On the origins of adaptive immunity: innate immune receptors join the tale (original) (raw)
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Evolution of Antigen Binding Receptors
Annual Review of Immunology, 1999
▪ This review addresses issues related to the evolution of the complex multigene families of antigen binding receptors that function in adaptive immunity. Advances in molecular genetic technology now permit the study of immunoglobulin (Ig) and T cell receptor (TCR) genes in many species that are not commonly studied yet represent critical branch points in vertebrate phylogeny. Both Ig and TCR genes have been defined in most of the major lineages of jawed vertebrates, including the cartilaginous fishes, which represent the most phylogenetically divergent jawed vertebrate group relative to the mammals. Ig genes in cartilaginous fish are encoded by multiple individual loci that each contain rearranging segmental elements and constant regions. In some loci, segmental elements are joined in the germline, i.e. they do not undergo genetic rearrangement. Other major differences in Ig gene organization and the mechanisms of somatic diversification have occurred throughout vertebrate evolut...
Origin and evolution of the adaptive immune system: genetic events and selective pressures
Nature Reviews Genetics, 2009
The adaptive immune system (AIS) in mammals, which is centred on lymphocytes bearing antigen receptors that are generated by somatic recombination, arose approximately 500 million years ago in jawed fish. This intricate defence system consists of many molecules, mechanisms and tissues that are not present in jawless vertebrates. Two macroevolutionary events are believed to have contributed to the genesis of the AIS: the emergence of the recombination-activating gene (RAG) transposon, and two rounds of whole-genome duplication. It has recently been discovered that a non-RAG-based AIS with similarities to the jawed vertebrate AIS-including two lymphoid cell lineages-arose in jawless fish by convergent evolution. We offer insights into the latest advances in this field and speculate on the selective pressures that led to the emergence and maintenance of the AIS. The adaptive immune system (AIS) is fascinating to both scientists and laymen: we have a specific yet incredibly diverse system that can fight myriad pathogens and has a 'memory'-the basis of vaccination-that enables a rapid response to previously encountered pathogens. The complexity of immune response regulation rivals that of the nervous system in terms of the connections forged and suppressed between cells, but immune cells must also traverse the body through blood, lymph and tissue until they encounter invading organisms. How did such a system arise, and can studies of non-mammalian vertebrates help us to understand the immunity gestalt? Antibodies were discovered over 100 years ago, and major questions relating to the generation of diversity were solved in the 1970s with the detection of somatic hypermutation 1 and variable-diversity-joining rearrangement (VDJ rearrangement) 2 of antibody (or immunoglobulin (Ig) or B cell receptor (BCR)) genes. In the 1980s, T cell receptors (TCRs) were discovered and there was universal agreement that they shared a common ancestor with BCR genes, based on their similar domain organization and reliance on the same rearrangement mechanism to generate diversity 3. After the discovery of enzymes that are involved in the rearrangement of BCR and TCR genes 4 and of
Ancient divergence of a complex family of immune-type receptor genes
Immunogenetics, 2006
Multigene families of activating/inhibitory receptors belonging to the immunoglobulin superfamily (IgSF) regulate immunological and other cell-cell interactions. A new family of such genes, termed modular domain immune-type receptors (MDIRs), has been identified in the clearnose skate (Raja eglanteria), a phylogenetically ancient vertebrate. At least five different major forms of predicted MDIR proteins are comprised of four different subfamilies of IgSF ectodomains of the intermediate (I)-or C2-set. The predicted number of individual IgSF ectodomains in MDIRs varies from one to six. MDIR1 contains a positively charged transmembrane residue and MDIR2 and MDIR3 each possesses at least one immunoreceptor tyrosine-based inhibitory motif in their cytoplasmic regions. MDIR4 and MDIR5 lack characteristic activating/inhibitory signalling motifs. MDIRs are encoded in a particularly large and complex multigene family. MDIR domains exhibit distant sequence similarity to mammalian CMRF-35-like molecules, polymeric immunoglobulin receptors, triggering receptors expressed on myeloid cells (TREMs), TREM-like transcripts, NKp44 and FcR homologs, as well as to sequences identified in several different vertebrate genomes. Phylogenetic analyses suggest that MDIRs are representative members of an extended family of IgSF genes that diverged before or very early in evolution of the vertebrates and subsequently came to occupy multiple, fully independent distributions in the present day.
© 2005 Nature Publishing Group RECONSTRUCTING IMMUNE PHYLOGENY: NEW PERSPECTIVES
| Numerous studies of the mammalian immune system have begun to uncover profound interrelationships, as well as fundamental differences, between the adaptive and innate systems of immune recognition. Coincident with these investigations, the increasing experimental accessibility of non-mammalian jawed vertebrates, jawless vertebrates, protochordates and invertebrates has provided intriguing new information regarding the likely patterns of emergence of immune-related molecules during metazoan phylogeny, as well as the evolution of alternative mechanisms for receptor diversification. Such findings blur traditional distinctions between adaptive and innate immunity and emphasize that, throughout evolution, the immune system has used a remarkably extensive variety of solutions to meet fundamentally similar requirements for host protection. 866 | NOVEMBER 2005 | VOLUME 5 www.nature.com/reviews/immunol
Nature Immunology, 2006
Although the origins of genes encoding the rearranging binding receptors remain obscure, it is predicted that their ancestral forms were nonrearranging immunoglobulin-type domains. Variable region-containing chitin-binding proteins (VCBPs) are diversified immune-type molecules found in amphioxus (Branchiostoma floridae), an invertebrate that diverged early in deuterostome phylogeny. To study the potential evolutionary relationships between VCBPs and vertebrate adaptive immune receptors, we solved the structures of both a single V-type domain (to 1.15 Å ) and a pair of V-type domains (to 1.85 Å ) from VCBP3. The deduced structures show integral features of the ancestral variable-region fold as well as unique features of variable-region pairing in molecules that may reflect characteristics of ancestral forms of diversified immune receptors found in modern-day vertebrates.
Novel Immune-type Receptor Genes and the Origins of Adaptive and Innate Immune Recognition
Integrative and Comparative Biology, 2003
SYNOPSIS. The prototypic forms of teleost novel immune-type receptors (NITRs) consist of a variable (V) region, a unique V-like C2 (V/C2) domain, a transmembrane region and a cytoplasmic tail containing immunoreceptor tyrosine-based inhibition motifs (ITIMs). NITRs encode diversified V regions in large multigene families but do not undergo somatic rearrangement. Studies in four different bony fish model systems have identified a number of different organizational forms of NITRs. Specifically, NITR genes encode Nterminal ectodomains of the V-type but otherwise vary in the: total number of extracellular immunoglobulin domains, number and location of joining (J) region-like motifs, presence of transmembrane regions, presence of charged residues within transmembrane regions, presence of cytoplasmic tails, and/or distribution of ITIM(s) within the cytoplasmic tails. V region-containing NITRs constitute a far more complex family than recognized originally and currently include individual members that potentially function through inhibitory as well as activating mechanisms. The genomic organization of the NITR gene cluster as well as the structural diversity and overall architecture of the NITR proteins is reminiscent of genes encoded at the mammalian leukocyte receptor cluster (LRC); however, there presently is no functional evidence to support an orthologous relationship between NITR and LRC gene products. Comparisons of the predicted structures of the NITRs have identified several short regions of sequence identity and a novel cloning strategy has been devised that selects for secretory and transmembrane proteins that encode these short motifs. Using this approach, related genes termed immune-type receptors (ITRs) have been identified in cartilaginous fish. Taken together, these studies indicate that leukocyte regulatory receptors, including those that mediate natural killer function, might have emerged early in vertebrate evolution and that the NITR/ITR genes represent a new and potentially highly significant link between innate and adaptive immune responses.
Extraordinary variation in a diversified family of immune-type receptor genes
Proceedings of the National Academy of Sciences, 2001
Immune inhibitory receptor genes that encode a variable (V) region, a unique V-like C2 (V͞C2) domain, a transmembrane region, and a cytoplasmic tail containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) have been described previously in two lineages of bony fish. In the present study, eleven related genes encoding distinct structural forms have been identified in Ictalurus punctatus (channel catfish), a well characterized immunological model system that represents a third independent bony fish lineage. Each of the different genes encodes an N-terminal V region but differs in the number of extracellular Ig domains, number and location of joining (J) region-like motifs, presence of transmembrane regions, presence of charged residues in transmembrane regions, presence of cytoplasmic tails, and͞or distribution of ITIM(s) within the cytoplasmic tails. Variation in the numbers of genomic copies of the different gene types, their patterns of expression, and relative levels of expression in mixed leukocyte cultures (MLC) is reported. V region-containing immune-type genes constitute a far more complex family than recognized originally and include individual members that might function in inhibitory or, potentially activatory manners. E xtended multigene families belonging to the Ig gene superfamily (IgSF) account for a diverse range of immunological functions including recognition of antigens and antigenic peptides by both somatically rearranging Ig and T cell antigen receptor (TCR) genes, as well as by major histocompatibility complex (MHC) molecules. The origins of the three diverse systems of effector molecules can be traced through analyses of these genes in extant species of representative early, jawed vertebrates (1). Recently, multigene families which encode novel immune-type receptors (NITR͞nitr) have been described in Spheroides nephelus (Southern pufferfish; ref. 2) and Danio rerio (zebrafish; ref. 3). The NITR genes described in these species encode two extracellular Ig domains [a variable (V) domain and a V-like C2 (V͞C2) domain], a transmembrane region, and most often, immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic tail. The general structural characteristics of the NITR V domain are common to the corresponding regions of both Ig and TCR (4); whereas ITIMs are found in several inhibitory receptors, which are encoded at the leukocyte receptor cluster (LRC) on human chromosome 19q13.3-13.4 and at a corresponding location on mouse chromosome 7 and include natural killer (NK) receptors, such as killer cell Ig-type receptors (KIRs) (5). Unlike NITR genes, LRC genes do not encode V regions. A number of questions arise regarding the distribution of the NITR genes in vertebrate phylogeny, their function, and the relatedness of NITR genes to other families of genes that are involved in immune function, specifically, the immune inhibitory receptors of the mammalian LRC.
Evolution of adaptive immune recognition in jawless vertebrates
Seminars in Immunology, 2010
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.
The molecular origins of the recombining immune system
1996
This dissertation examines the molecular origins of the recombining immune system. Two strategies were adopted involving the examination of the immune system of the most ancient extant organism possessing the vertebrate type immune response, the Carcharhine shark. First, the structural components of a primordial immunoglobulin (Ig) were examined on a molecular level. This revealed a new class of Ig termed IgW. Although IgW is the largest Ig yet described, with 7 bona fide Ig domains, it maintains the canonical residues typified by heavy chain V and C-regions. Because of these canonical residues, IgW is thought to both dimerise with light chains and associate with antigen as a typical heavy chain. IgW also possesses Vregions which are more similar to its own C-regions than any Ig yet described. In phylogenetic tree analysis, the IgW molecule is continually found to be the "root" of the Ig V and C-region trees constructed from the known Vand C-region genes. This, and IgW'...