Notch system in the linkage of innate and adaptive immunity

The lung is one of the most immunologically challenged organs and can be affected by a number of pathogens, including bacteria, virus, fungi, and parasites. The development and chronicity of pulmonary infection are determined by the early innate response to the pathogenic stimuli and are regulated at multiple levels. Initial studies have indicated that the interaction of Notch and Notch ligands plays a critical role during development, and further, the Notch system is an important bridge between APCs and T cell communication circuits. APCs are essential regulators of the innate immune response. They can respond to PAMPs through PRRs, which function in the recognition of pathogenic components and play an important role in the innate and adaptive immune response. T cells are essential regulators of adaptive immune responses and infectious diseases. However, the role of the Notch system in the cross-talk between APC and T cells during pulmonary infection is still poorly understood. In the present review, we discuss recent findings that explore the mechanisms underlying the role of Notch signaling in the linkage of innate and adaptive immunity, including pulmonary infection though PPRs and Notch activation.     

The impact of eicosanoids on the crosstalk between innate and adaptive immunity: the key roles of dendritic cells

The innate immune response is essentially the first line of defense against an invading pathogen. Through specialized receptors, known as pattern recognition receptors, especially Toll-like receptors, specialized cells of myeloid origin, including macrophages and dendritic cells (DCs) are able to phagocytose microorganisms and induce an innate inflammatory response. Although B and T lymphocytes recognize tissue antigens with high specificity, they are unable to initiate immune responses. The decision to activate an appropriate immune response is made by unique DC, the most professional antigen-presenting cells (APCs) which control the responses of several types of lymphocytes and play central role in the transition between innate and adaptive immunity. Increased secretion of inflammatory endogenous mediators such as cytokines and arachidonic acid-derived lipid mediators, also termed eicosanoids, can activate APC, particularly DC, which in turn induce an adaptive immune response. There is an increasing evidence that eicosanoids play an important role in connecting innate and adaptive immunity by acting on cells of both systems. Prostanoids, a major class of eicosanoids, have a great impact on inflammatory and immune responses. PGE(2) is one of the best known and most well-characterized prostanoids in terms of immunomodulation. Although cytokines are known as key regulators of immunity, eicosanoids, including PGE(2), PGD(2), LTB(4), and LTC(4), may also affect cells of immune system by modulating cytokine release, cell differentiation, survival, migration, antigen presentation, and apoptosis. By acting on various aspects of immune and inflammatory reactions, these lipid mediators emerge as key regulators of the crosstalk between innate and adaptive immunity.     

Antigen delivery by dendritic cells

Dendritic cells (DC) link the innate and adaptive arms of the immune system and thus orchestrate the immune response to pathogens. A novel immune intervention strategy to control infectious diseases is based on the use of the potent immunostimulatory properties of DC for vaccination and immunotherapy. Recent advances in our understanding of DC biology and the molecular mechanisms by which DC instruct the development of an appropriate immune response to microorganisms provide means for DC-based approaches to manipulate the immune system. In experimental systems, DC vaccination has been documented to mediate protection against a wide spectrum of infectious diseases caused by viral, bacterial, parasitic and fungal pathogens. The protocols for the generation, stimulation and antigen loading of DC are being optimized, and methods for DC targeting in situ are likely to become available soon, thus paving the way for clinical applications of DC-based vaccines.     

Volatile Anesthetics and Immunity

Historically, volatile anesthetics have demonstrated interesting interactions with both the innate and adaptive immune systems. This review organizes these interactions into four phases: recognition, recruitment, response, and resolution. These phases represent a range of proinflammatory, inflammatory, and innate and adaptive immune regulatory responses. The interaction between volatile anesthetics and the immune system is discussed in the context of pathogenesis of infectious disease.     

Control of adaptive immune responses by Toll-like receptors

Recently, there has been considerable interest in how adaptive immune responses are controlled by the innate immune system. In particular, researchers have focused on how the differentiation of CD4 T cells is directed upon priming by dendritic cells. The identification of the Toll-like receptors as a family of pattern-recognition receptors involved in controlling dendritic cell activation has focused attention on these receptors as possible regulators of adaptive immune responses. However, recent studies have suggested that Toll-like receptors may only control the induction of Th1 responses and that a separate system of recognition regulates Th2 responses.     

To be or not to be a pathogen: that is the mucosally relevant question

The human interface with the microbial world has so far largely been considered through the somewhat restrictive angle of host–pathogen interactions resulting in disease. It has consequently largely ignored the daily symbiosis with the microbiota, an ensemble of symbiotic microorganisms engaged in a commensal, and for some of them mutualistic, interaction. This microbiota heavily populates essential surfaces such as the oral and intestinal cavity, the upper respiratory tract, the vagina, and the skin. Host response to the pathogens is characterized by quick recognition combined with strong innate (i.e., inflammatory) and adaptive immune responses, causing microbial eradication often at the cost of significant tissue damage. Response to the symbiotic microbiota is characterized by a process called tolerance that encompasses a complex integration of microbial recognition and tightly controlled innate (i.e., physiological inflammation) and adaptive immune responses. This dichotomy in host response is critical at the gut mucosal surface that is massively colonized by a diverse population of bacteria. The host is therefore permanently facing the challenge of discriminating among symbiotic and pathogenic bacteria in order to offer an adapted response. This asks the fundamental existential question: “to be or not to be… a pathogen.” This review has attempted to consider this question from the host angle. What do host mucosal sensing systems see in the bacteria to which they become exposed to establish proper discrimination? A new facet of medicine resides in the dysfunction of this complex balance that has likely forged the complexity of the immune system.     

The master regulators of allergic inflammation: dendritic cells in Th2 sensitization

The development of Th2 responses to inhaled proteins represents a malfunction of the adaptive immune system in that protein antigens are not microbial in nature and should not elicit an adaptive immune reaction. This derailing of the immune system may result from false alarms generated by the innate immune system, resulting in unexpected dendritic cell (DC) maturation after exposure to allergens. Conditions in the local microenvironment during DC maturation may also result in the preferential induction of Th2 responses. Recent progress has been made in our understanding of the role of DCs in both Th2 sensitization to aeroallergens and the regulation of Th2 and Th1 immunity.     

Toll-like receptors and their function in innate and adaptive immunity

Over the past 3 years our knowledge about how we sense the microbial world has been fundamentally changed. It has been known for decades that microbial products, such as lipopolysaccharide, lipoproteins, or peptidoglycan, have a profound activity on human cells. Whereas the structure of many different pathogenic microbial compounds has been extensively studied and characterized, the molecular basis of their recognition by the cells of the innate immune system remained elusive for a long time. It was Charles Janeway [Cold Spring Harb Symp Quant Biol 1989;54/1:1-13] who developed the idea of microbial structures forming pathogen-associated molecular patterns that would be recognized by pattern recognition receptors. The discovery of the family of Toll receptors in species as diverse as DROSOPHILA and humans, and the recognition of their role in distinguishing molecular patterns that are common to microorganisms have led to a renewed appreciation of the innate immune system. Moreover, it is now clear that the activation of the innate immune system through mammalian Toll-like receptors has also an instructive role for the responses of the adaptive immune response and, thus, may influence allergic diseases such as asthma.     

TLRs, NLRs and RLRs: innate sensors and their impact on allergic diseases--a current view

Charles Janeway first wrote 1989 about how important recognition of "certain characteristics or patterns common on infectious agents but absent from the host" would be for our immune response [1]. Surprisingly, it almost took 10 years before his ideas would lead to the revolutionary findings that fundamentally changed the view of the innate immune system over the past decade. Recognition of invading microorganisms belongs to the primary tasks of the innate immune system and is achieved through different families of innate immune sensors. Among these, Toll-like receptors (TLRs), nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs) and Rig-I-like receptors (RLRs) have drawn major interests over the last decade. These receptor families are targeted by overlapping classes of pathogens and share functional domains and signal transduction pathways (see Fig. 1 and Table 1 for an overview of their structural organization, ligands, adaptors and activated pathways). This current view describes our present knowledge about these three main innate immune receptor families and their importance for adaptive immune responses such as asthma and allergy.     

Antibacterial immunity in respiratory tract: what role for the myeloid differentiation primary response protein 88 (MyD88) adaptor?

As an essential interface between the external environment and the organism, the respiratory tract is particularly exposed to the potential injuries due to microorganisms, such as bacteria. Against these aggressions, the immune system has a key role, involving detection of germs followed by the establishment of innate and adaptive immune processes. During these responses, the adaptor protein MyD88 has a central place in the development of immune response: i) it contributes to innate immune response through the production of cytokines and chemokines, allowing recruitment and activation of effector cells; ii) it is involved secondarily in the development and orientation of antibacterial adaptive response, iii) and participates in sustaining immune homeostasis. Its importance is reflected in human pathology (MyD88 hereditary deficiency) by increasing susceptibility to few pathogenic bacteria responsible for respiratory infections which mainly occur in the upper respiratory tract. Since it has a key role, MyD88 is an essential factor for antibacterial immunity and more broadly for anti-infectious immunity. This protein might be therefore a possible therapeutic target.     

Innate immune recognition: mechanisms and pathways

Summary: The innate immune system is an evolutionarily ancient form of host defense found in most multicellular organisms. Inducible responses of the innate immune system are triggered upon pathogen recognition by a set of pattern recognition receptors. These receptors recognize conserved molecular patterns shared by large groups of microorganisms. Recognition of these patterns allows the innate immune system not only to detect the presence of an infectious microbe, but also to determine the type of the infecting pathogen. Pattern recognition receptors activate conserved host defense signaling pathways that control the expression of a variety of immune response genes.     

Innate lymphocyte and dendritic cell cross-talk: a key factor in the regulation of the immune response

Dendritic cells (DC) are specialized in the presentation of antigens and the initiation of specific immune responses. They have been involved recently in supporting innate immunity by interacting with various innate lymphocytes, such as natural killer (NK), NK T or T cell receptor (TCR)-gammadelta cells. The functional links between innate lymphocytes and DC have been investigated widely and different studies demonstrated that reciprocal activations follow on from NK/DC interactions. The cross-talk between innate cells and DC which leads to innate lymphocyte activation and DC maturation was found to be multi-directional, involving not only cell-cell contacts but also soluble factors. The final outcome of these cellular interactions may have a dramatic impact on the quality and strength of the down-stream immune responses, mainly in the context of early responses to tumour cells and infectious agents. Interestingly, DC, NK and TCR-gammadelta cells also share similar functions, such as antigen uptake and presentation, as well as cytotoxic and tumoricidal activity. In addition, NK and NK T cells have the ability to kill DC. This review will focus upon the different aspects of the cross-talk between DC and innate lymphocytes and its key role in all the steps of the immune response. These cellular interactions may be particularly critical in situations where immune surveillance requires efficient early innate responses.     

Evolution of complement as an effector system in innate and adaptive immunity

For a long time, the complement system in mammals has been regarded as a biological system that plays an essential role in innate immunity. More recently, it has been recognized that the complement system contributes heavily to the generation and development of an acquired immune response. In fact, this ancient mechanism of defense has evolved from a primitive mechanism of innate immune recognition in invertebrate species to that of an effector system that bridges the innate with the adaptive immune response in vertebrate species. When and how did complement evolve into a shared effector system between innate and adaptive immunity? To answer this question, our group is interested in understanding the role of complement in innate and adaptive immune responses in an evolutionary relevant species: the teleost fish. The attractiveness of this species as an animal model is based on two important facts. First, teleost fish are one of the oldest animal species to have developed an adaptive immune response. Second, the complement system of teleost fish offers a unique feature, which is the structural and functional diversity of its main effector protein, C3, the third component of the complement system.     

Innate signaling and regulation of Dendritic cell immunity

Dendritic cells are crucial in pathogen recognition and induction of specific immune responses to eliminate pathogens from the infected host. Host recognition of invading microorganisms relies on evolutionarily conserved, germline-encoded pattern-recognition receptors (PRRs) that are expressed by DCs. The best-characterized PRR family comprises the Toll-like receptors (TLRs) that recognize bacteria or viruses. In addition to TLRs, intracellular Nod-like receptors and the membrane-associated C-type lectins (CLRs) function as PRRs. Many of these innate receptors also have an important function in natural host homeostatic responses, such as the maintenance of gut homeostasis. Clearly, more indications are hinting at a fine-tuning of immune responses by a concerted action of these PRRs on the recognition of pathogen components and the consequent signalling events that are created. It is becoming increasingly clear that these PRRs can initiate specific signalling events that modulate the production of inflammatory cytokines, phagocytosis, intracellular routing of antigen, release of oxidative species and DC maturation and the subsequent development of adaptive immunity. Notably, members within one family of PRRs can trigger opposite signalling features, indicating that the ultimate outcome of pathogen-induced immune responses depends on the pathogen signature and the collective PRRs involved.     

Dendritic cells and fungi

Fungi comprise a group of microorganisms that in the past 20 years has become increasingly important as a cause of human disease. Few fungi are professional but instead opportunistic pathogens, and some fungi can even act as allergens. Dendritic antigen-presenting cells function as a link between innate and adaptive immunity and are therefore important in recognition of pathogens. Effective defense requires the host to discriminate between different pathogens to induce an appropriate response. Signaling from different groups of microbes can be mediated via the Toll-like receptors (TLRs), leading to activation of conserved host defense signaling pathways that control the expression of a variety of immune response genes. Different dendritic cells (DCs) express different patterns of recognition molecules, which indicate that they are more or less efficient when responding to certain pathogens. DCs have an important role in the induction of cell-mediated immune responses to fungi, and the studies reviewed here show that fungi, or possibly fungi-derived factors, provide a powerful activation stimulus to DCs, resulting in DC maturation with upregulation of co-stimulatory molecules and production of cytokine patterns leading to different T cell responses. The possibility of using ex vivo-generated DCs as therapeutic tools for restoring anti-fungal immunity is a challenge for the future.     

The regulation of dendritic cell function by calcium-signaling and its inhibition by microbial pathogens

Dendritic cells (DC) are the sentinels of the immune system, linking innate with adaptive responses. The functional responses of DC are subject to complex regulation and serve as targets for pathogens. Ca2+-mediated signal transduction pathways serve a central regulatory role in DC responses to diverse antigens, including TLR ligands, intact bacteria, and microbial toxins. This review summarizes the major mechanisms of Ca2+-signaling that DC utilize to regulate maturation and antigen presentation, including a Ca2+-calmodulin (CaM)-CaM kinase II pathway that is localized to phagosomes and is targeted by the human intracellular pathogen, Mycobacterium tuberculosis. Restoration of functional Ca2+ signaling in DC may provide a novel mechanism to enhance therapy and promote vaccine efficacy to infectious diseases, including tuberculosis.     

The role of Toll-like receptors and Nod proteins in bacterial infection

Our understanding of innate immunity in mammals has greatly expanded following the discovery of the family of membrane-bound receptors, called the Toll-like receptors (TLRs). More recently, the nucleotide-binding oligomerisation domain (Nod) molecules, Nod1 and Nod2, which are cytoplasmic surveillance proteins, have also been shown to be involved in the innate immune response. These two classes of detection molecules, classified as "pattern recognition receptors" (PRRs), detect microbial ligands in order to initiate a defense response to fight infectious disease. These microbial ligands or "pathogen-associated molecular patterns" (PAMPs), detected by TLRs and Nods are often structural components of the microorganism that are not subject to much variation. These include such factors as lipopolysaccharide (LPS) and peptidoglycan from the cell walls of bacteria. In order to understand the role of TLRs and Nod proteins in infectious disease in vivo it is important to define the site of interaction between PRRs and PAMPS. Additionally, the challenge of mice deficient in the various PRRs in natural infection models will help to decipher the contribution of these molecules not only in the innate immune response against pathogen infection but also how these proteins may instruct the adaptive immune response in order to have a tailored immune response against a particular microbe.     

The porcine dendritic cell family

Considering the pivotal roles played by dendritic cells (DCs) in both innate and adaptive immune responses, advances in the field of porcine immunology DC biology have recently progressed rapidly. As with the more extensively studied murine and human DCs, porcine DC can be generated from bone marrow haematopoietic cells or monocytes, and have been analysed in various immunological and non-immunological tissues. Both conventional DC (cDC) and plasmacytoid DC (pDC) have been characterized. The function of porcine monocyte-derived DC has not only been characterized in terms of antigen presentation and lymphocyte activation, but also their response to various ligands of pattern recognition receptors. These have been characterized in terms of the induction of DC maturation and pro-inflammatory, Th1-like or Th2-like cytokines secretion. Porcine pDC most effectively sense virus infections and are characterized by their capacity to produce large quantities of IFN-alpha and the pro-inflammatory cytokines TNF-alpha, IL-6 and IL-12. As such, the DC family as a whole is a powerful ally in the host battle against pathogen attack. Nevertheless, DC in particular tissue environments or under particular stimuli can down-regulate immune response development. This is not only important for preventing over-activation of the immune system and also for ensuring tolerance against self or "friendly" substances including food components, but may also be used as a mechanism of pathogens to evade immune responses.     

Pattern recognition receptors: sentinels in innate immunity and targets of new vaccine adjuvants

The innate immune system plays an essential role in the host's first line of defense against microbial invasion, and involves the recognition of distinct pathogen-associated molecular patterns by pattern recognition receptors (PRRs). Activation of PRRs triggers cell signaling leading to the production of proinflammatory cytokines, chemokines and Type 1 interferons, and the induction of antimicrobial and inflammatory responses. These innate responses are also responsible for instructing the development of an appropriate pathogen-specific adaptive immune response. In this review, the focus is on different classes of PRRs that have been identified, including Toll-like receptors, nucleotide-binding oligomerization domain-like receptors, and the retinoic acid-inducible gene-I-like receptors, and their importance in host defense against infection. The role of PRR cooperation in generating optimal immune responses required for protective immunity and the potential of targeting PRRs in the development of a new generation of vaccine adjuvants is also discussed.     

Recognition of nucleic acid and nucleic acid analogs by Toll-like receptors 7, 8 and 9

The mammalian immune system senses pathogens through pattern recognition receptors (PRR) and responds with activation. Toll-like receptors (TLRs) that are expressed on immune and non-immune cells play a critical role in this process. As part of the innate immune response, TLRs lead to cellular activation and cytokine production with subsequent initiation of an adaptive immune response. TLR7-9 recognize single-stranded RNA, nucleoside analogs and single-stranded CpG-DNA, respectively, and their activation initiates the immune response against viruses and bacteria. Furthermore, the stimulation of these TLRs may be exploited for adjuvant therapy, vaccination and anti-tumor responses. However, a role in the generation or perpetuation of autoimmune diseases such as systemic lupus erythematosus (SLE) has also been suggested.