innate and adaptive immunity in the skin

Copyright McGraw-Hill Companies, Inc. All rights reserved.

Chapter 10Innate and Adaptive Immunity in the SkinRobert 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, includ-ing 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 keratino-cytes.

other MedIators.

Other secreted protein mediators that can be syn-thesized 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 en-semble of lipid mediators regulating inflammatory and immunologic reactions. They can produce and release the cyclooxygenase product prostaglandin E2, which has both proinflammatory and immuno-suppressive 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 chemoattrac-tant leukotriene B4, the proinflammatory 12-lipoxy-genase product 12(s)-hydroxyeicosatetraenoic acid, and 15-hydroxyeicosatetraenoic acid, an anti-in-flammatory and immunosuppressive metabolite of the 15-lipoxygenase pathway.

Another group of biologic response modifiers originating in keratinocytes and other epider-mal 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 oligomer-ization 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 peptidogly-can whereas NOD2 recognizes muramyl dipeptide (MDP), which is a breakdown product of peptido-glycan 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 transcrip-tion of host genes involved in innate and acquired immune responses. In addition, NOD2 can also activate the inflammasome leading to the pro-teolytic 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 infec-tion.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 camptodac-tyly.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

10 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 granulocytemac-rophage 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 acces-sory 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. Follow-ing 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 IIrestricted 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 con-trary, 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 apop-tosis cascade in the target. The second mechanism involves the release of cytoplasmic granules pres-ent 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 contribut-ing 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 contrib-ute 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 non-lymphoid 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 Sec-tion Functionality), human DN T reg cells seem to exert their suppressive function in an antigen-specific 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 trogocy-tosis (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

Chapter 10: Innate and Adaptive Immunity in the Skin 11


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 per-formed 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 posi-tive 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 direc-tion.140,141 In addition, several studies demonstrated that these cells function as antigen-specific effec-tor 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, indi-cating 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 expres-sion 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

of the IL-7 receptor (CD127) on naive T cells. FoxO1-deficient 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 un-dergo 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 gen-erated: 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 long-term 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 re-sponsiveness 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 pe-ripheral 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 repre-sent a transitory population rather than a distinct cell type, ending with the development of central memory T cells.153 Conversely, central memory T



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 differenti-ate into effector memory T cells upon secondary antigen challenge.154 In contrast, IL-15 seems to play a negligible role in promoting effector memory dif-ferentiation during primary immune responses, but it is apparently essential for the survival of effector memory T cells after pathogen clearance.154

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 epider-mis 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 stimu-lation with TGF- and IL-4 and do not express any of the established transcription factors for T-cell dif-ferentiation, suggesting a new lineage of T cells. IL-9, originally associated with Th2-dominated respons-es, 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.

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

host responses (see Section CD1-Dependent Anti-gen Presentation). On antigenic stimulation, NKT cells produce large quantities of cytokines, particu-larly IL-4 and IL-10, and can use them to suppress Th1 responses. The biologic relevance of these in vi-tro 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

antIgen presentIng cells

Further Studies of DDCs.Investigation of C-type lectin expression on DDCs demonstrated that CD209 (DC-specific intercellular adhesion molecule 3 grabbing nonintegrin mol-ecule/DC-SIGN) and CD206 (macrophagemannose receptor/MMR), both previously associated with DDCs, are expressed by macrophages in human lep-rosy lesions and tonsils as well as in TLR-activated peripheral monocytes in vitro.36 Supporting these results, recent data obtained from in situ immuno-fluorescence 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 mac-rophages 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 pres-ence of CD209+FXIIIa+ dermal DCs.

Another DDC subset of normal human skin can be defined by its CD141 (blood dendritic cell anti-gen 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. Interest-ingly, UV-induced cutaneous inflammation leads

Chapter 10: Innate and Adaptive Immunity in the Skin 13


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 CCR6-dependent cell migration.314 Studies on the ontog-eny 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 matu-ration/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 tran-sient 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-pre-vailing 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 anti-gens) by LCs to T cells221 and underscore the role of LCs in cutaneous immunosurveillance. In sharp con-trast to these findings, the other researchers found that the lack of LCs affects neither the sensitization nor the elicitation phase of CHS276 or even dem-onstrated 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 downregula-tory 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

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 dif-ferent timing of LC depletion in relation to hapten treatment. The situation became further com-plicated 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 CellspDCs 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 correspond-ing 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



Immature pDCs lack surface expression of classical costimulatory molecules such as CD80 and CD86 and are therefore incapable of inducing T-cell pro-liferation. Recently, it has been demonstrated that pDCs constitutively express the inducible costimu-lator ligand (ICOS-L; B7-H2), which binds to ICOS on T cells and, similar to CD28, generally has costimu-latory 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 plas-ma cells. In addition, IFN promotes the differentia-tion 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 endo-somal 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 develop-ment of psoriasis.19 Likewise, pDC-derived IFN- plays a major role in the maintenance of disease-specific symptoms of systemic lupus erythematosus. Self-nucleic acids form complexes with autoanti-bodies 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-se-creting 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 recep-tors.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 func-tional 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 dispro-portionate 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

innate and adaptive immunity in the skin

Documents