Teleost IgSF immunoregulatory receptors

In all animals innate immunity is the first line of immune defense from invading pathogens. The prototypical innate cellular responses such as phagocytosis, degranulation, and cellular cytotoxicity are elicited by leukocytes in a diverse range of animals including fish, amphibians, birds and mammals reinforcing the importance of such primordial defense mechanisms. In mammals, these responses are intricately controlled and coordinated at the cellular level by distinct subsets of immunoregulatory receptors. Many of these surface proteins belong to the immunoglobulin superfamily and in mammals elaborate immunoregulatory receptor networks play a major role in the control of infectious diseases. Recent examination of teleost immunity has begun to further illustrate the complexities of these receptor networks in lower vertebrates. However, little is known about the mechanisms that control how immunoregulatory receptors influence cellular decision making in ectothermic vertebrates. This review focuses on several families of recently discovered immunoglobulin superfamily members in fish that share structural, phylogenetic and in some cases functional relationships with mammalian immunoregulatory receptors. Further characterization of these teleost innate immune receptor families will provide detailed information regarding the conservation and importance of innate immune defense strategies throughout vertebrate evolution.     

Evolution and diversity of the complement system of poikilothermic vertebrates

Summary: In mammals the complement system plays an important role in innate and acquired host defense mechanisms against infection and in various immunoregulatory processes. The complement system is an ancient defense mechanism that is already present in the invertebrate deuterostomes. In these species as well as in agnathans (the most primitive vertebrate species), both the alternative and lectin pathway of complement activation are already present, and the complement system appears to be involved mainly in opsonization of foreign material. With the emergence of immunoglobulins in cartilaginous fish, the classical and lytic pathways first appear. The rest of the poikilothermic species, from teleosts to reptilians, appear to contain a well-developed complement system resembling that of homeothermic vertebrates. However, important differences remain. Unlike homeotherms, several species of poikilotherms have recently been shown to possess multiple forms of complement components (C3 and factor B) that are structurally and functionally more diverse than those of higher vertebrates. It is noteworthy that the multiple forms of C3 that have been characterized in several teleost fish are able to hind with varying efficiencies to various complement-activating surfaces. We hypothesize that this diversity has allowed these animals to expand their innate capacity for immune recognition.     

The fight between the teleost fish immune response and aquatic viruses

Teleost fish represent a transition point on the phylogenetic spectrum between invertebrates that depend only on innate immunity and mammals that heavily depend on adaptive immunity. The major mechanisms of the teleost fish innate immune response are suggested to be similar to mammals, although fine details of the process require further studies. Within the innate immune response the type I interferon (IFN) system is an essential innate antiviral component that protects fish from some virus infections. The current progress of cloning and functional characterization of fish antiviral genes is promising in further elucidation of the fish antiviral response. The adaptive immune system of fish utilizes cellular components more or less similar to mammals. Teleost fish produce IgM as a primary antibody response and lack isotype switching to mount virus-specific antibodies during the infection process. Despite this, the development of successful fish rhabdoviral vaccines suggest that vaccination may prove to be an effective way of promoting fish adaptive immune responses to viruses. This paper reviews the bony fish antiviral response with specific discussion on the evolutionary mechanisms that allow aquatic viruses to co-exist with their host. Detailed aspects of the teleost type I IFN system are also addressed.     

The fight between the teleost fish immune response and aquatic viruses

Teleost fish represent a transition point on the phylogenetic spectrum between invertebrates that depend only on innate immunity and mammals that heavily depend on adaptive immunity. The major mechanisms of the teleost fish innate immune response are suggested to be similar to mammals, although fine details of the process require further studies. Within the innate immune response the type I interferon (IFN) system is an essential innate antiviral component that protects fish from some virus infections. The current progress of cloning and functional characterization of fish antiviral genes is promising in further elucidation of the fish antiviral response. The adaptive immune system of fish utilizes cellular components more or less similar to mammals. Teleost fish produce IgM as a primary antibody response and lack isotype switching to mount virus-specific antibodies during the infection process. Despite this, the development of successful fish rhabdoviral vaccines suggest that vaccination may prove to be an effective way of promoting fish adaptive immune responses to viruses. This paper reviews the bony fish antiviral response with specific discussion on the evolutionary mechanisms that allow aquatic viruses to co-exist with their host. Detailed aspects of the teleost type I IFN system are also addressed.     

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.     

Antimicrobial mechanisms of fish leukocytes

Early activation and coordination of innate defenses are critical for effective responses against infiltrating pathogens. Rapid engagement of immune cells provides a critical first line of defense soon after pathogen infiltration. Activation leads to a well-orchestrated set of events that sees the induction and regulation of intracellular and extracellular antimicrobial defenses. An array of regulatory mediators, highly toxic soluble molecules, degradative enzymes and antimicrobial peptides provides maximal protection against a wide range of pathogens while limiting endogenous damage to host tissues. In this review we highlight recent advances in our understanding of innate cellular antimicrobial responses of teleost fish and discuss their implications to cell survival, immunomodulation and death. The evolutionary conservation of these responses is a testament to their effectiveness against pathogen infiltration and their commitment to effective maintenance of host homeostasis. Importantly, recent developments in teleost fish systems have identified novel host defense strategies that may be unique to this lower vertebrate group or may point to previously unknown innate mechanisms that also play a significant role in higher vertebrate host immunity.     

Characterization of the CCR3 and CCR9 genes in miiuy croaker and different selection pressures imposed on different domains between mammals and teleosts

The innate immune system can recognize non-self through pattern recognition receptors and provides a first line of antimicrobial host defense. Thus innate immunity plays a very important role in resistance against major bacterial disease in vertebrates. In the innate immune responses, the chemokine receptors act as the main receptors of chemokines which are released at the sites of infection, inflammation and injury. In this study, the Miichthys miiuy CCR3 and CCR9 genes were cloned and characterized, showing that MIMI-CCR3 possesses a highly conserved DRYLA motif similar to that of other fishes. MIMI-CCR3 and CCR9 were ubiquitously expressed in all tested tissues and the expressions were significantly up-regulated after infection with Vibrio anguillarum except that of CCR9 in spleen. Evolutionary analysis showed that all the ancestral lineages of CCR3 and CCR9 in mammals and teleosts underwent positive selection, indicating that the ancestor of terrestrial animals further evolved to adapt to terrestrial environments and the continuous intrusion of microbes stimulated the evolution of CCR genes in the ancestor of teleost. Multiple ML methods were used to detect the robust candidates for sites under positive selection. In total, 11 and 8 positively selected sites were found in the subsets of current mammal and teleost CCR3 genes, and 3 and 2 sites were detected in the subsets of current mammals and teleosts in CCR9. Interestingly, for mammal CCR3 and CCR9 genes, the robust candidates of positively selected sites were mainly located in the extracellular domains which were the ligand binding and pathogen interaction regions. For teleost CCR3 and CCR9 genes, the positively selected sites were not only located in the extracellular domains but also in the C-terminal and intracellular domains, indicating mammals and teleosts experienced different selection pressures upon their N-terminus, C-terminus and intracellular loops of CCRs.     

Innate immune memory in plants

The plant innate immune system comprises local and systemic immune responses. Systemic plant immunity develops after foliar infection by microbial pathogens, upon root colonization by certain microbes, or in response to physical injury. The systemic plant immune response to localized foliar infection is associated with elevated levels of pattern-recognition receptors, accumulation of dormant signaling enzymes, and alterations in chromatin state. Together, these systemic responses provide a memory to the initial infection by priming the remote leaves for enhanced defense and immunity to reinfection. The plant innate immune system thus builds immunological memory by utilizing mechanisms and components that are similar to those employed in the trained innate immune response of jawed vertebrates. Therefore, there seems to be conservation, or convergence, in the evolution of innate immune memory in plants and vertebrates.     

Evolution of adaptive immune recognition in jawless vertebrates

All extant vertebrates possess an adaptive immune system wherein diverse immune receptors are created and deployed in specialized blood cell lineages. Recent advances in DNA sequencing and developmental resources for basal vertebrates have facilitated numerous comparative analyses that have shed new light on the molecular and cellular bases of immune defense and the mechanisms of immune receptor diversification in the “jawless” vertebrates. With data from these key species in hand, it is becoming possible to infer some general aspects of the early evolution of vertebrate adaptive immunity. All jawed vertebrates assemble their antigen-receptor genes through combinatorial recombination of different “diversity” segments into immunoglobulin or T-cell receptor genes. However, the jawless vertebrates employ an analogous, but independently derived set of immune receptors in order to recognize and bind antigens: the variable lymphocyte receptors (VLRs). The means by which this locus generates receptor diversity and achieves antigen specificity is of considerable interest because these mechanisms represent a completely independent strategy for building a large immune repertoire. Therefore, studies of the VLR system are providing insight into the fundamental principles and evolutionary potential of adaptive immune recognition systems. Here we review and synthesize the wealth of data that have been generated towards understanding the evolution of the adaptive immune system in the jawless vertebrates.     

Examination of the stimulatory signaling potential of a channel catfish leukocyte immune-type receptor and associated adaptor

Expressed by various subsets of myeloid and lymphoid immune cells, channel catfish (Ictalurus punctatus) leukocyte immune-type receptors (IpLITRs) are predicted to play a key role in the initiation and termination of teleost cellular effector responses. These type I transmembrane proteins belong to the immunoglobulin superfamily and display features of immunoregulatory receptors with inhibitory and/or stimulatory signaling potential. Expanding on our previous work, which demonstrated that putative stimulatory IpLITR-types associated with the catfish adaptor proteins IpFcRγ and FcRγ-L, this study focuses on the functional significance of this immune receptor-adaptor signaling complex. Specifically, we generated an epitope-tagged chimeric receptor construct by fusing the extracellular domain of IpLITR 2.6b with the transmembrane region and cytoplasmic tail of IpFcRγ-L. This chimera was stably expressed in a rat basophilic leukemia (RBL) cell line, RBL-2H3, and following cross-linking of the surface receptor with an anti-hemagglutinin monoclonal antibody or opsonized microspheres, the chimeric teleost receptor induced cellular degranulation and phagocytic responses, respectively. Site-directed mutagenesis of the immunoreceptor tyrosine-based activation motif encoded within the cytoplasmic tail of the chimera confirmed that these functional responses were dependent on the phosphorylated tyrosines within this motif. Using a combination of phospho-specific antibodies and pharmacological inhibitors, we also demonstrate that the IpLITR/IpFcRγ-L-induced degranulation response requires the activity of Src homology 2 domain containing protein tyrosine phosphatases, phosphatidylinositol 3-kinase, protein kinase C, and mitogen-activated protein kinases but appears independent of the c-Jun N-terminal kinase and p38 MAP kinase pathways. In addition to this first look at stimulatory IpLITR-mediated signaling and its influence on cellular effector responses, the advantage of generating RBL-2H3 cells stably expressing a functional IpLITR-adaptor chimera will be discussed.     

The relationship between major histocompatibility receptors and innate immunity in teleost fish

Studies of the innate immune system have recently shown that, in addition to its role in producing the primary response that slows down pathogens, it may also play an important role in initiating and directing the type of response that the adaptive immune system makes. These discoveries have shown a complex web of control containing new roles for the innate immune system in organizing responses of T-cell to antigens being presented by major histocompatibility receptors, as well as new roles for those receptors in innate immune responses. Both of these activities are managed through feedback networks involving elements of both the innate and adaptive immune system. This paper will discuss these newly discovered interactions and how they are influencing current theories regarding the initiation of adaptive immune responses. In particular, it will highlight the recent progress that is being made towards understanding these relationships in the immune systems of teleost fish.     

Toll-like receptors: cellular signal transducers for exogenous molecular patterns causing immune responses

Innate immunity initiates protection of the host organism against invasion and subsequent multiplication of microbes by specific recognition. Germ line-encoded receptors have been identified for microbial products such as mannan, lipopeptide, peptidoglycan (PGN), lipoteichoic acid (LTA), lipopolysaccharide (LPS), and CpG-DNA. The Drosophila Toll protein has been shown to be involved in innate immune response of the adult fruitfly. Members of the family of Toll-like receptors (TLRs) in vertebrates have been implicated as pattern recognition receptors (PRRs). Ten TLRs are known and six of these have been demonstrated to mediate cellular activation by distinct microbial products. TLR4 has been implicated as activator of adaptive immunity, and analysis of systemic LPS responses in mice led to the identification of LPS-resistant strains instrumental in its identification as a transmembrane LPS signal transducer. Structural similarities between TLRs and receptor molecules involved in immune responses such as CD14 and the IL-1 receptors (IL-1Rs), as well as functional analysis qualified TLR2 as candidate receptor for LPS and other microbial products. Targeted disruption of the TLR9 gene in mice led to identification of TLR9 as CpG-DNA signal transducer. Involvement of TLR5 in cell activation by bacterial flagellin has been demonstrated. Further understanding of recognition and cellular signaling activated through the ancient host defense system represented by Toll will eventually lead to means for its therapeutic modulation.     

Structural and functional diversity of the lectin repertoire in teleost fish: Relevance to innate and adaptive immunity

Protein–carbohydrate interactions mediated by lectins have been recognized as key components of innate immunity in vertebrates and invertebrates, not only for recognition of potential pathogens, but also for participating in downstream effector functions, such as their agglutination, immobilization, and complement-mediated opsonization and killing. More recently, lectins have been identified as critical regulators of mammalian adaptive immune responses. Fish are endowed with virtually all components of the mammalian adaptive immunity, and are equipped with a complex lectin repertoire. In this review, we discuss evidence suggesting that: (a) lectin repertoires in teleost fish are highly diversified, and include not only representatives of the lectin families described in mammals, but also members of lectin families described for the first time in fish species; (b) the tissue-specific expression and localization of the diverse lectin repertoires and their molecular partners is consistent with their distinct biological roles in innate and adaptive immunity; (c) although some lectins may bind endogenous ligands, others bind sugars on the surface of potential pathogens; (d) in addition to pathogen recognition and opsonization, some lectins display additional effector roles, such as complement activation and regulation of immune functions; (e) some lectins that recognize exogenous ligands mediate processes unrelated to immunity: they may act as anti-freeze proteins or prevent polyspermia during fertilization.     

Structural and functional diversity of the lectin repertoire in teleost fish: relevance to innate and adaptive immunity

Protein-carbohydrate interactions mediated by lectins have been recognized as key components of innate immunity in vertebrates and invertebrates, not only for recognition of potential pathogens, but also for participating in downstream effector functions, such as their agglutination, immobilization, and complement-mediated opsonization and killing. More recently, lectins have been identified as critical regulators of mammalian adaptive immune responses. Fish are endowed with virtually all components of the mammalian adaptive immunity, and are equipped with a complex lectin repertoire. In this review, we discuss evidence suggesting that: (a) lectin repertoires in teleost fish are highly diversified, and include not only representatives of the lectin families described in mammals, but also members of lectin families described for the first time in fish species; (b) the tissue-specific expression and localization of the diverse lectin repertoires and their molecular partners is consistent with their distinct biological roles in innate and adaptive immunity; (c) although some lectins may bind endogenous ligands, others bind sugars on the surface of potential pathogens; (d) in addition to pathogen recognition and opsonization, some lectins display additional effector roles, such as complement activation and regulation of immune functions; (e) some lectins that recognize exogenous ligands mediate processes unrelated to immunity: they may act as anti-freeze proteins or prevent polyspermia during fertilization.     

Nonspecific cytotoxic cells and innate immunity: regulation by programmed cell death

Although programmed cell death (PCD) and the cellular pathology of apoptosis have been extensively studied in mammals and invertebrates, little is known regarding these important regulatory processes in cold blooded vertebrates, especially teleost fish. In the present review, select immunoregulatory properties of PCD/apoptosis in nonspecific cytotoxic cells (NCC) from catfish and tilapia were identified. The techniques used to define the characteristics of PCD in NCC were DNA ploidy, Annexin-V binding and cellular morphology. Using these procedures, we determined that the biochemical/genetic changes that NCC undergo during PCD are similar to those described in mammalian cells. We hypothesize that one immediate response of NCC to acute stress in teleost fish is the release of apoptosis regulatory factors (ARF) or stress activated serum factors (SASF) into the peripheral blood. These cytokine-like factors activate NCC by protecting them from initiation of: ‘activation induced cell death’ (AICD); from ‘receptor induced apoptosis’; and from initiation of dexamethasone induced DNA hypoploidy. We predict that the mechanism of these actions is enhanced NCC recycling capacity and initiation of migration of NCC into sites of inflammation.

In this review, studies were also summarized regarding the expression and release of ‘death and survival proteins’ by NCC. Although the survey was not exhaustive, we showed that tilapia NCC that were activated in vitro with SASF contained increased levels of two adaptor proteins (i.e. CAS, FADD) and soluble FasL. At present the relevance of expression of the adaptor proteins by NCC is not known, however, additional evidence for the role of FasL in NCC innate immune responses was presented. Interestingly, NCC contained constitutive cytosolic FasL, and activation with tumor cells caused a significant decrease in the cytoplasmic levels of this ‘death protein’. This indicated that FasL in NCC may function as a secretory cytokine-like molecule. Unlike mammalian NK cells and T-cells, activated NCC do not express membrane FasL. A level of phosphatase regulation of NCC apoptosis was indicated by demonstrating a reduced camptothecin induce DNA hypoploidy by pretreatment of NCC with the tyrosine phosphatase inhibitor sodium orthovanadate. This review emphasized the important regulatory functions of PCD/apoptosis for NCC in innate immune responses.     

Critical roles of Toll-like receptors in host defense

Drosophila Toll is involved not only in dorsoventral patterning of embryos but also in immune responses to microbial infection. Several Toll-like receptors (TLRs) have also been identified in mammals. They are expressed on macrophages or dendritic cells (DCs), which are essential sentinels for innate immunity. These cells utilize TLRs as a recognition and signal transducing receptor for microbial molecular components. The most characterized mammalian TLR, TLR4, is a receptor for lipopolysaccharides (LPS). TLR2 recognizes other components, such as peptideglycans (PGN). This recognition, called pattern recognition, is essential for the establishment of innate immunity, which is the basis for host defense. In this article, we review recent findings about this expanding receptor family.     

Role of Innate Immunity in the Pathogenesis of Type 1 and Type 2 Diabetes

The importance of innate immunity in host defense is becoming clear after discovery of innate immune receptors such as Toll-like receptor or Nod-like receptor. Innate immune system plays an important role in diverse pathological situations such as autoimmune diseases. Role of innate immunity in the pathogenesis of metabolic disorders such as type 2 diabetes, metabolic syndrome or atherosclerosis that has not been previously considered as inflammatory disorders, is also being appreciated. Here, the role of innate immunity in the development of type 1 diabetes, a classical organ-specific autoimmune disease, and type 2 diabetes will be discussed, focusing on the role of specific innate immune receptors involved in these disease processes.

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