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Originally published online as doi:10.1189/jlb.1003482 on January 14, 2004

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(Journal of Leukocyte Biology. 2004;75:721-730.)
© 2004 by Society for Leukocyte Biology

Controlling the Toll road to dendritic cell polarization

Alessandra Mazzoni and David M. Segal1

Experimental Immunology Branch, National Cancer Institute, Bethesda, Maryland

1Correspondence: Experimental Immunology Branch, National Institutes of Health, Building 10, Room 4B36, 9000 Rockville Pike, Bethesda, MD 20892. E-mail: dave_segal{at}nih.gov


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ABSTRACT
 
The activation of dendritic cells (DC) via Toll-like receptors (TLRs) plays a decisive role in shaping the outcome of primary immune responses. Following TLR engagement by microbial products, DC migrate from peripheral tissues to lymphoid organs and up-regulate major histocompatibility complex and costimulatory molecules, acquiring the unique capacity to prime pathogen-specific, naïve T cells. In addition, DC determine the character of the ensuing immune response by secreting cytokines that drive the development of T cells into T helper cell type 1 (Th1), Th2, or T regulatory effector cells. Three major factors influence the pattern of cytokines released by DC and accordingly, the Th balance: the lineage to which DC belong; the maturation stimulus; and inflammatory mediators present at the site of infection. A major focus of this review is the capacity of DC to integrate these factors and elicit distinct classes of immune responses.

Key Words: Toll-like receptors • innate immunity • cytokines • infection


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INTRODUCTION
 
The generation of a primary immune response depends on the efficient priming of naïve T cells by dendritic cells (DC; reviewed in refs. [1 2 3 ]). Immature DC (iDC) are strategically located at portals of pathogen entry such as the skin or the airway and gastrointestinal mucosae, where they rapidly endocytose endogenous and foreign substances from the surrounding microenvironment. Exposure to pathogens triggers the maturation of DC, a multistep process whereby DC sequentially induce innate and adaptive responses against invading pathogens. Initially, DC secrete cytokines and chemokines that recruit innate effector cells such as neutrophils and macrophages to the site of infection; these cells exert potent antimicrobial activities and keep the pathogen in check. Subsequently, the maturing DC migrate to draining lymph nodes, where they activate and expand antigen-specific T cells, effectors of adaptive immunity. Activated T cells migrate back to the site of inflammation, clear the infection, and give rise to memory. Clearly, pathogen recognition by DC is a crucial process in the host defense against infectious agents.

Even in the absence of an infection, DC play an important role in regulating T cell functions. iDC constitutively migrate from peripheral tissues to lymphoid organs, albeit at a slower rate than after microbial challenge. Once in the lymph nodes, iDC present self-antigens to autoreactive T cells that escaped thymic selection, resulting in the deletion of the autoreactive T cells or the induction of regulatory T (Treg) cells. Therefore, DC orchestrate T cells responses against self and nonself by eliciting immunity in response to a pathogen challenge and establishing peripheral tolerance in the steady state [4 ].


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THE RECOGNITION OF PATHOGENS BY TOLL-LIKE RECEPTORS (TLRs)
 
Detection of pathogens by DC is mediated by germ-line-encoded receptors known as pattern recognition receptors. These receptors recognize conserved molecular signatures of pathogens commonly referred to as pathogen-associated molecular patterns (PAMPs). Endocytic receptors, including DEC-205, the mannose receptor, and the scavenger receptors, promote the internalization of microbial products and direct them to antigen-processing compartments; TLRs, upon ligand recognition, trigger maturation of DC and the secretion of numerous cytokines and chemokines [5 ]. In humans, 10 TLR paralogs recognize PAMPs from a wide variety of pathogens including bacteria, viruses, and parasites. Examples include the recognition of lipopolysaccharides (LPS) from Gram-negative bacteria by TLR4 in complex with an accessory protein, myeloid differentiation protein-2 (MD-2); the detection of lipoproteins and peptidoglycans (PGN) from Gram-positive bacteria by complexes of TLR2 with TLR1 or TLR6; the triggering of TLR3 by double-stranded RNA (dsRNA) from viruses; and the recognition by TLR9 of unmethylated CpG motifs present in viral and bacterial DNA (reviewed in ref. [6 ]). The subcellular localization of each TLR is related to the PAMP it recognizes. For example, TLR9 is found in intracellular compartments, where recognition of bacterial DNA can occur after internalization and degradation of the bacteria. Conversely, TLR4/MD-2 complexes are often located on plasma membranes, as is the case with DC, where they detect LPS molecules exposed on bacterial surfaces or shed in the microenvironment [6 ]. However, TLR4/MD-2 complexes are located intracellularly in intestinal and pulmonary epithelial cells, presumably to protect against chronic inflammation [7 , 8 ].

The TLRs are type I integral membrane glycoproteins with ectodomains consisting largely of leucine-rich repeats that are thought to create PAMP-binding sites [9 ] and cytoplasmic signaling domains homologous to the signaling domains of the interleukin (IL)-1 family of receptors known as Toll IL-1 receptor (IL-1R; TIR) domains. In response to pathogen binding, the TIR domains recruit adaptor molecules (which also contain TIR domains) to the cytoplasmic side of the activated TLR, as discussed in a later section. This initiates a signaling cascade that eventually leads to the activation of nuclear factor (NF)-{kappa}B, activated protein-1 (AP-1), and other transcription factors, which induce the expression of a wide variety of target proteins including cell-surface proteins and soluble mediators of inflammation [6 ].


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DC MATURATION AND THE GENERATION OF EFFECTOR T CELLS: T HELPER CELL TYPE 1 (Th1), Th2, and Treg
 
TLR stimulation in DC induces intricate changes in the patterns of expression of chemokine receptors and adhesion molecules that allow DC to enter the lymphatic system and migrate to the draining lymph nodes [10 ]. At the same time, DC lose their endocytic capacities so that only antigens engulfed at the site of infection are processed and presented. In addition, the levels of expression of major histocompatibility complex (MHC) class I, class II, and costimulatory molecules are dramatically up-regulated, endowing mature DC with their unique capacity to prime antigen-specific, naïve T cells. In the lymphoid organs, mature DC act as professional antigen-presenting cells (APC) by providing signal 1 (T cell receptor cross-linking) and signal 2 (costimulation) to pathogen-specific, naïve T cells, thus inducing their activation and clonal expansion. In addition, mature DC secrete multiple cytokines and express membrane-bound molecules, such as OX40 ligand (OX40L; together, referred to as signal 3 [11 ]), which determine the character of the ensuing immune response. Antigen-specific T cells ultimately differentiate into Th1 or Th2 effector cells or Treg cells: Th1 cells primarily release interferon-{gamma} (IFN-{gamma}) and tumor necrosis factor-ß (TNF-ß), which in turn activate macrophages and cellular effectors of immunity, and Th2 cells favor humoral responses by secreting IL-4, IL-5, and IL-13, eventually promoting B cell isotype switching to immunoglobulin G (IgG)1, IgA, and IgE (reviewed in ref. [12 ]). Treg cells are thought to prevent autoimmune responses by specifically suppressing activation and proliferation of CD4 and CD8 effector T cells [13 , 14 ]. The importance of a correct Th choice is underscored by the fact that depending on the nature of the invading microorganism, the effective elimination of an infection requires a specific type of Th response. For example, Th1 immunity provides protection against intracellular bacteria and viruses, whereas Th2 responses are essential to fight off helminth infections. Conversely, dysregulated Th responses promote several pathological conditions, as in the case of allergy and asthma, which are characterized by excessive Th2 responses [15 ]. In addition, by specifically inducing the generation of Treg cells, some pathogens (e.g., Bordetella pertussis) subvert protective immune responses and establish long-lasting infections [16 ]. Therefore, the Th balance ultimately determines whether the outcome of immune responses is protective or unfavorable to the host.

A number of factors influence the Th1/Th2 balance, including the amount of antigen to which DC have been exposed (high antigen doses are usually associated with the generation of Th1 responses [17 18 19 ]), the ratio of T cells to DC (low ratios favor Th1 development [20 , 21 ]), and the costimulatory molecules preferentially expressed by DC (expression of OX40L or a high B7.2-to-B7.1 ratio generally promote Th2 responses [22 , 23 ]). However, DC-derived cytokines, present during the initial phases of T cell activation, play the most important role in this process. Specifically, IL-12 p75 and IL-27, two members of the IL-12 family of cytokines, drive polarization of T cells toward a Th1 phenotype, and recent reports indicate that type I IFNs are also instrumental in inducing Th1 cells [24 25 26 ]. Conversely, exposure of naïve T cells to IL-4, IL-5, and IL-10 (and IL-6 in the mouse system [27 ]) results in the induction of Th2 responses, and IL-10 also promotes Treg cell induction [28 ]. Therefore, the Th1/Th2/Treg balance and the effective clearance of an invading pathogen ultimately depend on the factors controlling the cytokines released by DC during priming of naïve T cells. Three main factors profoundly influence the pattern of cytokines secreted by mature DC: the DC lineage; the maturation stimulus; and the microenvironment where iDC are located. The striking ability of DC to trigger and fine-tune adaptive-immune responses comes from their capacity to integrate all this information and choose an appropriate set of polarizing cytokines in response to a pathogen challenge.


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DC SUBSETS AND THEIR TLR EXPRESSION
 
The defining feature of DC is the capacity to prime naïve T cells, but several subsets with distinct phenotypes, localization, and specificities for pathogens meet this criterion (reviewed in ref. [29 ]). In humans, two subsets have been identified to date: myeloid and plasmacytoid DC (mDC and pDC, respectively). mDC, phenotypically defined as CD14–, CD11c+, CD1a+ cells, are located mainly in peripheral tissues, although they can also be found circulating in the blood. Langerhans cells are mDC that are situated in the epidermis. mDC express all 10 TLRs with the exception of TLR9 [30 31 32 33 34 ] and therefore, recognize an abundant variety of PAMPs (Table 1 ). Human monocytes cultured in the presence of IL-4 and granulocyte macrophage-colony stimulating factor (GM-CSF) differentiate into cells with features similar to mDC and provide a good experimental model for studying this DC subset [39 ]. pDC are found circulating in the blood, which makes them particularly suited to detect blood-borne pathogens [40 41 42 43 ]. They are characterized by an intense staining for BDCA-2 (a lectin uniquely expressed by pDC with an as-yet unknown physiological function) [44 ], CD123 (the {alpha} chain of the IL-3R), and CD45RA. It is interesting that pDC possess a repertoire of TLRs, (TLR1, TLR6, TLR7, and TLR9 [30 , 33 , 34 ]), which complements the TLRs expressed by mDC, enabling the two subsets of DC to respond to distinct sets of PAMPs. pDC have an inherent ability to secrete large amounts of type I IFN in response to viruses and/or TLR9 ligands and therefore, are considered key players in antiviral immune responses [30 , 41 , 43 ]. However, recent observations indicate that at least in the mouse, some DC subsets other than pDC can secrete considerable levels of type I IFNs after viral challenge in a TLR3-independent manner [45 ]. In addition, several lines of evidence indicate that pDC are poor stimulators of naïve T cell proliferation, and their classification as professional APC is beginning to be questioned [17 , 46 ].


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  		Table 1. Expression of TLRs on Human and Mouse DC Subsets

Mouse DC are more heterogeneous than human and consist of at least five different subsets, all expressing CD11c (Table 1) . Secondary lymphoid organs contain two subpopulations of DC based on their expression of CD8{alpha}, and the CD8{alpha}– cells can be further subdivided into CD4+ and CD4– populations [47 ]. Mouse DC generated by in vitro culture of bone marrow precursors with GM-CSF stain negatively for CD8 and CD4, but how they are related to the corresponding CD8-negative cells isolated from the spleen is still unknown [37 ]. Spleen and lymph nodes also contain a pDC subset, which similar to the human counterpart, responds to viral challenge by secreting type I IFNs. Mouse pDC can be identified and isolated based on their expression of B220 and Gr-1 [38 , 48 , 49 ]. Lymph nodes contain an additional subset of DC having intermediate levels of CD8 and constitutively expressing a mature phenotype [35 , 50 ]. These cells derive from peripheral tissues; in subcutaneous lymph nodes, they originate from the dermis or the epidermis (and resemble Langerhans cells), whereas in mesenteric lymph nodes, they originate from the gut mucosae. Murine DC subsets exhibit a much broader distribution of TLR expression than the human populations (Table 1) . For example, mouse pDC express most TLRs and as a result, respond to a wider range of PAMPs than their human counterparts [17 , 36 ]. Unlike the case in human DC, TLR9 and TLR7 are expressed in most subsets of DC, with the exception of CD8+ DC, which lack TLR7 [36 , 51 ].


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T CELL POLARIZATION BY DC SUBSETS
 
Initial observations suggested that each DC subset, in humans and mice, possesses the intrinsic capacity to polarize naïve T cells toward a Th1 or Th2 phenotype. For example, human mDC stimulated the production of Th1 cells, and pDC produced Th2 cells following CD40L stimulation [52 ]. Similar conclusions were drawn for mouse CD8+ DC (Th1) and CD8– DC (Th2), even in the absence of a specific stimulus [53 , 54 ]. The intrinsic capacity of a DC subset to induce Th1 or Th2 cells was associated with its ability to release IL-12 upon maturation. This led to the notion that DC are committed to direct Th1 or Th2 differentiation depending on their lineage, and accordingly, human mDC and pDC were labeled DC1 and DC2, respectively [52 ]. This paradigm was challenged by subsequent studies showing that DC2 cells (pDC) promote strong Th1 responses when stimulated with a TLR9 ligand (a CpG oligodeoxynucleotide) or influenza virus, demonstrating that different stimuli, acting on the same DC population, can have opposite outcomes in the Th balance [25 , 55 ]. In spite of their plasticity in polarizing T cells, it is clear that each DC subset secretes a lineage-specific array of cytokines [56 ] and chemokines [57 ] following stimulation. The association of specific cytokine profiles with DC lineage was unequivocally demonstrated by stimulating human pDC and mDC, both of which express TLR7, with a TLR7 ligand. Although both subsets undergo similar phenotypic changes upon maturation, they show a different pattern of cytokine secretion after treatment with TLR7 agonists: Specifically, mDC release IL-12 but not type I IFNs, and pDC produce type I IFNs but not IL-12. Most importantly, however, both subsets promoted the differentiation of T cells into Th1 effectors [56 ], indicating that the character of an adaptive-immune response is ultimately determined by which PAMPs trigger iDC.


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PAMPs, TLRs, AND POLARIZATION OF DC
 
Transcriptional profiling by microarray analyses of human monocyte-derived DC treated with different classes of pathogens (bacteria, fungi, and viruses) revealed the existence of common and pathogen-specific genes [58 ]. Common genes—those that are regulated by all pathogens—control the expression of proteins that are used in responses against all microbes, for example, inflammatory cytokines and adhesion molecules necessary for the migration of maturing DC to the lymphoid organs. At the same time, distinct sets of genes are regulated in a pathogen-specific manner, allowing for the generation of an adaptive-immune response specifically tailored for a given pathogen. For example, activation of DC with dsRNA, a TLR3 ligand, but not with bacterial LPS, the prototypic TLR4 ligand, up-regulates the levels of type I IFNs, essential for antiviral responses, as well as proapoptotic genes that may induce early cell death of infected cells.

These findings have been extended by several groups, showing that although PAMPs that stimulate different TLRs induce similar changes in surface phenotype in DC, they often induce distinct patterns of cytokines, resulting in a Th1/Th2 polarization that is appropriate for the pathogen (Table 2 ). Thus, in human monocyte-derived DC, dsRNA has been shown to enhance the surface expression of MHC and costimulatory molecules and to induce the release of type I IFNs, leading to the development of Th1 effector cells [62 , 78 ]. Conversely, a soluble egg extract from the helminth Schistosoma mansoni (possibly acting via an unidentified TLR) promoted maturation of DC into Th2-polarizing APC by inducing OX40L on DC [69 , 78 ]; the interaction of OX40L with OX40 on CD4+ T cells has been shown to induce Th2 formation [23 , 79 ]. Similarly, the TLR4 and TLR2 ligands, LPS and PGN, induced comparable levels of maturation markers in human DC but distinct cytokine and chemokines profiles: IL-12 p35 was produced in response to LPS, whereas IL-8 and IFN-inducible protein 10 (IP-10) were secreted following stimulation with PGN [66 ]. Direct comparison of the polarizing activities of murine DC triggered with distinct TLR agonists further established that the microbial stimulus can dictate which cytokines are produced and what classes of immune response are elicited. In vivo studies revealed that LPS from P. gengivalis, a known TLR2 trigger, causes DC to prime a Th2 type of response, whereas LPS from E. coli, which signals via TLR4, promotes the development of IL-12-secreting DC with Th1-polarizing activities [59 , 80 ]. Similarly, the TLR2 ligand zymosan, a component of yeast cell wall, promotes the release of IL-10 and the generation of Th2 effector cells in mouse splenic DC, an effect observed also using intact yeast [21 , 81 ]. Finally, a soluble extract of STag, known to activate the chemokine receptor CCR5 together with an as-yet unidentified TLR, causes DC to release IL-12 and to drive differentiation of Th1 effector cells [21 , 82 , 83 ] (Table 2) .


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  		Table 2. Maturation and Environmental Stimuli Drive Polarization of DC Toward Th1 or Th2

It is interesting that some pathogens have evolved strategies to circumvent the generation of protective Th1 or Th2 immune responses by interfering with DC functions. In some cases, the pathogens actively prevent DC from undergoing maturation, as observed in Bacillus anthracis infections [84 ], resulting in unrestrained spread of the bacteria and disease progression. In other instances, following microbial stimulation, DC do undergo phenotypic maturation but release high levels of IL-10, which in turn promotes the generation of pathogen-specific Treg cells and the suppression of protective Th1 responses. Such an evasion strategy is successfully exploited by B. pertussis, the causative agent of whooping cough. In this case, Treg generation is dependent on the expression of a functional TLR4 on DC [16 , 85 ].


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CONDITIONING OF DC IN THE PERIPHERAL MICROENVIRONMENT
 
The specific anatomical compartment where an iDC resides and encounters a pathogen profoundly impacts the character of the immune response generated by the DC after it has migrated to the lymph nodes. For example, the lung microenvironment conditions resident DC to induce Th2 responses. This was clearly demonstrated with Leishmania major, a parasite that produces a strong Th1 response when given subcutaneously or intraperitoneally to C57/Bl6 mice: Quite surprisingly, delivery of the parasites intranasally resulted in the generation of Th2 effector cells [86 ]. A more detailed analysis revealed that pulmonary DC preferentially release IL-6 and IL-10 after challenge with L. major, thus explaining their preferential induction of Th2 responses [87 , 88 ]. DC located in mucosal tissues of the gastrointestinal tract also favor the development of Th2 responses: In fact, direct comparison of mouse DC isolated from Peyer’s patches (PP) with phenotypically similar DC populations isolated from the spleen demonstrated that the PP DC preferentially induced a Th2 response and the splenic DC, a Th1 response following microbial or CD40 stimulation [89 , 90 ]. Finally, a recent report showed that CD8-positive and -negative subsets of DC isolated from the liver secrete similar amounts of IL-12 when stimulated with CD40L; whereas in the spleen, only the CD8+ subset secretes IL-12 [91 ]. As the two DC subsets are located in different areas of the spleen (CD8– DC in the marginal zone and CD8+ DC in the T cell area [92 ]), it was hypothesized that these distinct microenvironments might differentially condition DC to release IL-12; specifically, the marginal zone might contain as-yet unidentified factors inhibiting IL-12 secretion from DC [91 ].


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THE INSTRUCTIONAL MODEL OF DC POLARIZATION
 
DC residing in peripheral microenvironments are constantly exposed to cytokines, growth factors, and local mediators released by surrounding cells that have the capacity to control their cytokine expression. Although it is difficult to identify the relevant tissue-specific factors under steady-state conditions, the identities of several mediators released locally in response to an infection or a proinflammatory stimulus are known. Tissue-resident cells including mast cells, macrophages, and endothelial cells release these mediators in response to inflammatory cytokines, microbial products, or allergens. The capacity of these mediators to affect DC function, especially cytokine secretion, forms the basis of the "instructional" model for DC polarization [11 ], illustrated in Figure 1 . According to this model, DC carry the information they have obtained at the site of infection from pathogens (activation) and environmental mediators (instruction) to the lymph nodes, where they prime antigen-specific T cells and induce a Th1/Th2 response appropriate for the invading pathogen. Two of the best-characterized mediators are IFN-{gamma} and IL-10, which bias the polarizing capacities of DC toward Th1 and Th2, respectively. Newly recruited natural killer cells are a major source of IFN-{gamma}, which exerts its Th1-promoting activity by enhancing IL-12 secretion in maturing DC [60 , 93 ]. Conversely, by its ability to suppress production of IL-12 in maturing DC, IL-10 favors the development of Th2 responses; however, IL-10 can also block the phenotypic maturation of DC when present at high doses, ultimately leading to tolerogenic DC [94 95 96 ]. Cellular sources of IL-10 include tissue macrophages and DC stimulated with various TLR ligands, for example LPS and lipotechoic acid [97 ], suggesting cross-talk between neighboring iDC.



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  		Figure 1. Integration of activation and instruction signals in the peripheral microenvironment regulates Th generation. Activation of DC induces phenotypic maturation, migration, and cytokine secretion. Multiple stimuli activate DC, including microbial products (PAMPs), which trigger TLRs, and inflammatory cytokines, such as IL-1 and TNF-{alpha}. TLRs and IL-1R and IL-18R belong to the TIR superfamily (SF) of receptors, which activate NF-{kappa}B, c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK). TNF-{alpha} and CD40L induce similar pathways by triggering receptors belonging to the TNF receptor (TNFR) SF. The TIR and TNFR SFs converge at TNFR-associated factor (TRAF)6, a common intermediate in their signaling pathways. Maturation can also be triggered by TSLP, which signals through members of the signal transducer and activator of transcription (STAT) family of transcription factors. Depending on which receptor is activated, maturation is accompanied by secretion of cytokines with Th1, Th2, or Treg-polarizing capacity (Th1, red; Th2, green; Treg, black). See Table 2 for a list of Th1 and Th2 PAMPs. Together with maturation stimuli, DC receive instruction signals from neighboring cells present in the microenvironment at the time of activation. These mediators comprise cytokines such as IL-10 and IFN-{gamma}, which activate Janus tyrosine kinase (JAK)-STAT signaling pathways and inflammatory molecules such as histamine and ATP, which cause an increase in intracellular levels of cyclic adenosine monophosphate (cAMP) and activation of protein kinase A (PKA) through G protein-coupled receptors (GPCR). These signals modulate the secretion of cytokines by DC in the draining lymph nodes, resulting in the regulation of Th polarization. VIP, Vasoactive intestinal peptide; TSLPR, TSLP receptor.

In addition to cytokines, a number of small molecule mediators such as histamine, prostaglandins, and ATP, released by activated tissue-resident cells, affect the polarizing capacities of DC. For example, PGE2, released by endothelial cells, stromal cells, and macrophages in response to inflammatory stimuli, acts on DC undergoing LPS-driven maturation and down-regulates the production of bioactive IL-12, skewing the differentiation of T cells toward a Th2 phenotype [67 , 98 ]. It is interesting that recent observations also indicate a role for PGE2 in promoting maturation and migration of Langerhans cells to lymph nodes, suggesting that modulation of DC by PGE2 involves multiple functions such as migration, phenotypic maturation, and cytokine secretion [99 , 100 ].


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INSTRUCTION BY MAST CELLS
 
The instructional model for DC polarization offers a good explanation for the etiology of several immune deviations observed in pathological conditions such as atopy and allergy, characterized by elevated levels of IgE and abnormal Th2 responses. Traditionally, mast cells are viewed as the primary effectors of immediate-type allergic reactions, but recent observations indicate that they also modulate innate- and adaptive-immune responses by acting on iDC and affecting their polarizing activities. Mast cells are distributed in peripheral tissues, in close proximity to iDC. They can be activated by cross-linking surface IgE by their cognate antigen allergen or directly, by bacteria and bacterial products. IgE-mediated activation causes mast cells to rapidly discharge the content of cytoplasmic granules, which contain preformed cytokines (e.g., TNF-{alpha}), proteases, and histamine. At later times, IgE-activated mast cells synthesize a number of cytokines including IL-1, IL-4, IL-5, GM-CSF, as well as lipid-derived mediators such as leukotrienes and prostaglandins (reviewed in ref. [101 ]). Mast cells can also be activated by bacteria in TLR-dependent and independent manners, resulting in the slow release of cytokines and lipidic mediators and less frequently, in degranulation (reviewed in ref. [102 ]).

Immediate- and late-phase mast-cell mediators have been shown to endow DC with Th2-promoting activity. Histamine, the most abundant component in human mast-cell granules, profoundly influences the repertoire of cytokines and chemokines released by LPS-activated human DC. Of note, the secretion of proinflammatory cytokines, IL-12, IL-1ß, and IL-6, is dramatically inhibited by histamine, and the anti-inflammatory IL-10 is enhanced. Phenotypic maturation is not affected by histamine, and therefore, human DC that were matured in the presence of histamine are good stimulators of T cell proliferation and induce the preferential development of Th2 effector cells [64 , 103 104 105 ]. Similarly, PGD2, a major product of the cyclooxygenase pathway in activated mast cells, induces the secretion of Th2-inducing cytokines in murine and human maturing DC [68 , 106 ]. It is interesting that one mast cell mediator, TSLP, induces direct maturation of DC into Th2-polarizing cells, in contrast with the other mediators that are effective only in conjunction with a maturation stimulus [75 ]. TSLP is an IL-7-like cytokine that is released by epithelial cells and mast cells. DC that have been exposed to TSLP exhibit a mature phenotype and prime naive T cells to produce Th2 cytokines including IL-4, IL-5, and IL-13.

Although mast-cell mediators are best known as the causative agents of immediate-type hypersensitivity reactions, by acting on DC and promoting Th2 responses, they also have the potential of aiding in the establishment of chronic allergy, as Th2 cells facilitate the production of IgE. Thus, if a DC in the periphery were to endocytose a pathogen in the context of Th2-promoting mast-cell mediators, it would migrate to the draining lymph nodes and induce pathogen-specific Th2 cells that would provide help to B cells making pathogen-specific IgE. This IgE would then sensitize mast cells in the periphery so that a second encounter with the same pathogen would result in mast-cell degranulation; we hypothesize that this process could create a positive-feedback mechanism, favoring the generation of IgE and contributing to the severity of allergic diseases. Such a scenario could explain the elevated levels of IgE and Th2 cells frequently observed in atopic patients.


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MOLECULAR BASES FOR FUNCTIONAL PLASTICITY OF DC
 
The molecular mechanisms that allow diverse TLR ligands to elicit shared and distinct arrays of genes in DC are just beginning to be unraveled. Analysis of TLR signaling pathways has demonstrated that together with a core response, which culminates in the activation of NF-{kappa}B and MAPKs, individual TLRs also activate other signaling pathways through distinct adaptor molecules. The core signaling pathway of all TLRs begins with the recruitment of the cytosolic adaptor molecule, MyD88, to the intracellular (TIR) domain of the TLR. MyD88 contains a TIR domain, which interacts homotypically with the TIR domain of the TLR, and a death domain, by which it recruits members of the IL-1R-associated kinase (IRAK) family of ser/thr kinases to the TLR/MyD88 complex [107 ]. The phosphorylation of IRAK-1 by IRAK-4 initiates a signaling cascade, which uses TRAF6, ultimately leading to the activation of NF-{kappa}B, p38 MAPK, and Jun kinase [6 , 108 , 109 ]. TRAF6 plays a pivotal role in the activation of DC, as TRAF6-deficient DC fail to mature, fail to secrete inflammatory cytokines, and fail to prime naïve T cells in response to TLR and CD40 stimulation [110 ]. The MyD88-dependent signaling pathway mediates the induction in all TLRs (with the possible exception of TLR3 [111 , 112 ]) of proinflammatory cytokines such as TNF-{alpha}, IL-1, IL-6, and IL-12, as demonstrated by analysis of MyD88 knockout mice [6 ]. In addition to MyD88, four TIR domain-containing adaptor molecules have been identified to date: TIRAP/Mal, TRIF/TICAM1, TRAM, and SARM [111 , 113 114 115 116 117 118 ]. For example, TLR4 recruits MyD88, Mal/TIRAP, TRIF/TICAM1, and TRAM, whereas TLR3 recruits only TRIF/TICAM1. Like MyD88, TRIF/TICAM1 promotes NF-{kappa}B activation, but it also has the unique capacity to activate IFN regulatory factor 3 (IRF-3), resulting in the induction of IRF-3-dependent genes including IFN-ß, IP-10, and inducible nitric oxide synthase. As these genes are not induced following activation of other TLRs such as TLR2, which activates MyD88 and Mal/TIRAP, differential adaptor use by the TLRs likely accounts for differential gene expression observed after TLR triggering in DC [119 ].

The question of how DC integrate TLR- and environment-derived signals at the molecular level to produce a set of cytokines distinct from that induced by TLR ligation alone is even more complex. It is still unclear whether TLR transduction pathways are directly affected by signaling events activated by secondary stimuli such as IFN-{gamma}, histamine, and prostaglandins. For example, histamine inhibits IL-12 release in human DC via the histamine H2 receptor, which like several other environmental factors that affect DC-polarizing capacities, signals via trimeric G proteins [120 ]. The H2 receptor specifically signals through Gs, which in turn, activates adenylate cyclase, resulting in an increase in intracellular cAMP [64 ]. cAMP activates PKA, which phosphorylates several substrates including the transcription regulatory protein, cAMP response element-binding protein (CREB)/activating transcription factor. In this way, Gs-coupled receptors control the expression of genes that contain CREBs in their promoter regions, including cytokines such as IL-10 [121 ]. In human DC, IL-10 is induced by TLR and H2 stimulation several hours before IL-12. IL-10 inhibits IL-12 production, and the fact that the IL-10R activates the Jak/Stat pathway suggests that activated Stats might operate directly on the IL-12 promoter. However, histamine can suppress TLR-dependent IL-12 production in the absence of IL-10 [64 ], indicating that other factors can affect IL-12 transcription in DC. In line with this hypothesis, PGE2, another cAMP-elevating agent, has been found to enhance the binding of an as-yet unidentified repressor molecule to a specific purine-rich sequence in the promoter of the human IL-12 p40 gene, indicating that the coordinated binding of multiple transacting proteins induced by distinct signaling pathways regulates the expression of cytokine genes [122 ]. Finally, the recent discovery that TLR signaling induces nucleosome remodeling at the promoter region of IL-12 p40 points to another mechanism by which environmental stimuli can potentially modulate the TLR-dependent induction of inflammatory cytokines [123 ].

It is beyond the scope of this article to review the large and growing literature of cytokine regulation, but the few examples given above are intended to emphasize the importance that the cytokine regulatory regions in DC have in the generation of T cell responses. The remarkable capacity of DC to integrate signals from external stimuli most probably derives in large part from the abilities of cytokine promoters to bind and respond to the large variety of transcription factors that are activated by the stimuli. As indicated in Figure 1 , these stimuli can be catagorized as activating or instructional. Activating stimuli induce DC maturation, migration, and cytokine secretion and result in the activation of NF-{kappa}B, AP-1, and other transcription factors that are targets of MAPKs. Instructional stimuli tend not to act on their own but instead, modify the activating stimuli. Transcription factors induced by instructional stimuli include the many targets of GPCR, especially targets of PKA and STATs. It is likely that combinations of these factors, assembling on cytokine promoters, induce a T cell response that is best suited for neutralizing an invading pathogen.

Received October 16, 2003; revised December 3, 2003; accepted December 4, 2003.


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