Norimitsu Kadowaki

Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan

TABLE OF CONTENTS

1. Abstract

2. Introduction

3. Human DC subsets

4. Developmental origin of mDCs and pDCs

5. Functions of mDCs and pDCs in innate immunity

6. Induction of different types of adaptive T cell responses by mDCs

7. Induction of different types of adaptive T cell responses by pDCs

8. Application of human DC subsets to immunotherapy

9. Summary and perspective

10. References

1. ABSTRACT

Induction of appropriate types of innate and adaptive immune responses depending on the nature of antigens is crucial to cope with a variety of pathogens and concurrently to avoid pathological reaction to self antigens. Recent studies have been elucidating that the diversity of immune responses is critically controlled by dendritic cells (DCs). Two DC subsets have been identified in humans: myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). The DC subsets recognize different microbial pathogens by expressing distinct repertoires of Toll-like receptors, and induce different types of innate and adaptive immune responses depending on environmental factors. Particularly, pDC precursors produce vast amounts of type I interferons in response to viruses and thus play an important role in anti-viral immunity. In addition, type I interferons derived from pDCs are instrumental in activating mDCs. Elucidating cellular and molecular mechanisms by which functions of the two DC subsets are modulated will lead to understanding the pathogenesis of various immune-related diseases and to developing novel immunological therapies.

2. INTRODUCTION

The immune system has evolved to eliminate a variety of microbial pathogens and at the same time to avoid responding to self antigens and innocuous antigens. Elucidating how this demanding task is accomplished is the main theme of immunology. Recent studies have been revealing that dendritic cells (DCs) are deeply involved in the process of differential responses to different types of antigens(1).

During innate immune responses at the site of infection, immature DCs located in inflamed tissues incorporate pathogens, and become activated in response to pathogens themselves and proinflammatory cytokines. Thereafter, the activated (also called mature) DCs migrate to draining lymph nodes and stimulate naïve T cells to differentiate into functionally competent effector T cells. Importantly, such T cell responses, especially those of CD4⁺ T helper (Th) cells, are heterogeneous; naïve CD4⁺ T cells differentiate into effector Th cells that produce different combinations of cytokines. These divergent Th cell responses, the prototypes of which are called Th1 and Th2 responses, induce different types of immune responses appropriate to eliminate given pathogens. On the other hand, naïve CD4⁺ T cells are able to develop into immunosuppressive T cells that inhibit immune responses to self antigens(2). How these different types of T cell responses are induced after the interaction with DCs is an important issue to understand the pathogenesis of various immune-related disorders and to develop novel immunological therapies.

In humans, DCs are composed of two subsets: myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). Recent studies have revealed that these DC subsets perform different functions in both innate and adaptive immune responses. At the same time, both of the DC subsets have functional plasticity to induce appropriate T cell responses depending on the types of stimuli. In this review, I discuss the diversity of DC subsets in humans from the perspective of their roles in (1) innate and adaptive immune responses and (2) tumor immunotherapy.

3. HUMAN DC SUBSETS

In human peripheral blood, two DC subsets have been recognized based on the expression of CD11c(3). The CD11c⁺ cells in blood express myeloid markers such as CD13, CD33, and CD11b(3), whereas the CD11c^- cells do not express significant levels of myeloid markers(3). Freshly isolated CD11c^- cells have plasmacytoid morphology with well developed rough endoplasmic reticulum and Golgi apparatus(4). The CD11c⁺ DCs are generally called myeloid DCs (mDCs) based on the expression of myeloid markers, whereas CD11c^- DCs are called plasmacytoid DCs (pDCs) based on its plasmacytoid morphology at the DC precursor stage. mDCs are subdivided using several markers: BDCA-1 (CD1c), BDCA-3, and CD16(5, 6).

In addition to these primary DC-committed cells, it is well established that monocytes differentiate into immature DCs in the presence of granulocyte-macrophage colony stimulating-factor (GM-CSF) plus interleukin (IL)-4(7), or GM-CSF plus interferon (IFN)-alpha (8). It has been reported that mDCs in blood develop macrophage morphology as well as the expression of butyrate esterase and CD14 in response to macrophage-colony stimulating factor (M-CSF)(9), suggesting that at least a subpopulation of mDCs in blood is capable of differentiating into macrophages and is thus related to monocyte-derived DCs in terms of cellular origin. However, the precise relationship between mDCs in blood and monocyte-derived DCs remains to be determined. Here we designate CD11c⁺ mDCs in peripheral blood as "blood mDCs", and blood mDCs and monocyte-derived DCs collectively as "mDCs".

4. DEVELOPMENTAL ORIGIN OF mDCs And pDCs

The developmental origin of pDCs has been intensively studied. Initially, pDCs were considered to have lymphoid origin, based on the lack of myeloid markers(3, 4), the expression of mRNA for several lymphoid-related molecules (pT alpha, CD3, RAG1), and D-J rearrangement of a TCR beta gene locus(10). However, using an in vitro culture system, it has been shown that human pDCs can derive from both common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs)(11). Recently, using an in vivo system in which human CMPs and CLPs are transferred to immunodeficient mice, it has been shown that both CMPs and CLPs can give rise to pDCs as well as mDCs, and that transcriptional signatures of both DC subsets are preserved irrespective of their cell lineage origin(12). These studies suggest that DCs use unique developmental programs that cannot be categorized into the conventional myeloid or lymphoid pathway. It remains to be determined whether common mDC/pDC precursors exist.

5. FUNCTIONS OF mDCs AND pDCs IN INNATE IMMUNITY

Although type I IFN is the first cytokine reported and is essential in anti-viral immune responses(13), identification of the main producers of type I IFN in human blood had been elusive(14). We(15) and others(16) have found that pDC precursors produce vast amounts of type I IFNs (IFN-alpha/beta/omega), especially IFN-alpha (17), upon viral stimulation, thus representing the long-sought, main producers of type I IFNs in human blood. After producing type I IFNs upon viral stimulation, pDC precursors develop to DCs(17). During this process, pDC precursors produce most of the type I IFNs within 24 hours (18). Type I IFNs produced by pDC precursors are likely to play a crucial role in anti-viral immune responses(19).

Recent studies have revealed that the recognition of pathogen-associated molecules by cell types in the innate immune system through Toll-like receptors (TLRs) is the essential step towards the induction of innate immune responses followed by adaptive immune responses(20). Thus, we compared the expression patterns of TLR mRNA in different subsets of antigen-presenting cells (APCs), i.e. monocytes, blood mDCs, and pDC precursors(21). Importantly, pDC precursors exhibit distinct expression profiles of TLRs compared with monocytes and blood mDCs (21)(Figure 1). Strong expressions of mRNA were found in monocytes for TLR1, TLR2, TLR4, TLR5, and TLR8; in blood mDCs for TLR1, TLR2, TLR3, and TLR5; in pDC precursors for TLR7 and TLR9. Thus, myeloid APCs share several TLRs, whereas pDCs express distinct TLRs. Accordingly, monocytes respond to TLR2 ligands (peptidoglycan from gram-positive bacteria and lipoteichoic acid from various types of bacteria) and TLR4 ligand (lipopolysaccharide (LPS) from gram-negative bacteria) to produce TNF-alpha and IL-6(21). Blood mDCs respond to TLR3 ligand (poly I:C mimicking double-stranded RNA in virus-infected cells) to produce IFN-alpha/beta and IL-12p70(21, 22). pDC precursors respond to TLR7 ligand (anti-viral reagents imidazoquinolines(23) and viral single-stranded RNA as a physiological ligand(24, 25)) and TLR9 ligand (unmethylated CpG DNA from viruses and bacteria) to produce IFN-alpha(21, 22). Studies using murine pDCs have shown that TLR9 is responsible for the recognition of viruses by pDC precursors(26, 27). Taken together, myeloid APCs (monocytes and blood mDCs) mainly recognize bacterial components and produce proinflammatory cytokines tumor necrosis factor (TNF)-alpha, IL-6, IL-12, whereas pDC precursors mainly recognize viral components and produce a large amount of type I IFNs (Figure 1). Thus, the two DC subsets may induce different modes of innate immunity suitable for eliminating either bacteria or viruses. In particular, because pDCs have poor endocytic activity(4, 28) but are able to present viral antigens(29, 30), these cells are well equipped to induce anti-viral innate and adaptive immune responses.

Due to the pleiotropic effects of type I IFNs on various immune cells(31), pDCs augment the functions of monocytes(32), blood mDCs(33), B cells(34), CD8⁺ T cells(35), NK cells(36, 37), and NKT cells(38) in vitro. Monocytes differentiate into DCs in response to serum from lupus patients, and IFN-alpha in the serum is responsible for the differentiation into DCs, suggesting that pDCs are involved in the pathogenesis of lupus by producing IFN- alpha (32). Consistent with this, pDCs stimulated with CpG oligodeoxynucleotide (ODN) have been shown to induce monocytes to differentiate into DCs in an IFN-alpha-dependent manner(39, 40). HIV-activated pDCs induce maturation of blood mDCs by producing IFN-alpha and TNF-alpha(33). pDCs induce B cells to differentiate into immunoglobulin-secreting plasma cells by producing IFN-alpha and IL-6(34). pDCs stimulated with CpG ODN enhance proliferation of peptide-specific CD8⁺ T cells(35), and promote NK cell cytotoxicity and IFN-gamma production through type I IFN and the ligand for glucocorticoid-induced tumor necrosis factor receptor (GITRL) (36, 37). When NKT cells were preincubated with a pDC-conditioned supernatant, there was an increase in the proliferation of NKT cells cocultured with alpha-galactosylceramide-loaded mDCs(38). These studies indicate that pDCs play a pivotal role in augmenting cellular and humoral immune responses by producing the pleiotropic cytokine, IFN-alpha.

6. INDUCTION OF DIFFERENT TYPES OF ADAPTIVE T CELL RESPONSES BY mDCs

The human immune system has evolved to have two separate mechanisms for protection against different types of microbes. In response to intracellular microbes, such as bacteria, viruses, and intracellular parasites, DCs are induced to produce IL-12 and type I IFNs (41, 42). These activated DCs can then stimulate CD4⁺ Th cells to differentiate into IFN-gamma-producing Th1 cells (43, 44). The activated Th1 cells, in turn, help to activate macrophages and CD8⁺ cytotoxic T cells to kill intracellular microbes. In response to extracellular parasites, such as helminthes, activated DCs induce CD4⁺ Th cells to differentiate into Th2 cells (41, 45, 46). Th2 cells produce proallergic cytokines such as IL-4, IL-5, and IL-13, which trigger IgE production. IgE, in turn, activates mast cells and eosinophils to eradicate the extracellular microbes.

DCs play a critical role in directing different effector T cell responses (43, 47). mDCs have a capacity to produce IL-12 in response to the microbial stimuli and, thereby, to induce Th1 development(48). However, this capacity varies with the type of signals delivered to DCs (Figure 1A, B). For example, LPS derived from Escherichia coli (49, 50), Mycobacterium tuberculosis (51), and double-stranded viral RNA (21, 52, 53), all activate mDCs to produce IL-12 and to induce Th1 development, whereas LPS from Porphyromonas gingivalis (49, 54), Der p 1 (house dust mite allergen) (55, 56), and Schistosoma mansoni egg extract (52, 57, 58), all activate mDCs to induce Th2 development, which is associated with a lower capacity of the DCs to produce IL-12. Thus, different microbes and their components induce mDCs to produce different levels of IL-12, which leads to different types of Th responses appropriate to eliminate given pathogens.

Environmentally bioactive substances produced by inflammatory processes that act as a cyclic AMP upregulator, such as prostaglandin (PG) E₂(58) and histamine(59), enhance TNF-alpha-dependent mDC maturation but suppresses bioactive IL-12 p70 production, resulting in Th2 responses (Figure 1A).

Due to the proximity of DCs and mast cells in skin and mucosa, activation of mast cells may affect DC functions. Indeed, we showed that IgE-activated mast cells in combination with proinflammatory factors induce IL-12-nonproducing, Th2-promoting mDCs (60) (Figure 1A). Thus, the interaction between DCs and IgE-activated mast cells in a proinflammatory environment may be instrumental in maintaining and augmenting Th2 responses in allergy.

Thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine, may be a key physiological mediator that cause allergic inflammation through DCs. TSLP strongly activates human blood mDCs to upregulate costimulatory molecules and to secrete Th2-attracting chemokines TARC and MDC, but neither IL-12 nor pro-inflammatory cytokines (61, 62). These TSLP-activated DCs in turn induce allogeneic naïve CD4⁺ T cells to undergo robust proliferation and to differentiate into Th2 cells by expressing OX40 ligand(63) (Figure 1B). These findings, together with high TSLP expression in keratinocytes from the skin lesions of patients with atopic dermatitis (62), suggest that TSLP plays a critical role in the initiation of allergic inflammation.

Immunosuppressive cytokines such as IL-10 and transforming growth factor (TGF)-beta, as well as steroid, cyclosporin A, and 1-alpha, 25-dihydoxyvitamin D3, inhibit the maturation of mDCs as well as their IL-12 production (64-69). These DCs cannot drive DC-mediated Th1 responses but rather induce DC-mediated regulatory T cells (or possibly Th2 cells), similar to the immature steady-state DCs (70, 71).

Taken together, mDCs are capable of inducing naïve CD4⁺ T cells to differentiate into Th1, Th2, and even regulatory T cells, depending on the stimuli the DCs receive from the environment. IL-12 is a dominant factor in inducing a Th1 response.

7. INDUCTION OF DIFFERENT TYPES OF ADAPTIVE T CELL RESPONSES BY pDCs

Following an innate immune response, pDCs switch their functional properties from type I IFN producers to mature DCs that directly modulate T cell functions. Signaling through TLR7 and TLR9 by viruses or by synthetic ligands can stimulate pDCs to produce IFN-alpha/beta and rapidly undergo maturation (17, 22, 72).

Virus-stimulated pDCs induce human naïve CD4⁺ allogeneic T cells to differentiate into IFN-gamma- and IL-10-producing cells (17), which have an immunoregulatory function(73) (Figure 1C). In contrast to pDCs stimulated with virus or CpG ODN, IL-3-stimulated pDCs do not produce IFN-alpha, and prime naïve CD4⁺ T cells to produce Th2 cytokines by expressing OX40 ligand (4, 17, 74) (Figure 1C). The biological significance of pDC differentiation into mature DCs in the presence of IL-3 is unclear.

Several studies have indicated tolerogenic functions of pDCs. The pDCs induced by IL-3 with CD40 ligand prime naive CD8⁺ T cells to differentiate into IL-10-producing suppressor T cells, which inhibit bystander proliferation of CD8⁺ T cells in an IL-10-dependent manner (75). Recent studies have shown that, in humans, freshly isolated pDC precursors induce CD4⁺ T cell anergy (76) and pDC-derived DCs activated by CpG ODN prime naïve CD4⁺ T cells to differentiate into CD4⁺CD25⁺ regulatory T cells characterized as Foxp3⁺ IL-10-producing suppressor T cells (77). We have also shown that virus-stimulated pDCs induce naïve CD4⁺ T cells to differentiate into IFN-gamma- and IL-10-producing cytotoxic regulatory T cells that express granzymes and perforin(73) (Figure 1C). Thus, pDCs that have been stimulated with various stimuli induce IL-10-producing regulatory T cells. Of note, it has been shown that inducible costimulator (ICOS) ligand highly expressed on pDCs is responsible for the IL-10 production by T cells(78) (Figure 1C). This finding indicates that pDCs have an intrinsic ability to induce IL-10-producing regulatory T cells by expressing ICOS ligand, which discriminates pDCs from mDCs.

In anti-viral immunity, pDCs appear to be capable of priming influenza virus-specific primary and secondary CD4⁺ and CD8⁺ T cell immune responses in vitro and in vivo (29, 30). Although pDCs have been considered to be have a poor capacity to cross-present exogenous antigens on MHC class I molecules(79) partly due to their poor phagocytic activity (4, 28), it has recently been shown that pDCs can cross-present HIV antigens from apoptotic cells as efficiently as mDCs(80). Given the tolerogenic activity of pDCs repeatedly shown by the in vitro studies, it remains to be determined whether such presentation of viral antigens leads to T cell stimulation or T cell anergy in vivo.

8. APPLICATION OF HUMAN DC SUBSETS TO IMMUNOTHERAPY

A variety of ligands for TLRs is under clinical development as adjuvants in immunotherapy for cancer, infection, and allergy(81). Due to the broad range of TLR expression, DCs represent principal targets of such adjuvants. In particular, TLR9 ligands, CpG ODNs, which induce pDCs to produce type I IFNs, are promising adjuvants due to multiple immunostimulatory effects of type I IFNs. In addition, topical administration of imidazoquinolines, which stimulate pDCs and mDCs through TLR7 and TLR8, respectively, and induce recruitment of pDCs to the skin(82), is under clinical trials for skin cancers (basal cell carcinoma and melanoma)(81). Infiltration of mDCs and pDCs has been reported in tumors lesions, such as ovarian cancer(83), melanoma(84), head and neck cancer(85), and lung cancer(86). The pDCs in tumor sites under steady state are incapable of activating T cells and instead induce IL-10-producing regulatory T cells(83, 87). It is possible that stimulation of pDCs in tumor sites with CpG ODNs activates adjacent mDCs through type I IFNs, which may evoke tumor-specific immune responses.

There are three classes of immunostimulatory CpG ODNs(88): A class ODN that potently stimulates pDCs to produce IFN-alpha, B class ODN that stimulates B cells and pDCs with a much lower level of IFN-alpha production than A class, and C class ODN that stimulates both B cells and pDCs with a moderate level of IFN-alpha production. B class ODNs have been used in clinical trials for B-cell lymphoma (in combination with anti-CD20 monoclonal antibody, rituximab)(89), melanoma (in combination with MART-1 peptide)(90), and non-small cell lung cancer (in combination with chemotherapy)(88). The administration of CpG ODNs was safe, and remarkable increases in the number of MART-1-specific CD8⁺ T cells were induced in the melanoma patients(90), indicating the potency of pDC activation in enhancing antigen-specific T cell responses.

CpG ODNs and imidazoquinolines are under clinical trials for viral infections, such as hepatitis B, hepatitis C, HIV, genital herpes, and influenza(81). CpG ODNs are also used for allergic rhinitis and asthma in an attempt to counterbalance Th2 responses with vaccine-induced Th1 responses(81).

Administration of myeloid DCs, mainly monocyte-derived DCs, which were pulsed with tumor antigens in the form of peptide, mRNA encoding tumor antigens, tumor lysate, or apoptotic tumor cells, has been widely applied for various types of cancers, and exhibits clinical responses in about 10% of patients(91).

9. SUMMARY AND PERSPECTIVE

In host defense, many of the "danger signals" of infection are integrated by DCs and then converted into appropriate types of immune responses. The specialized roles of each DC subset in innate and adaptive immune responses have been well characterized in this decade. In the future, further knowledge of the molecular mechanisms that control functional plasticity of the DC system may lead to improvements in the treatment of a wide variety of diseases, such as cancers, infections, allergy, and autoimmune disorders.

So far, for clinical trials, DCs have been mainly used for tumor immunotherapy. DCs have been prepared ex vivo in many cases, but it takes substantial cost and labor. Immunotherapy using DCs prepared ex vivo is still need to be pursued in an attempt to improve clinical outcomes, particularly by applying DC therapy to patients with minimal tumor burden. For the future, antigens will be targeted to DCs in vivo by administrating a tumor antigen conjugated with a DC-targeting component, such as an antibody specific to surface molecules on DCs (92). In this case, induction of DC maturation using appropriate adjuvants is mandatory to induce anti-tumor immunity instead of tolerance. In this context, activation of both mDCs and pDCs in appropriate sites, i.e. tumor sites and lymphoid tissues, using appropriate TLR ligands will synergistically augment anti-tumor immune responses. Development of technology that realizes such advanced immunotherapy is expected in the near future.

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Abbreviations: APC: antigen-presenting cell, DC: dendritic cell, CLP: common lymphoid progenitor, CMP: common myeloid progenitor, GITR: glucocorticoid-induced tumor necrosis factor receptor, GM-CSF: granulocyte-macrophage colony stimulating-factor, ICOS: inducible costimulator, IFN: interferon, IL: interleukin, LPS: lipopolysaccharide, M-CSF: macrophage-colony stimulating factor, mDC: myeloid dendritic cell, ODN: oligodeoxynucleotide, pDC: plasmacytoid dendritic cell, PG: prostaglandin, TGF: transforming growth factor, Th: T helper, TLR: Toll-like receptor, TNF: tumor necrosis factor, TSLP: thymic stromal lymphopoietin

Key Words: Dendritic cells, Innate immunity, Adaptive immunity, T cells, Toll-like receptor, Interferon, Th1, Th2, Immunotherapy, Review