TLR7 binding

with either synthetic (imiquimod) or natural (HIV,

influenza virus) ligands. Again, they upregulate
IFN- and, consequently, surface expression of
TNF-related apoptosis-inducing ligand (TRAIL) is
induced. TRAIL expression renders them capable
of cytotoxic activity toward virus-infected and
tumor cells expressing proapoptotic TRAIL receptors.324,354 Accordingly, pDCs were shown to induce
TRAIL-dependent apoptosis in HIV-infected TRAIL
R1-expressing CD4+ T cells.355 Interestingly, ligation
of BDCA-2 inhibits TRAIL production and cytotoxic
capacities of pDCs,356 indicating an important functional role of BDCA-2. Meanwhile several studies
have also shown the importance of pDC-derived
type I IFNs in cancer immunity, autoimmunity and
bacterial infections.357 In order to prevent a disproportionate host-harming IFN production, pDCs are
equipped with several inhibiting surface receptors
including BDCA-2, ILT7, FcRI358, and NKp44.359
When cultured with IL-3 and CD40L, pDCs do not
produce IFN-, but upregulate OX40L and prime
naive T cells to produce predominantly type II
cytokines like IL-4, IL-5, and IL-10.360 Nevertheless,
their ability to process/present exogenous antigen
appears to be rather limited as compared to their
myeloid counterpart, probably due to their limited
antigen uptake capacity. Recent evidence, however,
suggests that pDCs can phagocytize, process, and
present particular forms of exogenous antigen
when encapsulated in certain microparticles.361
This implies a new role of pDCs in the induction of
adaptive immunity stimulated by phagocytosed
exogenous particle-like structures. In fact, clinical
trials have been initiated using tumor-associated
antigen-pulsed pDCs as immunogens.362

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