Dendritic cells and C-type lectin receptors: coupling innate to adaptive immune responses

Dendritic cells (DCs) have an important function in the initiation and differentiation of immune responses, linking innate information to tailored adaptive responses. Depending on the pathogen invading the body, specific immune responses are built up that are crucial for eliminating the pathogen from the host. Host recognition of invading microorganisms relies on evolutionarily ancient, germline-encoded pattern recognition receptors (PRRs) that are highly expressed on the cell surface of DCs, of which the Toll-like receptors (TLRs) are well characterized and recognize bacterial or viral components. Moreover, they bind a variety of self-proteins released from damaged tissues including several heat-shock proteins. The membrane-associated C-type lectin receptors (CLRs) recognize glycan structures expressed by host cells of the immune system or on specific tissues, which upon recognition allow cellular interactions between DCs and other immune or tissue cells. In addition, CLRs can function as PRRs. In contrast to TLRs, CLRs recognize carbohydrate structures present on the pathogens. Modification of glycan structures on pathogens to mimic host glycans can thereby alter CLR interactions that subsequently modifies DC-induced polarization. In this review, we will discuss in detail how specific glycosylation of antigens can dictate both the innate and adaptive interactions that are mediated by CLRs on DCs and how this balances immune activation and inhibition of DC function.     

Dendritic cell subtypes as primary targets of vaccines: the emerging role and cross-talk of pattern recognition receptors

Preventive vaccination is the most successful approach against infectious diseases and has a great impact on world health. Vaccines operate through the activation of innate immunity that helps to stimulate antigen-specific T- and B-lymphocytes. These events are orchestrated by dendritic cells (DCs) that are able to sample foreign structures and concomitantly sense 'danger signals'. Thus, DCs provide a functional link between innate and acquired immunity, and due to their regulatory potential are referred to as natural adjuvants. Human conventional and plasmacytoid DCs express different sets of well-characterized Toll-like membrane receptors (TLRs) that recognize a broad range of conserved molecular patterns of pathogens. The recently discovered cytosolic Nod-like receptors (NLRs) and RIG-like helicases (RLHs) also turned out to participate in pathogen recognition and modulation of immune responses through interacting signaling pathways. As a result of their collaboration, the TLR, NLR and RLH recognition systems induce the secretion of different combinations of cytokines that play a fundamental role in T-cell activation and instruction. Ligands of the innate recognition systems emerge as new adjuvants for vaccine design, whereas manipulation of the signaling pathways mediated by these receptors offers new avenues for fine tuning immune responses and optimizing immunotherapies.     

Retagging identifies dendritic cell-specific intercellular adhesion molecule-3 (ICAM3)-grabbing non-integrin (DC-SIGN) protein as a novel receptor for a major allergen from house dust mite

Dendritic cells (DCs) have been shown to play a key role in the initiation and maintenance of immune responses to microbial pathogens as well as to allergens, but the exact mechanisms of their involvement in allergic responses and Th2 cell differentiation have remained elusive. Using retagging, we identified DC-SIGN as a novel receptor involved in the initial recognition and uptake of the major house dust mite and dog allergens Der p 1 and Can f 1, respectively. To confirm this, we used gene silencing to specifically inhibit DC-SIGN expression by DCs followed by allergen uptake studies. Binding and uptake of Der p 1 and Can f 1 allergens was assessed by ELISA and flow cytometry. Intriguingly, our data showed that silencing DC-SIGN on DCs promotes a Th2 phenotype in DC/T cell co-cultures. These findings should lead to better understanding of the molecular basis of allergen-induced Th2 cell polarization and in doing so paves the way for the rational design of novel intervention strategies by targeting allergen receptors on innate immune cells or their carbohydrate counterstructures on allergens.     

Innate instruction of CD4+ T cell immunity in respiratory bacterial infection

The innate immune system recognizes invading microbes via conserved pattern recognition receptors and uses inflammatory signals to concert adaptive defense mechanisms. However, microbial and host parameters involved in CD4 T cell priming and direction of Th1, Th2, and Th17 differentiation in the context of infections with complex pathogens in vivo are incompletely understood. In this study, we used Legionella pneumophila, which triggers membrane-bound and cytosolic pattern recognition receptors, to study the innate instruction of adaptive immunity. Upon airway infection, T cells were primed exclusively in the lung-draining lymph nodes and differentiated into Th1/Th17 effector cells upon arrival in the lung. Although engagement of membrane-bound pattern recognition receptors was sufficient for initial T cell activation and proliferation, cytosolic pattern recognition was required for effector T cell differentiation. In the absence of cytoplasmic pattern recognition, MyD88 was key for T cell priming, whereas, in its presence, MyD88-mediated signals were crucial for Th17 differentiation. Specifically, cytosolic sensing of Legionella-derived flagellin, inflammasome activation, and IL-1 signaling contributed to Th17 development. In the absence of TLR signaling, a simultaneous Th1/Th2 response developed that was independent of the inflammasome-IL-1 axis. Collectively, these data illustrate the important role for various pattern recognition receptors triggered by complex pathogens and how they each instruct specific differentiation programs in responding CD4 T cells.     

Regulation of dendritic cell function through toll-like receptors

Higher animals establish host defense by orchestrating innate and adaptive immunity. This is mediated by professional antigen presenting cells, i.e. dendritic cells (DCs). DCs can incorporate pathogens, produce a variety of cytokines, maturate, and present pathogen-derived peptides to T cells, thereby inducing T cell activation and differentiation. These responses are triggered by microbial recognition through type I transmembrane proteins, Toll-like receptors (TLRs) on DCs. TLRs consist of ten members and each TLR is involved in recognizing a variety of microorganism-derived molecular structures. TLR ligands include cell wall components, proteins, nucleic acids, and synthetic chemical compounds, all of which can activate DCs as immune adjuvants.     

Role of Nods in bacterial infection

Research into intracellular sensing of microbial products is an up and coming field in innate immunity. Nod1 and Nod2 are members of the rapidly expanding family of NACHT domain-containing proteins involved in intracellular recognition of bacterial products. Nods proteins are involved in the cytosolic detection of peptidoglycan motifs of bacteria, recognized through the LRR domain. The role of the NACHT-LRR system of detection in innate immune responses is highlighted at the mucosal barrier, where most of the membranous Toll like receptors (TLRs) are not expressed, or with pathogens that have devised ways to escape TLR sensing. For a given pathogen, the sum of the pathways induced by the recognition of the different "pathogen associated molecular patterns" (PAMPs) by the different pattern recognition receptors (PRRs) trigger and shape the subsequent innate and adaptive immune responses. Knowledge gathered during the last decade on PRR and their agonists, and recent studies on bacterial infections provide new insights into the immune response and the pathogenesis of human infectious diseases.     

In the trenches of plant pathogen recognition: Role of NB-LRR proteins

As in nearly every discipline of plant biology, new insights are constantly changing our understanding of plant immunity. It is now clear that plant immunity is controlled by two layers of inducible responses: basal responses triggered by conserved microbial features and specific responses triggered by gene-for-gene recognition of pathogen effector proteins by host resistance (R) proteins. The nucleotide-binding domain leucine-rich repeat (NB-LRR) class of R proteins plays a major role in the combat against a wide range of plant pathogens. The variation that has been generated and is maintained within these conserved proteins has diversified their specificity, subcellular localisations, activation and recognition mechanisms, allowing them to specifically adapt to different plant–pathogen interaction systems. This review addresses recent advances in the molecular role of NB-LRR proteins in pathogen recognition and activation of plant defence responses.     

Toll样受体信号转导对树突状细胞活化的影响

树突状细胞（dendriticcells,DCs）是目前已知功能最强的抗原提呈细胞（antigenpresentingcell,APC）,是介导固有免疫和适应性免疫的桥梁,在机体抗感染、抗肿瘤等方面发挥重要作用。Toll样受体（toll．1ikereceptor,TLRs）是一类重要的模式识别受体（paRemrecognitionreceptors,PRRs）,可识别入侵的病原体相关分子模式（pathogen-associatedmoleculepatterns,PAMPs）,通过招募接头蛋白、活化蛋白激酶和激活转录因子进行信号传导,从而引起效应细胞的活化和促炎因子的释放。不同亚型的DCs分布有不同的TLRs,多种TLRs可识别外来入侵的病原体成分,发挥重要的免疫学作用：诱导DCs分化成熟,摄取递呈抗原,促进DCs分泌多种细胞因子发挥作用。在炎症、病毒感染、自身免疫性疾病和肿瘤等疾病状态下,DCs表面TLRs的表达上调或下调,并且存在功能障碍,可影响DCs的分化成熟,导致其功能低下,这与疾病的发生和发展密切相关。本文综述了TLRs及其信号通路对树突状细胞的活化及功能的影响。     

PRRs in pathogen recognition

The innate immune system provides the first line of host defense against invading microorganisms before the development of adaptive immune responses. Innate immune responses are initiated by germline-encoded pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Toll-like receptors (TLRs) are pattern-recognition receptors that sense a wide range of microorganisms, including bacteria, fungi, protozoa and viruses. TLRs exist either on the cell surface or in the lysosome/endosome compartment and induce innate immune responses. Recently, cytoplasmic PRRs have been identified which detect pathogens that have invaded the cytosol. This review focuses on the pathogen recognition of PRRs in innate immunity.     

A nonredundant role for canonical NF-κB in human myeloid dendritic cell development and function

The plastic role of dendritic cells (DCs) in the regulation of immune responses has made them interesting targets for immunotherapy, but also for pathogens or tumors to evade immunity. Functional alterations of DCs are often ascribed to manipulation of canonical NF-κB activity. However, though this pathway has been linked to murine myeloid DC biology, a detailed analysis of its importance in human myeloid DC differentiation, survival, maturation, and function is lacking. The myeloid DC subsets include interstitial DCs and Langerhans cells. In this study, we investigated the role of canonical NF-κB in human myeloid DCs generated from monocytes (monocyte-derived DCs [mo-DCs]) or CD34(+) progenitors (CD34-derived myeloid DCs [CD34-mDCs]). Inhibition of NF-κB activation during and after mo-DC, CD34-interstitial DC, or CD34-Langerhans cell differentiation resulted in apoptosis induction associated with caspase 3 activation and loss of mitochondrial transmembrane potential. Besides regulating survival, canonical NF-κB activity was required for the acquisition of a DC phenotype. Despite phenotypic differences, however, Ag uptake, costimulatory molecule and CCR7 expression, as well as T cell stimulatory capacity of cells generated under NF-κB inhibition were comparable to control DCs, indicating that canonical NF-κB activity during differentiation is redundant for the development of functional APCs. However, both mo-DC and CD34-mDC functionality were reduced by NF-κB inhibition during activation. In conclusion, canonical NF-κB activity is essential for the development and function of mo-DCs as well as CD34-mDCs. Insight into the role of this pathway may help in understanding how pathogens and tumors escape immunity and aid in developing novel treatment strategies aiming to interfere with human immune responses.     

Calcitonin Gene-Related Peptide Regulates Type IV Hypersensitivity through Dendritic Cell Functions

Dendritic cells (DCs) play essential roles in both innate and adaptive immune responses. In addition, mutual regulation of the nervous system and immune system is well studied. One of neuropeptides, calcitonin gene-related peptide (CGRP), is a potent regulator in immune responses; in particular, it has anti-inflammatory effects in innate immunity. For instance, a deficiency of the CGRP receptor component RAMP 1 (receptor activity-modifying protein 1) results in higher cytokine production in response to LPS (lipopolysaccharide). On the other hand, how CGRP affects DCs in adaptive immunity is largely unknown. In this study, we show that CGRP suppressed Th1 cell differentiation via inhibition of IL-12 production in DCs using an in vitro co-culture system and an in vivo ovalbumin-induced delayed-type hypersensitivity (DTH) model. CGRP also down-regulated the expressions of chemokine receptor CCR2 and its ligands CCL2 and CCL12 in DCs. Intriguingly, the frequency of migrating CCR2⁺ DCs in draining lymph nodes of RAMP1-deficient mice was higher after DTH immunization. Moreover, these CCR2⁺ DCs highly expressed IL-12 and CD80, resulting in more effective induction of Th1 differentiation compared with CCR2⁻ DCs. These results indicate that CGRP regulates Th1 type reactions by regulating expression of cytokines, chemokines, and chemokine receptors in DCs.     

Host responses from innate to adaptive immunity after vaccination: Molecular and cellular events

The availability of effective vaccines has had the most profound positive effect on improving the quality of public health by preventing infectious diseases. Despite many successful vaccines, there are still old and new emerging pathogens against which there is no vaccine available. A better understanding of how vaccines work for providing protection will help to improve current vaccines as well as to develop effective vaccines against pathogens for which we do not have a proper means to control. Recent studies have focused on innate immunity as the first line of host defense and its role in inducing adaptive immunity; such studies have been an intense area of research, which will reveal the immunological mechanisms how vaccines work for protection. Toll-like receptors (TLRs), a family of receptors for pathogen-associated molecular patterns on cells of the innate immune system, play a critical role in detecting and responding to microbial infections. Importantly, the innate immune system modulates the quantity and quality of longterm T and B cell memory and protective immune responses to pathogens. Limited studies suggest that vaccines which mimic natural infection and/or the structure of pathogens seem to be effective in inducing long-term protective immunity. A better understanding of the similarities and differences of the molecular and cellular events in host responses to vaccination and pathogen infection would enable the rationale for design of novel preventive measures against many challenging pathogens.     

Interactions of tumor cells with dendritic cells: balancing immunity and tolerance

Dendritic cells (DCs) are antigen-presenting cells specialized to initiate and maintain immunity and tolerance. DCs initiate immune responses in a manner that depends on signals they receive from pathogens, surrounding cells and their products. Most tumors are infiltrated by DCs. Thus, interactions between DCs and dying tumor cells may determine the balance between immunity and tolerance to tumor cells. In addition, DCs also display non-immunologic effects on tumors and the tumor microenvironment. Therefore, improved understanding of the cross talk between tumor cells and DCs may suggest new approaches to improve cancer therapy.     

Characterizing gene movements between chromosomes in Drosophila

Drosophila have a variety of innate immune strategies for defending itself from infection, including humoral and cell mediated responses to invading microorganisms. At the front lines of these responses, are a diverse group of pattern recognition receptors that recognize pathogen associated molecular patterns. These patterns include bacterial lipopolysaccharides, peptidoglycans, and fungal β?1,3 glucans. Some of the receptors catalytically modify the pathogenic determinant, but all are responsible for directly facilitating a signaling event that results in an immune response. Some of these events require multiple pattern recognition receptors acting sequentially to activate a pathway. In some cases, a signaling pathway may be activated by a variety of different pathogens, through parallel receptors detecting different pathogenic determinants. In this chapter, we review what is known about pattern recognition receptors in Drosophila, and how those lessons may be applied towards a broader understanding of immunity.