Tissue-resident dendritic cells and diseases involving dendritic cell malfunction

International Immunopharmacology 34 (2016) 1–15

Contents lists available at ScienceDirect

International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp

Review

Tissue-resident dendritic cells and diseases involving dendritic cell malfunction☆ Keqiang Chen a,b,c,⁎, Ji Ming Wang b,⁎⁎, Ruoxi Yuan c, Xiang Yi b, Liangzhu Li b, Wanghua Gong b,d, Tianshu Yang a, Liwu Li c, Shaobo Su a a

Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA Laboratory of Inflammation Biology, Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0910, USA d Basic Research Program, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA b c

a r t i c l e

i n f o

Article history: Received 25 November 2015 Accepted 5 February 2016 Available online xxxx Keywords: Dendritic cells Resident DCs DC-related diseases Autoimmunity Cancer

a b s t r a c t Dendritic cells (DCs) control immune responses and are central to the development of immune memory and tolerance. DCs initiate and orchestrate immune responses in a manner that depends on signals they receive from microbes and cellular environment. Although DCs consist mainly of bone marrow-derived and resident populations, a third tissue-derived population resides the spleen and lymph nodes (LNs), different subsets of tissuederived DCs have been identified in the blood, spleen, lymph nodes, skin, lung, liver, gut and kidney to maintain the tolerance and control immune responses. Tissue-resident DCs express different receptors for microbeassociated molecular patterns (MAMPs) and damage-associated molecular patterns (DAMPs), which were activated to promote the production of pro- or anti-inflammatory cytokines. Malfunction of DCs contributes to diseases such as autoimmunity, allergy, and cancer. It is therefore important to update the knowledge about resident DC subsets and diseases associated with DC malfunction. Published by Elsevier B.V.

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . Tissue-resident dendritic cells (DCs) . . . . . . . . 2.1. Skin-resident DCs . . . . . . . . . . . . . 2.2. Blood-resident DCs . . . . . . . . . . . . 2.3. Lung-resident DCs . . . . . . . . . . . . . 2.4. Liver-resident DCs . . . . . . . . . . . . . 2.5. Gastrointestinal tract-resident DCs . . . . . 2.6. Kidney-resident DCs . . . . . . . . . . . . 2.7. Spleen-resident DCs . . . . . . . . . . . . 2.8. Lymph node (LN)-resident DCs . . . . . . . Diseases involving tissue-resident DCs . . . . . . . 3.1. Allergic asthma . . . . . . . . . . . . . . 3.2. Autoimmune diseases . . . . . . . . . . . 3.2.1. Rheumatoid arthritis (RA) . . . . . 3.2.2. Psoriasis . . . . . . . . . . . . . 3.2.3. Systemic lupus erythematosus (SLE) 3.3. Sarcoidosis . . . . . . . . . . . . . . . . 3.4. Inflammatory bowel diseases (IBDs) . . . . 3.5. Infectious diseases . . . . . . . . . . . . .

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☆ This project was funded in part by federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E and was supported in part by the Intramural Research Program of the NCI, NIH. This project was also supported in part by the grants from the National Natural Science Foundation of China (31470844). ⁎ Correspondence to: Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China. ⁎⁎ Corresponding author. E-mail addresses: [email protected] (K. Chen), [email protected] (J.M. Wang).

http://dx.doi.org/10.1016/j.intimp.2016.02.007 1567-5769/Published by Elsevier B.V.

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4.

Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Tumor infiltrating DCs initiate the antitumor immune responses 4.2. Apoptosis of DCs in tumor microenvironment . . . . . . . . 4.3. Dysfunctional DCs in tumor microenvironment . . . . . . . . 4.4. DC-based vaccines in cancer immunotherapy . . . . . . . . . 4.4.1. Design of DC-based vaccines . . . . . . . . . . . . 4.4.2. Route of delivery for antigen-loaded DC vaccines . . . 4.4.3. Lymph node homing of DC-based vaccines . . . . . . 4.4.4. Application of DC-based vaccines . . . . . . . . . . 5. Translating DC biology into medicine . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

2. Tissue-resident dendritic cells (DCs)

DC development takes place in the bone marrow and is a continuous process due to the requirement for replenishment of mature DCs in peripheral tissues. DCs can be divided into at least five broad groups based on phenotypic, functional and developmental criteria (Table 1). These groups include plasmacytoid DCs (pDCs), migratory and lymphoid tissue-resident CD8+ DC-like DCs, migratory and lymphoid tissueresident CD11b+ DCs, Langerhans cells and monocyte-derived DCs, which are derived from a range of progenitors [1–4]. Langerhans cells are generated from fetal liver and yolk sac during embryonic development [5,6], whereas common DC progenitors (CDPs) give rise to plasmacytoid DCs and other conventional DC subsets. Pre-DCs are downstream of CDPs and have lost the capacity to generate pDCs, but are capable of generating lymphoid tissue-resident CD8+ DCs and CD11b+ DCs [7] possibly with their migratory counterparts referred as to CD103+ and CD11b+ DCs, respectively, found in many tissues [8,9]. pDCs can also be derived from lymphoid-primed multipotent progenitors (LMPPs) of bone marrow origin [10]. The capacity of DCs to capture antigens from the environment is increased even when there is no overt infection or inflammation, probably allowing for silencing the immune system in the presence of harmless environmental antigens. In response to danger signals such as bacterial and viral PAMPs, DCs rapidly promote T cell-mediated immunity to selectively eliminate infected cells. After capturing antigens, DCs migrate through lymphatics to reach secondary lymphoid organs, where DCs present processed antigenic peptides to stimulate naïve T cells in the context of MHC molecule. There also is evidence showing steady-state migration of DCs into lymph nodes under physiological conditions, which may serve to generate tolerant T cells to self and nondangerous antigens. Viewing the complexity of DC system accumulated during the past decades, the aim of this review is to provide an overview of the recent developments in the understanding of the distribution of tissue resident DC subsets in different organs and the relevance of resident DCs to the pathogenesis of human diseases, including auto-immunity, inflammation, allergic diseases, and cancer.

2.1. Skin-resident DCs

Table 1 Mouse DC subtypes.a DC subsets

Phenotype

CD11cint, B220+ CD8α+, CD11blo/‐,CD103+/‐, Langerin+/‐, DEC205+, Sirpα‐, Clec9A+, XCR1+ CD11b+ DCs CD4+/‐,CD8‐,CD11b+, Sirpα+, DEC205‐ Langerhans cells CD11bint, EpCAMhi, Langerin+, DEC205+, CD103‐ Monocyte-derived CD11b+, DEC205+ DCs Plasmacytoid DCs CD8+ DC-like DCs

a

Ref. [1].

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9 9 9 9 10 10 10 10 10 11 11 11 11

DCs in the epidermis and dermis recognize invading pathogens and are dedicated antigen-presenting cells (APCs) to initiate both innate and adaptive immunity. Early studies revealed two main populations of DCs present in the normal skin: epidermal Langerhans' cells (LCs) and dermal (or interstitial) DCs (DDCs). They both express CD11c, MHC-class I, MHC II, CD1b, CD45, CCR6, IFN-γR, IL-1R1, IL-1R2, TNFR-2 and CD32. LCs also are CD324-, Birbeck granule- and CD207-positive; while DDCs do not express CD324, Birbeck granule and CD207, but CD11b, CD1d, CCR2, IL-2R2a, IL-7R, IL4R, CD64, CD206, CD209 and Factor XIII. However, DDCs were recently further divided into CD11b+ and CD103+ subsets (Or XCR1+ DCs). Mouse CD11b+ DCs are further divided into monocyte-derived counterpart (CD14+ DCs in humans) and pre-DCderived counterpart (CD1c+ DCs in humans). In human skin, DCs comprise up to four different subsets: Langerhans cells, CD1c+ DCs, CD14+ DCs and a newly identified CD141+ subset [11]. Therefore, Langerhans cells are found in human and mouse: human CD141+ DCs match mouse CD103+ dermal DCs and human CD1c+ DCs of pre-DC origin (blood borne precursor) and CD14+ DCs of monocyte origin combine to correspond to mouse CD11b+ dermal subset DCs. Mouse dermis additionally contains a minor population of cDCs known as doublenegative DCs that are XCR1− CD207− and express very low levels of CD11b [12,13]. This population expresses a DC lineage-specific transcription factor, ZBTB46, and the development depends on IFNregulatory factor 4 (IRF4) and FLT3L. In mouse, migratory counterpart of double-negative DCs is found in the skin-draining lymph nodes under both steady-state and inflammatory conditions with unknown specific functions. No human equivalent of mouse double-negative dermal DCs has been identified as yet (Table 2).

2.2. Blood-resident DCs Two main DC precursor subtypes are identified in human blood: DCs and pDCs. They are relatively immature and express only low levels of adhesion and costimulatory molecules. Blood DCs (0.26% in leukocytes) descend from the myeloid lineage and express blood DC antigen (BDCA)-1, CD11c, and Toll-like receptors TLR2, TLR4, TLR5, and TLR3. The cells secrete mainly IL-12 in response to bacterial components. pDCs (0.2% in leukocytes) express BDCA-2 (or CD303) and CD123, and are specialized in antiviral innate immune responses by producing copious amounts of type I interferons (IFN-γ) upon exposure of intracellular TLR9 and TLR7 to DNA and RNA viruses. In addition, a small third population (0.02% of leukocytes) of blood DCs are distinguishable based on the expression of CD11c and BDCA-3 (or CD141), but not BDCA-1, CD123 and BDCA-2 [14]. Mouse blood DCs are less well characterized with a majority of circulating MHC class II+ CD11c+ as pDCs and low

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Table 2 Skin-resident DCs in mouse and human.a Mouse

Human

Subsets

Other name

Langerhans cell CD103+ DC Monocyte-derived DC Pre-DC DN DC a

XCR1+ DCs, CD11b− CD207+ DC, CD11b− CD103+ DC CD11b+ DC XCR1− CD207− DC

Subset

Additional marker

Langerhans cell CD141+ DC Monocyte-derived DC CD1c+ DC ND

CD1a+ CD207+ XCR1+ CD14+ -

Ref. [13].

numbers of MHC class II+ CD11c+ and MHC class II− CD11c+ DC progenitors that give rise to CD8α+ and CD8α− DCs in lymphoid organs.

interstitium [28]. In normal human lung parenchyma, two subsets of DCs (CD11c+/BDCA-1+; and CD11c+/BDCA-3+) and one pDC subset (CD11c−/BDCA-2+) have been identified [29].

2.3. Lung-resident DCs 2.4. Liver-resident DCs DC compartment in the lung is composed of cells of various origins and functions to form a complex network of sentinels. Lung DCs can be categorized as conventional DCs, pDCs and monocyte-derived DCs (MoDCs), each representing an independent developmental lineage. Generally, conventional DCs and MoDCs are identified by high expression of the integrin CD11c and the major histocompatibility complex (MHC) class II. The cells are then categorized into populations that express the integrin CD103 or the integrin CD11b. Due to the fact that MoDCs share with CD11b+ DCs various commonly used markers, the Fc receptors CD64 and/or FcεRIα must further be used to distinguish those two subsets. On the other hand, pDCs are identified by intermediate level expression of CD11c as well as high level expression of the pDC marker PDCA-1 and B cell-associated marker B220 [15–17] (Table 3). DCs in an anatomical location in the lung also are helpful to define their traits. There is a network of airway DCs located immediately above and beneath the basement membrane of the respiratory epithelium [18,19]. DCs in the lung parenchyma are in larger numbers and are mostly within interalveolar septa [20]. A small number of DC subset is found in the bronchoalveolar lavage fluid (BALF). In BALF, 0.06% cells are pDCs [21]. In the absence of inflammation, DCs are distributed in an average density of several hundred cells per square millimeter of large airways with less than a hundred DCs per square millimeter in smaller intrapulmonary airways [18]. In mice, the largest DC population in the lung is the integrin αE (CD103) β7-positive and I-AhighCD11chighDCs, which reside in the mucosa, vascular wall of the trachea and large conducting airways. These DCs express a wide variety of adhesion and co-stimulation molecules, endocytose avidly, present Ag efficiently, and produce IL-12. They express high levels of the Langerhans cell marker Langerin and the tight junction proteins Claudin-1, Claudin-7, and ZO-2, while lacking the expression of CD11b [22]. CD103− CD11b+ CD11c+ myeloid DCs can be found in the submucosa of the conducting airways in particular in inflammation [23,24]. The lung interstitium accessible by enzymatic digestion also contains CD11b+ and CD11b− DCs that extravase alveolar lumen and migrate to the mediastinal lymph nodes (MLN) [25–27]. pDCs are CD11b− CD11cint cells and express SiglecH and bone marrow stromal Ag-1 (recognized by moAbs mPDCA-1 or 120G8). pDCs are predominantly found in the lung Table 3 Lung-resident DCs. DC subsets

Phenotype

CD103+ DCs CD11b+ DCs MoDCs

CD103+++, DNGR-1+++, CD207+, CD24+++, CD11c+++, F4/80+, MHC II+++, CD11b+ CD103+, Sirpα+, MerTK+, CD24++, CD11c+++, F4/80++, MHC II+++, CD11b+ Sirpα+, CD64+, MerTK++, CD24+, CD11c+++, Ly6C+, F4/80+++, MHC II+++, CD11b+++ PDCA-1+++, Siglec H+++, CD24+, CD11c+, Ly6C+, F4/80+, MHC II+, CD11b+

pDCs

The liver contains several types of APCs including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs) and DCs [30]. LSECs line the sinusoids and have a distinct morphology in comparison with vascular endothelial cells that line arterial branches as well as central and portal veins. In contrast with vascular endothelial cells, LSECs do not express CD31 (PECAM-1, pgIIa endothelial cell adhesion molecule), which is expressed at tight junctions of vascular endothelial cells and exhibit higher constitutive levels of CD54 (ICAM-1, intercellular adhesion molecule 1) and CD106 (VCAM-1, vascular cell adhesion molecule). Hepatocytes have been reported to act as APCs in certain situations although they are not considered as primary regulators of immune responses within the liver. Kupffer cells (KCs), the resident macrophages of the liver, patrol the portal venous system via sinusoidal lumen and can adhere to LSECs, occasionally causing temporary obstruction of sinusoid blood flow. In the normal liver, hepatic DCs typically reside around the portal triads and, like DCs in peripheral sites, are able to efficiently capture, process, and transport Ag to regional lymphoid tissues [31]. Freshly isolated hepatic DCs are predominantly immature, expressing surface MHC but few costimulatory molecules necessary for T cell activation. Compared with more mature bone marrow (BM) derived or spleen DCs, hepatic DCs poorly stimulate naïve allogeneic T cells [32–34]. Different markers used to identify rodent and human liver DCs are listed in Table 4. CD11c is a common but not universal marker for DC detection in mice. Other markers, such as CD205, have been used to identify specific murine DC subsets. Two principal subsets identified in mouse liver as well as in lymphoid tissues are the so-called myeloid (CD8a− CD11b+) and lymphoid related (CD8a+ CD11b−) subsets of DCs. These DCs are distinguished by their reciprocal expression of CD8a and CD11b and Table 4 Phenotype of liver DCs. Species Maturity

Markers

Immature CD11c+ CD40loCD80loCD86loMHC IIlo CD11c− CD11b+ CD11c+ CD11b− B220− CD11c+ CD205− F4/80− CD205+ OX2+ CD11b+ CD24+ CD44+ CD45+ CD11cloCD16/32lo CD40lo CD80lo CD86loCD205loF4/80lo Mature CD11c+ MHC IIhiCD86hi CD11c+ CD54+ CD205+ MHC II+ CD11bmod CD86modCD/CD18mod B220− CD3e− Gr1− Other CD205hi B220+ CD‐ CD19‐ Human Immature CD11c+ CD45+ MHC II+ CD83loCD86loMHC IIlo Mature CD200+ CD83+ CD86+ Mouse

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were initially thought to be distinct lineages and have diverse functions. Recent evidence has shown that these subsets derive from common precursors thus rigid lineage affiliations between these subsets may not exist. pDCs or type 1 IFN producing cells (a unique cell type of the haematopoietic system) have recently been identified in mouse lymphoid tissues. These DCs are CD11c+ CD11b− CD19− B220+ and Gr1+ and may play crucial roles in antiviral immunity. Whether they are present in normal liver has yet to be determined. In human liver, there are similar subsets of DCs with blood origin, which comprise 3 major nonmonocytic subpopulation: pDCs expressing CD303 (BDCA2) and lacking CD11c; and two myeloid CD11c+ subpopulations sets – CD1c+ DCs expressing CD1c (BDCA1) and CLEC9A+ DCs expressing CLEC9A as well as high levels of CD141 (BDCA3) [34].

Table 6 Phenotype of kidney DCs.a

2.5. Gastrointestinal tract-resident DCs

lack F4/80. Also, 5–10% kidney DCs lack both markers, but they express CD103 [8], suggesting their CD8-like DC properties distinguished by their ability to cross-present antigens to CD8+ T cells [9,44]. In human, kidney biopsies have identified CD11b-like DCs characterized by the expression of BDCA-1 marker [45,46]. Some of these DCs co-express lectin DC-SIGN and CD68, the latter is a macrophage marker similar to F4/80. Notably, about 20% of human kidney DCs express BDCA-2, a marker for pDCs. BDCA-2+ DCs from human kidney produce type I IFN in response to viral infection. In contrast, murine kidney DCs lack phenotypic markers for pDCs (Table 6). Examination of kidney DCs in situ in CX3CR1-GFP+ mice reveals that kidney DCs constitute a true anatomic surveillance network within the parenchyma rather than a random dispersion in steady state. In CX3CR1-GFP+ mice, stellate-shaped myeloid kidney DCs forms a contiguous network throughout the entire interstitium, encasing all nephrons. Myeloid kidney DCs that resemble pre-DC (analogous to the globular shape of resident pre-pDCs) are also present in low density within the mesangium of CX3CR1GFP/+ mice. Importantly, in normal human kidneys, a similar anatomic surveillance network of kidney DCs exists throughout the interstitium and mesangium. Therefore, in steady state, kidney DCs are positioned such that they respond immediately to “danger” or “tolerogenic” signals of self or nonself sources anywhere within the parenchyma.

DCs are present throughout the intestinal tract, including the lamina propria (LP) of the small and large intestines, isolated lymphoid follicles, Peyer's patchs (PPs), and mesenteric lymph nodes (MLN). In the small intestine, DCs were found in lamina propria and express high levels of CD11c and MHC II, whereas macrophages in lamina propria express low levels of CD11c and MHC II. Representative DC subsets and their functions are listed in Table 5 with some subsets overlapping in phenotype [35]. In PPs, there are at least 4 subsets of CD11c+ DCs based on the expression of CD11b and CD8a: CD11b+ CD8a−, CD11b− CD8a+, CD11b− CD8a−, and CD11bint CD8a+. MLN may contain 2 additional populations of DCs, CD11c+ CD4+ DC and CD4− CD8− DEC-205int DCs [36–39]. Traditionally, PPs are the main site for induction of mucosal immunity with the presence of B-cell and T-cell follicles. Specialized M cells pass particulate antigens from the lumen to APCs located in the subepithelial dome and in the interfollicular T cell regions [37,40]. In C57BL6 mice, LP of the small intestine is home to a higher frequency of DCs (11%) [41]. Functionally, LP DCs are divided into 2 major classes according to their ability to differentially activate lymphocytes, distinguished by the expression of CD103 [42]. CD103+ DCs are also found in MLNs and likely represent a population of DCs migrating from LP, since these cells are reduced in number in mice deficient in the DC homing chemokine receptor CCR7 (Ccr7−/− mice) [43]. 2.6. Kidney-resident DCs A distinct population of approximately 2% of the total glomerular cells has been identified in rat kidney. These cells express Ia (MHC class II) and surface Fc receptors. They display significant phagocytic capacity and potently stimulate primary mixed lymphocyte reaction (MLR), thus showing some phenotypic and functional features of DCs. In normal mouse kidneys, 90–95% of CD11c+ DCs are negative for CD8 and CD45RA (B220), indicating that the majority of mouse kidney DCs are of the myeloid lineage. Small numbers of lymphoid (CD11c+ CD8+ B220−) DCs are identified in the kidneys of mice but not human [13]. pDCs (CD11c+ CD8− B220+) are also detected in mouse kidneys. However, the complexity of mouse kidney DC subsets is high by phenotypic variability, since about 10–15% of kidney DCs express CD11b, but they Table 5 Small intestine-resident DCs in human.a DC subsets

Phenotype

CD103+ DCs CD103+ CD8+ DCs CX3CR1+ DCs Tip DCs TLR5+ DCs pDCs

CD11chi, MHC IIhi, CD103+, CD11b+ CD11chi, MHC IIhi, CD103+, CD8+, CD11blow CD11chi, MHC IIhi, CX3CR1+, F4/80+, CD11b+ CD11chi, MHC IIhi, TNF-α+, iNOS+, CD11b+ TLR5+, CD11chiCD11bhi, F4/80+ CD11cint, B220+, mPDCA1+

a

Ref. [35].

DC subsets Mouse CD11b-like DCs CD8α-like DCs Human CD11b-like DCs CD8α-like DCs pDCs a

Phenotype CD11chi, F4/80+(90%), CX3CR1+, CD11b+, CD207−, CD8α−, SIRPα+ CD11chi, CD11b−, CLEC9A+, XCR1+, CD103+, CD207+ CD11chi, F4/80+, BDCA-1+, CD207−, CD14+, SIRPα+ CD11chi, BDCA-3+, CLEC9A+, XCR1+, CD207−, CD14−, SIRPα−, CD1α+ BDCA-2+, CD11c−

Ref. [44,45].

2.7. Spleen-resident DCs In mice, splenic DCs constitutively express MHC class II and CD11c. They are classified into 3 major subsets including CD4+ CD8− CD11b+ DCs that localize mostly in the marginal zone and CD8+ CD4− CD11b− DCs mostly in the T-cell zone. The third CD4− CD8− CD11b+ subset DCs are called double-negative DCs [47] (Table 7). CD8+ DCs are specialized in MHC class I presentation, whereas CD4+ subset is specialized in MHC class II presentation. CD8+ DCs also cross-present cellassociated antigens, whereas CD4+ DCs are unable to do so. In the spleen, 5% DCs or their immediate progenitors are actively cycling at any given time [7,48]. 2.8. Lymph node (LN)-resident DCs LN DCs are more heterogeneous to include blood-derived lymphoid tissue-resident CD8+, CD4+, and double-negative spleen equivalent

Table 7 Spleen-resident DCs in mice.a DC subsets +

CD8 DCs CD8− DCs CD4− CD8− DCs a

Ref. [47].

Phenotype CD4− CD8highCD11b− CD205high CD4− CD8lowCD11b+ CD205high CD4+ CD8− CD11b+ CD205− CD4− CD8− CD11b+ CD205− CD4− CD8− CD11b+ CD205+

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DCs, and migratory DCs entering via afferent lymphatics that vary according to the draining site [38,47]. In human LNs, two populations of resident DCs and three main populations of skin-derived migratory DCs were identified in skin-draining LNs [49]. Resident DC subsets induce the production of both Th1 and Th2 cytokines by naive allogeneic T lymphocytes and also cross-present antigen without in vitro activation. Among migratory DCs, one subset was poor at both CD4+ and CD8+ T cell activation, whereas the other subsets induced only Th2 polarization. In human, skin-draining LNs host both resident and migratory DC subsets with distinct functional abilities [49]. 3. Diseases involving tissue-resident DCs It is clear that tissue-resident DC homeostasis requires constant replacement with new cells [15,50–52]. For example, in mice the kidney and heart DCs are replaced within 2–4 weeks after lethal irradiation. Whereas, in the vagina, airway epithelia, and gut the replacement of DCs is more rapid and occurs within 7–13 days. Tissue-resident DCs in cooperation with newly recruited circulation DCs, contribute to a variety of diseases including allergy, autoimmune, inflammation and cancer progression. Following are several major disease studies that involved the participation of tissue-resident DCs. 3.1. Allergic asthma Inhalation of harmless protein antigen in mouse lungs usually results in immunological tolerance in which when the antigen is subsequently given to mice with adjuvant e.g. the Th2 adjuvant alum, it no longer induces an immunological response that leads to inflammation [28,53]. There are two pathways to control the inhalational tolerance: by silencing Ag-reactive T cells as well as inducting and/or expanding regulatory T cells (Tregs) in the mediastinal lymph nodes (MLN) [53– 55]. The induction and/or expansion of Tregs in the mediastinal LNs are dominant and can be transferred to other mice. Lung-resident DCs are responsible for tolerance induction [54]. In the homeostasis, lungresident DCs ingest inhaled Ag and with up-regulated homing receptor CCR7, migrate to the draining LNs, where such DCs activate T cells to induce tolerance. CCR7-deficient mice fail to induce tolerance to inhaled innocuous environmental Ags due to impaired DC homing [54]. Under physiological conditions, activation of resident lung DCs is a common event leading to Th2 sensitization. It is therefore possible that under homeostatic conditions, the degree of DC maturation is constantly in check [17]. Th2 sensitization is inducible by intratracheal adoptive transfer of GM-CSF cultured bone marrow DCs, which most closely resemble mature monocyte-derived CD11b+ DCs. The tolerance is not inducible by Flt3L-cultured bone marrow-derived DCs, which more resemble immature steady-state resident DCs in LNs and the spleen [28]. pDCs is also responsible for tolerance induction in the lung. When pDCs are depleted from the lungs, tolerance to inhaled Ags is abolished. pDCs directly suppress the capacity of myeloid DCs to generate effector T cells. pDCs can also stimulate the generation of Treg cells, possibly in an inducible T-cell co-stimulator ligand (ICOS-L)-dependent manner. In mice depleted of pDCs, there was a release of extracellular ATP responsible for inducing myeloid DC maturation. Th2 sensitization to inhaled OVA was abolished when ATP signaling was blocked using a broad spectrum P2X and P2Y receptor antagonist suramin. One possible mechanism is that ATP indirectly controls DC function via changes in mast cell and eosinophil function. Mast cells, which release cytokines, PGD2 and sphingosine metabolites, and eosinophils, which release leukotrienes and eosinophil-specific enzymes, also regulate DC function. However, the exact conditions regulating ATP release in the lungs is unclear [56]. However, the normally tolerating properties of resident DCs are changed by cytokines as exemplified by studies of thymic stromal lymphopoietin (TSLP) in asthma. TSLP drives the maturation of human DCs from blood and skin to elicit unusual Th2 cells that secrete not

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only IL-4, -5 and 13 but also high levels of TNF. TSLP-treated mature DCs express OX40L/CD252/TNFSF4, a TNF family member. OX40L can promote T cells to develop a Th2-type of memory along with the production of allergic mediators such as prostaglandin D2 [57,58]. Following short-term allergen inhalation, there is a rapid recruitment of CCR2+ Ly6C+ myeloid DC precursors from the circulation to the airway mucosa [59,60]. In mouse or rat models of asthma, there is an 80-fold increase in the number of myeloid DCs in the airway mucosa layer and in bronchoalveolar lavage fluid [61–63]. The interaction between DCs and T cells may occur both locally in the airways and in secondary lymphoid tissues. In contrast to DCs in naive animals, airway DCs in OVAchallenged mice show a mature phenotype and form clusters with primed T cells in the airway mucosa that lead to further functional maturation of DCs [64]. Models of parasite-induced eosinophilic airway inflammation have defined a subset of long-lived CD11b+ CD11c+ F4/ 80+ cells with a prolonged antigen-presenting capacity [65]. Airway DCs produce a chemokine CCL17 that selectively attracts CCR4expressing memory Th2 cells to the lung to facilitate interaction with DCs [66]. However, local antigen presentation is not the only interaction between DCs and primed T cells in the airway. After antigen challenge of primed mice, there is an increased migration of airway DCs into MLNs where antigen presentation and T cell activation occur. Thus, inflammatory DCs are critical for promoting the progression of allergic airway disease [62–64]. Defects in DC function attenuate the development of OVA-induced airway inflammation in animal models. For example, in airway inflammation, a chemokine CCL2 is critical for the mobilization of DC precursors from BM to the circulation and subsequent migrate into the perivascular regions in the lung. It is therefore not surprising that mice deficient in the CCL2 receptor CCR2 (CCR2−/−) mice showed defective trafficking of antigen-loaded lung DCs associated with reduced Th2 responses and protection from OVA-induced airway inflammation [67–70]. Another G-protein coupled receptor Fpr2 is also involved to DC trafficking in mouse model of asthma as Fpr2−/− mice show markedly reduced severity in OVA-induced allergic airway inflammation associated with diminished recruitment of CD11c+ DCs into peribronchiolar regions of the inflamed lung and reduced Th 2 immune responses [71]. Further investigation revealed that an endogenous Fpr2 ligand CRAMP controls DC trafficking from the perivascular regions to the peribronchiolar regions in the inflamed lung during allergic asthma [72]. These observations establish a paradigm of sequential DC trafficking mediated by a chemoattractant receptor signal relay initiated by CCR2 followed by Fpr2 and CCR7 to complete the journey of DCs to LN for Th2 priming. The mechanisms of allergy involving lung-resident DCs and BMderived inflammatory DCs are illustrated in Fig. 1. 3.2. Autoimmune diseases Autoimmune diseases are chronic inflammatory conditions caused by inappropriate responses to self-antigens. In mouse models of autoimmune cardiomyopathy [73] and systemic lupus erythematosus (SLE) DCs bearing self-antigens are able to induce autoimmunity, in which antibodies are formed against several self-antigens, especially nucleoproteins [74]. pDCs and DCs in patients with autoimmune diseases show abnormal features of functionality [75,76]. In multiple sclerosis (MS), DCs show increased expression of co-stimulatory molecules such as CD80 and CD40, increased secretion of pro-inflammatory cytokines such as IL-12 and TNF-α, but decreased expression of PD-L1, indicating an active T cell priming [75,77]. Thus, a key feature in autoimmune diseases is the imbalance in the production of certain cytokines [58]. 3.2.1. Rheumatoid arthritis (RA) DCs have been found in synovium and joint fluid in RA, often in the center of a cluster of T cells [78]. These DCs express MHC II, costimulatory molecules CD40, CD80, CD86, adhesion molecules such

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Fig. 1. The Role of DCs in the pathogenesis of asthma. In asthma, allergen is taken up by DCs across the mucosal impermeable barrier. The epithelial cell derived cytokines and chemokines including IL-25, IL-33, TSLP also can stimulate resident DCs to change the tolerance properties. Activated resident DCs migrate from the lungs to the T-cell area of MLNs via CCR7, where mature DCs promote T cell differentiation and under certain circumstances generate Th2 responses. Following short-term allergen inhalation, there is a rapid recruitment of CCR2+ Ly6C+ myeloid DC precursors from the circulation to the airway mediated by a chemoattractant receptor signal relay initiated by CCR2 followed by Fpr2 and CCR7 to complete the journey of DCs to MLN for Th2 priming.

as DC-SIGN and chemokine receptors such as CCR7. DCs can polarize T cells into Th1 or Th2 phenotype depending on the cytokine environment. It is thought that the abundance of cytokines including IL-1, IL6, TNF-α, GM-CSF, IL-8 (CXCL8) and IL-10 in the rheumatoid synovium is involved in the migration and activation of DCs [79]. These DCs can stimulate T cells in an autologous but not allogeneic MLR. It has been reported that TNF-α plays an essential role in the pathogenesis of RA [80]. Excessive production of TNF may result in ectopic maturation of DCs that should otherwise mediate peripheral tolerance. DCs themselves may act as a major source of TNF. Since DCs are central to the pathogenesis of RA, DCs may be logical targets for treatment [81]. On the other hand, DCs themselves could be used to deliver therapeutic gene products in autoimmune disease. For example, since IL-4 is generally absent from the joint in RA, DCs genetically modified to express IL-4 have been used to treat or prevent collagen arthritis in mice with success [78]. 3.2.2. Psoriasis Psoriasis is a chronic inflammatory disorder characterized by an erythematous scaly plaque of the skin and is occasionally accompanied by systemic complications including cardiovascular diseases and metabolic syndrome. A number of CD11c+ myeloid (m)DCs are recruited and accumulated in the dermis of psoriatic skin [82]. Psoriatic mature mDCs are characterized by DC-lysosomal-associated membrane protein (DCLAMP) or CD83 expression. Those mature mDCs frequently aggregate with lesion-infiltrating T cells, which resemble the lymphoid-clusters of secondary lymphoid organs or inflamed peripheral tissues [82–86]. These cluster-forming mature mDCs could act as the cellular nidus to promote psoriasis progression by autoantigen presentation and activation of T cells [86]. Alefacept, a human lymphocyte function-associated antigen-3 (LFA-3) fusion protein, was used to block the interaction between co-stimulatory molecule LFA-3 and CD2 expressed on DCs and T cells, as a biological regimen to treat psoriatic patients and obtained clinical benefits accompanied with the decreased number of lesioninfiltrating DCs and T cells [82,87]. Another biological regimen,

Efalizumab, is used to inhibit cell-to-cell adhesion between T cells and DCs thereby reducing T cell activation [86]. High levels of iNOS and TNF-α can also be observed in psoriasis skin lesions [82,86]. CD11c+ mDCs, also called Tip-DCs, are unique cellular sources for iNOS and TNF-α in psoriatic dermis. Blockade of TNF-α using Etanercept led to a significant reduction in the severity of psoriasis [88], indicating that TNF-α-producing inflammatory mDCs are critically involved in the pathogenesis of psoriasis [86]. The role of DCs in the pathogenesis of psoriasis is summarized in Fig. 2. 3.2.3. Systemic lupus erythematosus (SLE) SLE is immunologically, characterized by the loss of tolerance to selfantigens, dysregulated autoreactive T- and B-cell activation, production of autoantibodies (auto-Abs) and perturbed cytokine activities. The serological hallmark of SLE is the prominent elevation of pathogenic auto-Abs against nuclear antigens including double-stranded DNA (dsDNA), nucleosomes and various small nuclear ribonucleoproteins (snRNPs),which causes the formation and deposition of immune complexes leading to tissue inflammation and damage in kidneys, skin, joints and central nervous system [89,90]. SLE appears to be associated with an increased production of type I IFNs [91]. Genomic studies of blood cells indicate that most if not all patients with SLE overexpress IFN-inducible genes [92,93]. Exposure of normal monocytes to SLE patient serum generates functional DCs. The effect of SLE patient serum is blocked by anti-type I IFN antibody [91]. The involvement of IFN in lupus pathogenesis is also supported by mouse studies, as known by the observation that progeny from mice with a null mutation of type I IFN receptor bred with lupus-prone mice exhibited decreased morbidity and prolonged survival. Type I IFN considerably accelerates the development of autoimmune symptoms in lupus-prone NZB/NZW mice [94]. Combination of type I IFN and GMCSF results in the differentiation of monocytes into mature DCs, which present antigens from dying cells into T cells to elicit immunogenic rather than tolerogenic responses [91]. Type I IFN has

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Fig. 2. The contribution of DCs to the pathogenesis of psoriasis. TNF-α and inducible nitric oxide synthase (iNOS)-producing DCs (Tip-DCs) are inflammatory DCs migrating from bone marrow to the psoriatic skins. Tip-DCs produce TNF-α and iNOS to enhance the psoriatic inflammation. Tip-DCs also produce IL-12 and IL-23, which promote Th1 and Th17 cell development and expansion. Th17 acts on keratinocytes via IL-22 and IL-17A to produce CCL20 and LL37. High level of CCL20 in epidermis recruits CCR6-bearing Th17 cells, which further activate keratinocytes to release CCL20 in a positive feedback manner. Psoriatic lesional self-RNA combine LL37 to generate self-RNA/LL-37 complex, which activates resident immature DCs to become mature DCs (DC-LAMP+). These DCs aggregate with T cells in the lesion via CCL19/CCR7 or CCL20/CCR6 interaction.

pleiotropic effects on multiple cell types. IFN-α/β lowers the threshold for B cell activation [95], enhances primary Ab responses, promotes isotype switching and immunological memory in vivo by direct stimulation on B and T cells and/or through DC-dependent mechanisms [96, 97]. pDCs play a central role in the pathogenesis of SLE. pDC derived IFNα directly promotes the differentiation of plasmablasts from activated B cells, and together with IL-6 induces plasmablasts to fully develop into CD38+ CD20− Ig-secreting plasma cells [98], promoting the production of auto-Abs [99]. pDCs are capable of rapidly producing large amount of

type-I IFNs 200–1000 times more than other immune cell types upon microbial challenge [100]. From SLE patients, the bone marrowderived pDCs exhibited activated phenotypes with higher expression of CD40 and CD86 and induced stronger T-cell proliferation [101], reduced ChemR23 chemokine receptor expression and enhanced migratory ability of pDCs, which are suggestive of an activated status of pDCs in SLE patients [102]. Apart from directly augmenting the functions of autoreactive T and B cells, type I-IFN also acts indirectly through promoting the differentiation of blood-derived monocytes and activation of mDC, which then up-regulates MHC-II and co-stimulatory

Fig. 3. pDCs and SLE pathogenesis. Auto-antigens, such as nucleic acids, nucleoproteins, LL37 and HMGB-1, combine auto-antibodies to form immune complexes (ICs), which activate pDCs via Fcγ receptors. ICs and Fcγ complexes were endocytosed and delivered to endosomes in DCs to activate TLR 7/9 for type-I IFN production. Type I-IFN promotes the differentiation of monocytes and maturation of DCs, which then up-regulate MHC-II and co-stimulatory molecules for autoreactive helper (Th) and cytotoxic (Tc) T cells, enhancing autoreactive B cell survival and proliferation. Type I-IFN also directly augments the functions of autoreactive T and B cells. Activated cytotoxic T cells induce systemic inflammation, tissue damage, cell apoptosis and necrosis, which can promote DC maturation. Type-I IFN induces neutrophil (Neu) apoptosis to release pDC-activating neutrophil extracellular traps (NETs).

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molecules for autoreactive helper (Th) and cytotoxic (TC) T cell activation; and enhances BAFF and APRIL expression for promoting autoreactive B cell survival and proliferation. In SLE pathogenesis, pDCs are activated by immune complexes (ICs) which are composed of auto-Abs clustering with auto-Ags released by necrotic/apoptotic cells via binding Fcγ receptors, endocytosed to activate TLR 7/9 to elicit type-I IFN production. ICs also induce platelet activation which further potentiates type-I IFN production in pDC through a CD40-dependent mechanism. ICs also are composed of neutrophilderived antimicrobial peptides and self-DNA produced by activated neutrophils in the form of web-like structures known as neutrophil extracellular traps (NETs) and efficiently triggered innate pDC activation via Toll-like receptor 9 (TLR9) [103]. Three series of oligonucleotide (ODN)-based inhibitors have been developed to inhibit Toll-like receptor (TLR) 9, TLR7 and both TLR7 and TLR9. Specificity of these inhibitors is confirmed by inhibition of IFN-α production by pDCs in response to DNA or RNA viruses, mammalian DNA or RNA, and ICs. These inhibitors of TLR7 or 9 signaling thus represent novel therapeutic agents with potential for the treatment of lupus [104]. The role of pDCs and type I IFN in the pathogenesis of SLE is summarized in Fig. 3. 3.3. Sarcoidosis Sarcoidosis is a noncaseating granulomatous disease [105], likely of autoimmune etiology that causes inflammation and tissue damage. In sarcoidosis patient BAL fluid, there was a 2-fold enrichment of myeloid DCs, which are immature and have decreased expression of maturation marker CD83 and CD86 [106]. In cutaneous sarcoidosis granulomas, immature DCs were accumulated in the lung [107]. In contrast to immature DCs found in the lung, many mature LAMP1+ DCs surround granulomas in lymph nodes, where DCs may actively present antigen and stimulate T cell proliferation [108]. There are two theories to explain the lack of DC maturation in the lung including short lung DC half-life and suppression by alveolar macrophage-derived anti-inflammatory cytokines [109,110]. IL-12 as a Th1 T cell-polarizing cytokine [111,112] is constitutively expressed by DCs at high levels in sarcoidosis patient BAL. IL-12 induces more IL-12 release by APCs further polarizing T cells toward the Th1 lineage. Similarly, IL-18 released by DCs/macrophages acts on T cells through IL-18R to up-regulate IL-12Rb2 and IFN-γ. IL-12 also induces IL-18R expression by Th1 T cells, therefore, there is a synergism between IL-12 and IL-18 that promotes sarcoidosis pathogenesis [113,114]. IFN-γ is also a highly expressed cytokine in sarcoidosis patient BAL [115]. IFN-γ may promote sarcoidosis pathogenesis through inhibition of macrophage peroxisome proliferators-activated receptor γ (PPARγ) [116], which is an important negative regulator of inflammation [117]. In steady-state, PPARγ is constitutively expressed by alveolar macrophages and promotes their phagocytosis and IL-10 production [118]. PPARγ also inhibits DCs from releasing TNFα, IL-12 and matrix metalloproteases (MMPs) [119]. In sarcoidosis, normally immunosuppressive alveolar macrophages may no longer be able to control inflammatory DCs, leading to excessive cellular and adaptive immune responses. MMP-8 and MMP-9 produced by activated alveolar macrophages are increased in sarcoidosis patient BAL without compensatory increase in the levels of tissue inhibitor of metalloproteinase. These MMPs thus cause lung damage and subsequent fibrosis [120]. IFN-γ induces the production of chemokines CXCL9, CXCL10, and CXCL11 by DC/macrophage to recruit T cells by activating the receptor CXCR3 on T cells [121,122]. These observations demonstrate sarcoidosis as an autoimmune disease promoted by self-antigen primed DC and macrophage primed Th1 responses. However, it is unclear about the nature of what immunosuppressive factors at end-organ sites that prevents DC maturation [105]. 3.4. Inflammatory bowel diseases (IBDs) IBDs, including Crohn's disease and ulcerative colitis, are chronic relapsing inflammatory diseases of the gastrointestinal tract [123,124].

Ulcerative colitis is the most common form of IBD [125] characterized by a continuous pattern of inflammation beginning in the rectum and extending progressively into the colon with exacerbated severity. Crohn's disease frequently develops a discontinuous pattern of inflammation, which may occur anywhere in the gastrointestinal tract with the distal small intestine and colon as the most common locations. DCs may play a pathogenic role in human IBD and mouse models. The function of mucosal DC subsets is tightly regulated by local microenvironment, which includes immune cells, nonimmune cells, and luminal bacteria, all of which participate in preserving intestinal homeostasis. Deregulation at different levels may affect DC function and cause intestinal pathology. Dysfunctional DCs may prime abnormal T cell responses to the enteric microbiota in organized lymphoid tissues and sustain T cell reactivity within the inflamed mucosa and release proinflammatory cytokines. Also, the imbalance between Th17 cell- and Treg-inducing DC subsets favors Th17 cell differentiation to drive inflammation. It is established that host genetic susceptibility plays an important role in the susceptibility to IBD. The first Crohn's disease susceptibility gene identified in 2001 was CARD15 which encodes nucleotide oligomerization domain receptor 2 (NOD2) [126,127] involved in autophagy pathways [128,129]. Autophagy is the process by which cytoplasmic components are sequestered into double membrane vacuoles to fuse with lysosomes. This process is important in microbial defense processes such as capture of intracellular bacteria during phagocytosis, antigen presentation, and inflammasome activation [130]. In human DCs, autophagy is induced through NOD2 stimulation and DCs isolated from Crohn's disease patients with ATG16L1 and/or NOD2 polymorphisms have defective autophagy in addition to altered antigen presentation and bacterial control [128]. Polymorphism in the autophagy gene IRGM promoter has also been linked to increased risk of developing Crohn's disease [131]. Thus, autophagy pathway may be a potential drug target for modifying DC function in the treatment of Crohn's disease. Preliminary results have shown that rapamycin, an antibiotic, which triggers autophagy by forming a complex with FKB12 to inhibit mTOR, is commonly used to up-regulate autophagy in cell culture [132]. Rapamycin has been successfully used to treat a patient with severe refractory Crohn's disease and shown protection in a murine colitis model [124,133,134]. 3.5. Infectious diseases DCs play an important role in host resistance to microbial infection. When microbial antigens are injected in combination with DCs, animals acquire adaptive immunity to a number of microorganisms including Borrelia burgdorferi, Chlamydiae, Leishmania major, Fungi, Toxoplasma gondii, Malaria and HIV. Conversely, DC depletion reduces responses to viruses such as CMV26, HSV-2 and LCMV27. In human, during bacterial sepsis and Dengue virus infection, a poor prognosis is associated with the absence of circulating DCs [58]. Several microbes have the capacity to actively block DC maturation. These include Coxiella burnetii, Salmonella typhi, anthrax lethal factor protein, Plasmodia, and Mycobacterium ulcerans mycolactone [135] as well as viruses such as vaccinia, herpes simplex, HIV, CMV, varicella zoster, HCV, Ebola/Marburg/Lassa fever and measles. An interesting exception is the capacity of attenuated yellow fever virus to infect and cause the maturation of DCs to present antigens to T cells [136]. For example, Hepatitis B and C viruses (HBV and HCV) infect liver and are major prognostic factors for hepatocellular carcinoma (HCC). After HBV or HCV infection, viral replication continues and particles are released into the circulation. DCs in the liver are capable of taking up viral antigens, processing and presenting the antigens to other immune cells. DCs secrete IL-12, TNF-α, IFN-γ and IL-10 to regulate the function of other immune cells. DCs also control the function of immune cells by production of co-stimulatory molecules [58]. Several reports have indicated functional alterations of DC subsets in HBV infection [137] with reduced ability of pDCs to secret IFN-γ in response to TLR9,

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but not to TLR7, agonists [138]. HBV antigen is responsible for pDC disability partly by up-regulating suppressor molecule SOCS-1 [138] with reduction in pDC frequency as well as their TLR9 expression [139]. HCV infection also impairs the ability of monocyte-derived DCs to stimulate allogeneic CD4 T cells [140,141], providing evidence for HCVinduced DC disability. 4. Cancer In malignant tumors, DCs display different phenotype and activity with either pro-tumorigenic or anti-tumorigenic functions. Although DCs may induce and maintain the antitumor immunity, DCs may also lose antigen-presenting activity in the tumor environment or polarize into immunosuppressive/tolerogenic regulatory DCs, which suppress effector T cells and support tumor growth. Therefore, better understanding DC biology in tumor environment is important for improving therapeutic effect by adjusting proper functioning of DCs in cancer patients [142]. 4.1. Tumor infiltrating DCs initiate the antitumor immune responses DCs infiltrating primary tumors (TIDCs) play an important role in antitumor immune surveillance, as TIDC migrating to the regional lymph nodes are capable of presenting tumor antigens to naïve tumor-specific T cells. It is generally believed that tumor-specific T lymphocytes activated in the lymph nodes by TIDCs are specialized in crosspresentation and reach tumors through inflammation-induced ligand/ receptor pairs. Immune responses also develop independently on secondary lymphoid organs in tertiary lymphoid structures associated with tumor mass. Recent reports revealed that under some conditions naïve T lymphocytes are able to infiltrate tumors and undergo activation, as delivery of lymphotoxin-α to mouse melanoma elicits the formation of a lymphoid-like tissue with the presence of clonally expanded T cells, not detected in the lymph nodes [143]. Naïve T lymphocytes can also reach tumors in the absence of inflammation and undergo proliferation and differentiation into cytotoxic effectors [144] stimulated by TIDCs. This may explain the presence of high levels of tumor infiltrating DCs and clinical significance. Infiltration of DCs into primary tumor lesions is associated with significantly prolonged patient survival and reduced incidence of metastatic disease in patients with oral, head and neck, nasopharyngeal, lung, bladder, esophageal, and gastric carcinomas [145]. Immunohistochemical (IHC) analysis of DCs in the tumor glandular epithelium and surrounding interstitial tissues demonstrated that the proportion of invading S100and HLA-DR-positive DCs was negatively correlated with the clinical stage and lymph node metastasis [146]. A low number of S-100+ TIDCs were more predictive of poor survival than lymph node involvement. In the majority of solid tumors, more TIDCs are present in welldifferentiated and less-invasive lesions which proved that TIDC density inversely correlates with tumor grade and stage with prognosis correlation [142]. CD1a and the maturation marker DC-LAMP were also detected on DCs in cutaneous malignant melanoma. CD1a+ DCs infiltrate melanoma cell nests and the surrounding stroma, while DC-LAMP+ mature DCs are generally found in the peritumoral areas, associated with lymphocytic infiltrates [147]. The number of CD1a+ and DC-LAMP+ DCs infiltrating melanoma shows strong inverse correlation with the thickness of melanomas lesions. High peritumoral density of DC-LAMP+ DCs is associated with significantly activated T cells and longer patient survival, therefore is considered as a sign of immune response associated with better outcome of the disease. 4.2. Apoptosis of DCs in tumor microenvironment The number of DCs in tumor environment represents cancer aggressiveness. The number of LCs is increased in benign skin lesions, whereas in malignant tumors LCs is not only markedly reduced or absent but also

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grossly stunted and deformed in outline [148]. Because the growth of a primary malignant melanoma is vertical, epidermal LCs are rare in the central part of the tumor [149]. Patients with early stage breast cancer have significantly higher proportion of apoptotic blood DCs as compared to healthy volunteers [150]. The presence of significantly high rate of apoptotic TIDCs in endometrioid adenocarcinoma compared to normal endometrium has also been reported. Cancer patients have lower levels of CD34-derived and CD14-derived DCs, similar to tumorbearing mice with low levels of bone marrow-derived DCs [142]. The higher rate of apoptotic DCs in malignant tumors is a result of multiple tumor-derived factors [151]. Several tumor-derived factors including gangliosides, neuropeptides, NO and other molecules may decrease the longevity of DCs. Gangliosides are a family of acidic glycosphingolipids [152]. GD3 is a minor ganglioside in most normal tissues except placenta and thymus [153], but is highly expressed during development and in pathological conditions, in particular in a variety of tumors such as tumors of neuroectodermal origin including melanoma, medulloblastoma, and neuroblastoma. GD3 as a tumor-associated ganglioside also is found in meningiomas, gliomas, soft tissue sarcomas, leukemias, colorectal and pancreatic carcinomas, metastatic breast and lung cancer [154]. GD3 gangliosides decrease the viable yield in DC culture and induce significant DC apoptosis at concentrations close to those detected in the sera from melanoma patients [155]. GD3 gangliosides enhance human epidermal LC spontaneous apoptosis [156]. MUC2 (Mucin 2) purified from conditioned medium of a colorectal cancer cell line increases apoptosis in human monocyte-derived DCs, which is partially mediated by the ligation of MUC2 mucins with Siglec-3 on DCs [157]. High mobility groupbox-1 (HMGB1) is a multifunctional cytokine secreted by cancer cells, which accelerates cancer cell growth, invasion and angiogenesis, and induces apoptosis of macrophages and DCs [158]. In human colon cancer invading into the subserosal layer, 50% nodal metastasis-positive cases showed higher HMGB1 concentrations and lower CD205+ DC numbers in lymph nodes than metastasisnegative cases [158]. 4.3. Dysfunctional DCs in tumor microenvironment Tumor cells have the capacity to evade immune surveillance and exploit DC function for their advantage [159]. In multiple myeloma (MM), DCs support the clonogenic growth of tumors. Peripheral blood DCs (PBDCs) from MM patients showed significantly lower expression of HLA-DR, CD40, and CD80 with impaired induction of allogeneic T-cell proliferation. Remarkably, such DCs are unable to present the patientspecific tumor idiotype to autologous T cells [160]. In murine melanoma specimens there are two populations of DCs, myeloid and plasmacytoid DCs [161]. Most of these DCs display immature phenotypes and do not present tumor-derived antigen to induce the proliferation of tumorspecific CD4+ and CD8+ T cells [161,162]. MUC-1 is overexpressed and secreted by breast cancer cells. MUC-1 is endocytosed by DCs but mostly retains in early endosomes, leading to its inefficient processing and presentation to T cells [163,164]. Furthermore, MUC-1 inhibits the capacity of DCs to secrete IL-12, thereby skewing the development of T-cell responses toward Th2 [165]. In melanoma tumor derived IL-10 interferes with DC differentiation and maturation, yielding tolerogenic DCs that induce tumor antigen-specific anergy. IL-6 secreted by breast cancer cells skews monocyte differentiation into macrophages but not DCs. At the early stages of tumorigenesis, immune response may be misled and used to promote cancer development. In breast cancer immature DCs are attracted into the tumor bed, while mature DCs are confined to peritumoral areas. DCs at tumor sites skew CD4+ T-cell differentiation toward T cells secreting high levels of Th2 (IL-4 and IL-13) cytokines, which promote early tumor progression. IL-13 secreted by such T cells appears to be responsible for the tumor growth, as blocking IL-13 partially inhibits tumor growth in a humanized mouse model of breast cancer [166]. Tumor cells may also educate DCs to activate

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suppressive T cells, such as FOXP31 [167] and IL-13-producing CD41 T cells [166] and natural killer T cells (NKT cells). In addition, tumor cells also can express IL-6, VEGF (vascular endothelial growth factor) and IL-10, which suppress DCs through STAT3 signaling [79].

4.4. DC-based vaccines in cancer immunotherapy A central tenet of DC-based cancer immunotherapy is the generation of antigen-specific cytotoxic T lymphocyte (CTL) responses. Tumorassociated antigens (TAA) and DCs play pivotal roles in this process. Other factors such as the site and frequency of injection; and the ability of DCs to migrate to lymph nodes also are important components of successful DC therapy.

4.4.1. Design of DC-based vaccines Large numbers of DC can easily be generated in closed systems from the monocyte fraction of the peripheral blood by adding GM-CSF and IL4 to the culture medium. Further maturation may be achieved by adding cytokines such as TNF-α, prostaglandin E2, IL-1b, IL-6 or monocyteconditioned medium [168]. Two approaches to DC-based vaccines are being developed: antigen-loaded ex vivo-generated DCs and in vivo DC targeting. In vaccines of antigen-loaded ex vivo-generated DCs, different strategies have been developed to load DCs with TAA, including synthetic peptides derived from the known antigens [169], tumor lysates [170], tumor RNA [171], and dying tumor cells [172] to induce antigenspecific immune responses. These DCs have been concomitantly treated with conditioning factors such as a standard mixture of cytokines (TNFα, IL-1β, IL-6, and PGE2) or Toll-like receptor (TLR) ligands that induce DC maturation to convert them into potent APCs. An alternative approach to generating ex vivo-modified DCs is to transduce DCs in vivo. This approach has been demonstrated in a mouse system by using lentiviral vectors encoding GFP (GFP-LV) [173]. After subcutaneous GFP-LV administration, transduced DCs and lymphocytes are detected in the draining lymph node for up to 10 days and after two months in splenic cells with generation of longterm effective CD8+ T cell responses [173]. TAA can be more specifically targeted to endogenous DCs by coupling the antigen to antibodies against DC receptors (DEC-205, DC-SIGN, DNGR-1). For example, coupling the human mesothelin antigen to an antibody specific for murine DEC-205 resulted in the generation of both cellular and humoral responses in mice, although additional adjuvant signals (poly I:C and anti-CD40) are required [174]. Vaccines comprising antigen coupled to TLR ligands also lead to efficient CTL activation by endogenous DCs [175]. Other in vivo targeting approaches are directed toward generating a predominantly antibody response as the presence of antibodies against certain melanoma-associated gangliosides has been associated with increased disease-free patient survival.

4.4.2. Route of delivery for antigen-loaded DC vaccines Several different routes have been tested in clinical trials including intravenous, intradermal, intralymphatic, intranodal, intratumoral and subcutaneous delivery [176–178]. iDCs and mDCs delivered intravenously initially home to the lungs, followed by localization to the liver and spleen, but undetected in lymph nodes or tumor [177,179]. Subcutaneous DC delivery was ineffective for promoting DC migration to lymph nodes [177], whilst DCs injected intradermally are able to migrate to draining lymph nodes, albeit very inefficiently with most remaining at the injection site [178]. By intranodal injection, DCs could be detected in adjacent nodes, although the rate of DC migration is highly variable [178]. mDCs are able to penetrate deep into T cell areas and interact with T cells, while iDC remained on the periphery [178]. Intralymphatic delivery may be anatomically more efficient than other methods, as DCs migrated rapidly to regional lymph nodes [176,179].

4.4.3. Lymph node homing of DC-based vaccines DC migration from peripheral tissues to lymph nodes to initiate T cell priming, is a complex process involving chemokines (e.g. CCL3, CCL4, CCL20, CCL19, CCL21) and their receptors (e.g., CCR1, CCR5, CCR6 and CCR7), adhesion molecules, matrix metalloproteases and lipid mediators (e.g., sphingolipids, PGE2) [178]. Effective DC therapy most probably requires the efficient entry of administered DCs to lymph nodes, but the complex maturation and migration processes in vivo may be difficult to replicate in ex vivo-generated DCs. Following DC vaccine injection, only less than 5% of the cells reach lymph nodes [180]. Some tumor antigens such as allogeneic melanoma-derived cell lysate (referred to as TRIMEL) induces a phenotypic maturation and increases the expression of surface CCR7 on TAPCells (tumor-antigen-presenting cells), enhancing their migration in vitro, as well as their in vivo relocation to lymph nodes [170]. Multiple intradermal injections with small amounts of DC-based vaccine, de facto targeting multiple lymph nodes, may improve the homing of DCs to lymph nodes and increase the clinical efficacy of DC-based immunotherapy [181]. A recent report showed that preconditioning the vaccine site with tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumor-antigen-specific DCs [182]. 4.4.4. Application of DC-based vaccines DCs have been the subject of numerous studies seeking new immunotherapeutic strategies against cancer. The expanding knowledge of DC immunobiology and the definition of the optimal characteristics for antitumor immune responses have allowed a more rational development of DC-based immunotherapies in recent years. The following is a brief overview about the application of DC-based vaccines in tumor treatment. A. Breast cancer: A preclinical study demonstrated that immunization with DCs transfected with an adenovirus encoding HER2 protein delayed the onset of spontaneous HER2/neu over-expressing mammary tumors in BALB/c transgenic mice (BALB-neuT mice expressing the rat neu oncogene under the control of a chimeric mouse mammary tumor virus) [183]. Among six patients with breast or ovarian cancer immunized subcutaneously with DCs loaded with two peptides derived from HER2, the tumor in one patients was stabilized for 8 months [184]. In another clinical trial, 13 patients with HER2 overexpressing tumors were injected with DCs loaded with HERs. Immunized patients developed a specific immune response against the peptides with high levels of CD4+ T cells. Surgically measured tumor size was smaller than pre-therapeutic size measured by MRI [185]. B. Glioma: DC-based immunotherapy successfully induced an antitumor immune response and increased the survival of patients. The therapy was safe without major side effects [186]. It has been reported that the overall survival of patients with grade IV glioma was 480 days following DC-based vaccine treatment significantly superior to control group [187,188]. C. Melanoma: 24 patients with metastatic melanoma phase II were injected subcutaneously into the inguinal region with DCs pulsed with 5 melanoma-associated synthetic peptides. The overall survival analysis revealed a significant prolonged survival of patients given with DC vaccine. There were no major side effects of the therapy [189]. D. Prostate cancer (PCa): 37 patients with local recurrence of prostate cancer after primary treatment failure were given 6 iDC-based vaccines of HLA-A2-restricted PSM-P1 and PSM-P2 (prostate specific membrane antigen) at 6-week intervals. One complete responder, 10 partial responders, a 50% reduction of PSA (prostate-specific antigen) and a significant resolution in lesions were observed [190,191]. In another Phase II trial, 33 patients with hormone-refractory metastatic PCa, 6 partial and 2 complete responders were identified [192,193]. Following delivery of six PSMA4-loaded mature DC vaccines to 3 patients intradermally at biweekly intervals, partial remission, but no CTL responses against PSMA4 were observed [194]. In another clinical

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trial, following delivery of mature DCs loaded with PSMA4 in combination with peptides from other TAs (tumor antigens), 50% patients with hormone-refractory cancer showed a transient decline in PCa serum marker PSA [195]. E. Neuroblastoma: 4 patients with follicular B-cell lymphoma who received a series of 3 or 4 injections of DCs exposed to autologous tumor antigens displayed cellular response to tumor proteins, which sustained for several months after the vaccination [196]. One patient with relapsed neuroblastoma after completion of standard therapy for neuroblastoma, including multiagent chemotherapy, tumor resection, stem cell transplantation, radiation therapy, and anti-GD2 monoclonal antibodies, was given the chemotherapy agent decitabine to upregulate cancer testis antigen expression, followed by a DC-based vaccine targeting the cancer testis antigens MAGE-A1, MAGE-A3, and NY-ESO-1. After 3 cycles of decitabine and DC vaccine, the tumor in this patient showed complete remission with an increase in MAGE-A3-specific T cells [197].

5. Translating DC biology into medicine DCs play a central role in host defense but also initiating many diseases. DCs either intensify or subdue T-cell responses, depending on the circumstances in which active responses or tolerance should be induced to provide opportunities for therapies aimed at the stream events triggered by DCs. A patient's response to pathogenic factors involves a myriad of processes orchestrated by DCs that control antigen presentation and clonal selection (the recognition repertoire) as well as lymphocyte expansion, differentiation and memory (the response repertoire). Each feature of DCs is an intricate area from which a deeper understanding of diseases and hypothesis of intervention should be developed. Our knowledge of DC biology is likely to be markedly extended to dissect the pathogenic processes of diseases for prevention and treatment. Especially, progress has been made in DC biology of mice, including isolated DCs and highly selected populations of T cells with a single transgenic antigen receptor. However, DCs used to therapies need to take into consideration of the control of immune responses including in situ in intact animals, better within the natural immune repertoire, using clinically relevant antigens, and with new adjuvants that act on DCs in defined ways [58]. It should be reminded that immune systems of mice and men differ in considerable aspects and more studies are required in patients because many pathogenic factors, tumors, microbe, allergen, stimulus for autoimmune or autoinflammatory disease are not easily or completely to be modelled in mice. Nevertheless, existing evidence of the potential effectiveness of DC therapy, in particular in cancer, provides optimism for future investigation and development. Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. Acknowledgement We thank Dr. J. J. Oppenheim for critically reviewing the manuscript; Ms. S. Livingstone for secretarial assistance. References [1] W.R. Heath, F.R. Carbone, The skin-resident and migratory immune system in steady state and memory: innate lymphocytes, dendritic cells and T cells, Nat. Immunol. 14 (10) (2013) 978–985. [2] E. Segura, E. Kapp, N. Gupta, J. Wong, J. Lim, H. Ji, W.R. Heath, R. Simpson, J.A. Villadangos, Differential expression of pathogen-recognition molecules between dendritic cell subsets revealed by plasma membrane proteomic analysis, Mol. Immunol. 47 (9) (2013) 1765–1773.

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