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Review Article Collaboration of Toll-Like and RIG-I-Like Receptors in Human Dendritic Cells: Triggering Antiviral Innate Immune Responses

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Review Article Collaboration of Toll-Like and RIG-I-Like Receptors in Human Dendritic Cells: Triggering Antiviral Innate Immune Responses View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Debrecen Electronic Archive Am J Clin Exp Immunol 2013;2(3):195-207 www.ajcei.us /ISSN:2164-7712/AJCEI1309001 Review Article Collaboration of Toll-like and RIG-I-like receptors in human dendritic cells: tRIGgering antiviral innate immune responses Attila Szabo, Eva Rajnavolgyi Department of Immunology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary Received September 24, 2013; Accepted October 8, 2013; Epub October 16, 2013; Published October 30, 2013 Abstract: Dendritic cells (DCs) represent a functionally diverse and flexible population of rare cells with the unique capability of binding, internalizing and detecting various microorganisms and their components. However, the re- sponse of DCs to innocuous or pathogenic microbes is highly dependent on the type of microbe-associated molecu- lar patterns (MAMPs) recognized by pattern recognition receptors (PRRs) that interact with phylogenetically con- served and functionally indispensable microbial targets that involve both self and foreign structures such as lipids, carbohydrates, proteins, and nucleic acids. Recently, special attention has been drawn to nucleic acid receptors that are able to evoke robust innate immune responses mediated by type I interferons and inflammatory cytokine production against intracellular pathogens. Both conventional and plasmacytoid dendritic cells (cDCs and pDCs) ex- press specific nucleic acid recognizing receptors, such as members of the membrane Toll-like receptor (TLR) and the cytosolic RIG-I-like receptor (RLR) families. TLR3, TLR7/TLR8 and TLR9 are localized in the endosomal membrane and are specialized for the recognition of viral double-stranded RNA, single-stranded RNA, and nonmethylated DNA, respectively whereas RLRs (RIG-I, MDA5, and LGP2) are cytosolic proteins that sense various viral RNA species. In this review we discuss the significance of detecting the genomic content of viruses by DC subsets capable of linking innate and adaptive immunity, and several viral evasion mechanisms that may allow us to better understand these responses. A particular attention is paid to the possible collaboration of TLR and RLR sensors in anti-viral protection. Keywords: Pattern recognition receptors, cross-talk, dendritic cell subsets, interferon, inflammation Introduction present the stored material for naive circulating T-lymphocytes [2-4]. The nature, combination Dendritic cells (DCs) play a pivotal role in bridg- and duration of tissue-derived molecular sig- ing innate and adaptive immunity and in orches- nals determine the functional activities of DCs trating strictly controlled immune responses, and have an impact on the polarization, magni- which ensure restoration of the resting state tude, regulatory or stimulatory nature and dura- and the maintenance of self tolerance, or sup- tion of T-lymphocyte responses. port the generation of effector and memory cells. Tissue resident DCs are able to engulf Under steady state conditions DCs are present extracellular particles and soluble material and throughout the body at low numbers represent- by continuous sampling of their environment ing ~1-2 % of white blood cells. They are charac- they collect the actual molecular composition terized by high versatility, flexibility and multiple of a given tissue. Stress, inflammation or patho- functional activities combined with their dual genic evasion may alter the amount and con- capacity to induce self tolerance or trigger tent of the engulfed material and trigger the immune responses. They also act as the most local stimulation of DCs [1]. The first response efficient antigen presenting cells (APC) to acti- of tissue resident DCs to activation signals is vate and instruct the differentiation of inntate, the expression of cytokines, chemokines and CD4+ and CD8+ T-lymphocytes and have been their receptors followed by the rapid migration shown to be indispensible for inducing CD8+ to secondary lymphoid organs to transport and cytotoxic T-cell priming [5]. Epithelial surfaces, TLR and RLR signaling in dendritic cells such as the bronchial and intestinal tracts are markers, in their internalizing capacity, and continuously exposed to high doses of environ- migratory potential to lymph node-derived che- mental antigens and pathogens, consequently mokines. Furthermore, a marked difference they are considered more tolerogenic than the was found in the production of cytokines upon skin or other tissues, which also can be stimulation by CD40 ligand (CD40L) or various attacked by infectious agents, traumatic or Pattern Recognition Receptor (PRR) ligands toxic shock. These environmental changes are [15, 16]. It was also shown that the ligand monitored preferentially by mechanisms of the induced activation of the peroxisome prolifera- innate immune system through epithelial, tor-activated receptor-gamma (PPARγ), a mem- endothelial and stromal cells in collaboration ber of the nuclear hormone receptors, can with tissue resident macrophages, DCs and skew monocyte-derived DCs differentiation mast cells [6]. To our present view, the major towards the CD1a- subset. As the expression of function of DCs is to alarm the immune system CD1 molecules (CD1a, b, c) could be down reg- against foreign and dangerous interventions, ulated by PPARγ, while CD1d expression was and to protect self tissues from damage to increased suggested opposing regulation of maintain self-tolerance. Discovering the coordi- the expression of these lipid presenting mole- nation of these seemingly counteracting tasks cules. In this context the pathways involved in may open up new avenues for stimulating or this counter regulation were identified as serum regulating immune responses and to develop lipids and lipoproteins, known modulators of preventive or therapeutic interventions for PPARγ activity and consequently the dichotomy treating inflammatory and autoimmune diseas- of CD1a- and CD1a+ cells [17]. A recent study es or cancer, as well as designing new types of confirmed our previous findings showing indi- vaccines based on DCs biology [7-10]. vidual differences in CD1a expression by dem- onstrating CD1a deficiency as a common and Development and specialization of human genetically regulated phenomenon in the dendritic cell subtypes and subsets human population indicating a biologically rele- vant regulation [18]. Our findings and these + DCs arise from bone marrow-derived CD34 new results identified the CD1a membrane pro- hematopoietic stem cells (HSC), which main- tein as a marker of the phenotypically and func- tain their functional flexibility and are able to tionally distinct CD1a+ DC subset. generate various DCs subsets. The two major subsets of DCs involve bone marrow derived Pattern recognition receptors of human den- plasmacytoid DCs (pDCs) and conventional dritic cells DCs (cDC), which exhibit distinct phenotypic and functional attributes [11, 12]. Based on An important biological function of DCs relies their origin DCs can be further classified as on the continuous sampling of their tissue envi- conventional circulating CD1c+ and CD1c- blood ronment, responding to stress and danger sig- DCs and monocyte-derived DCs [13]. Further nals and transducing the collected molecular separation identified the rare but highly spe- information to other cell types of the immune cialized CD141+ blood DC population with the system. DCs are equipped with unique sets of unique capacity to cross-present viral antigens, phylogenetically conserved PRRs, which are the monocyte derived CX3CR1+ non-migrating specialized to recognize Microbe Associated DC subset associated to the gut epithelium, Molecular Patterns (MAMPs) and Danger and CD103+ DC present in the gut lamina pro- Associated Molecular Patterns (DAMPs) [19, pria and in mediastinal lymph nodes [14]. This 20]. The response of DCs to MAMPs and DAMPs heterogeneity reflects the functional specializa- is executed by the activation of resting DCs by tion of defined DC subsets and suggests a microbial components, noxious or toxic insults. rational distribution of labor at the level of DCs. Activation of DCs results in the expression of costimulatory molecules, the production of By analyzing more than 200 healthy donors we cytokines, chemokines and other soluble medi- have previously described that the ratio of the ators. Both resting and stimulated DCs are able CD1a+ and CD1a- monocyte-derived DCs to change their tissue location and migrate (moDCs) vary among individuals. Our results through peripheral and lymphoid tissues. also indicated that CD1a+ and CD1a- moDCs Activation of DCs by MAMPs and DAMPS results differ in the expression of some phenotypic in the rapid, chemokine-mediated transloca- 196 Am J Clin Exp Immunol 2013;2(3):195-207 TLR and RLR signaling in dendritic cells tion of DCs to draining lymph nodes where they tissue injury. The list of endogenous DAMPs is have the chance to contact antigen-specific continuously growing but their impact on T-lymphocytes to initiate adaptive immune immune homeostasis are yet to be clarified. A responses [21, 22]. This process also ensures recent review focuses on the role of these the transfer of molecular information collected endogenous molecules in eliciting inflamma- in the periphery towards other cell types of both tion and cell death by activating innate PRRs innate and adaptive immunity such as neutro- [29]. Growing body of evidence also suggests phil granulocytes,
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