Key Points
Innate immunity has a long phylogenetic history, encompassing species as diverse as sea anemones, insects and mammals. By contrast, adaptive immunity, which involves lymphocyte-like cells and the antigen-binding receptors they express, is restricted to vertebrates.
A major departure in adaptive immunity is evident within vertebrate species. Jawed vertebrates use V(D)J recombination of immunoglobulin and T cell receptors, whereas jawless vertebrates rearrange variable lymphocyte receptors encoding leucine-rich repeats to form an alternative type of immune receptor.
Homologues of molecules that previously were thought to be unique to the rearrangement and diversification of immunoglobulin and T cell receptors have been identified in invertebrate species, in which these forms of immune recognition molecules are absent.
The enormously complex, multifactorial and highly regulated cellular processes that generate receptor variation in somatic cells arose through the integration of molecular systems that are not exclusively associated with immune diversity.
Reconstructing the nature of ancestral forms of adaptive immune receptors is compromised by the absence of crucial intermediates; however, it is possible to infer some of the main steps that gave rise to the antigen receptor-bearing immunocytes of jawed vertebrates.
Abstract
Adaptive immunity is mediated through numerous genetic and cellular processes that generate favourable somatic variants of antigen-binding receptors under evolutionary selection pressure by pathogens and other factors. Advances in our understanding of immunity in mammals and other model organisms are revealing the underlying basis and complexity of this remarkable system. Although the evolution of adaptive immunity has been thought to occur by the acquisition of novel molecular capabilities, an increasing amount of information from new model systems suggest that co-option and redirection of pre-existing systems are the main source of innovation. We combine evidence from a wide range of organisms to obtain an integrated view of the origins and patterns of divergence in adaptive immunity.
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Acknowledgements
The work in the laboratory of G.W.L. is supported by US National Institutes of Health grants AI23338 and AI57559. The work in the laboratory of J.P.R. is supported by Canadian Institutes for Health Research grant MOP74667 and National Science and Engineering Research Council of Canada grant NSERC 458115/211598. The work in the laboratory of S.D.F. is supported by the Intramural Research Program of the US National Institutes of Health, National Institute on Aging.
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Glossary
- Somatic hypermutation
-
(SHM). The process by which point mutations are introduced in the heavy- or light-chain variable region gene segments, resulting in a change in the expressed protein, which may alter affinity or specificity for antigen.
- V(D)J recombination
-
The lineage-specific RAG1- and RAG2-mediated assembly of functional immunoglobulin and T cell receptor genes from individual variable (V), diversity (D) and joining (J) gene segments. This process occurs exclusively in B and T cell progenitors.
- Recombination signal sequences
-
(RSSs). Highly conserved heptamer and nonomer sequences that flank recombining segmental elements in immunoglobulin and T cell receptor genes. These sequences are separated by 12 or 23 base pair spacers that are required to direct the recombination of compatible elements.
- Recombination-activating gene 1
-
(RAG1). A protein that, along with RAG2, forms a DNA recombinase complex which catalyses V(D)J recombination. During the joining phase additional ubiquitous DNA repair factors are recruited. Both genes are exclusively expressed in developing lymphocytes.
- Gene conversion
-
An immunoglobulin gene diversification process closely related to somatic hypermutation. In general, U:G base mismatches are repaired by copying sequence information from upstream pseudo V segments into the rearranged VJ and VDJ exon of the IgL and IgH genes, respectively. In birds and rabbits it occurs before antigen encounter.
- Tetrapods
-
Four-limbed vertebrates that include the amphibians and amniotes (reptiles, birds and mammals). These groups share some common immune features, such as class-switch recombination.
- Activation-induced cytidine deaminase
-
(AID). An enzyme that acts on single-stranded DNA and converts cytidines to uracils. It is typically expressed in B cells after antigen encounter. Its mutagenic activity is restricted to immunoglobulin loci.
- Phylogeny
-
The study of evolutionary relatedness among groups or species of organisms. Similar analyses can be applied to relatedness among genes.
- Lampreys and hagfish
-
Two extant groups of the jawless vertebrate lineage that have anatomical and physiological differences from jawed vertebrates. Lampreys undergo metamorphosis from a larval form, termed an ammocoete, and approximately half of the species are parasitic in adult life. Hagfish are ocean dwelling species that feed on decaying animal matter and small crustaceans.
- Leucine-rich repeat
-
(LRR). A protein structural motif that is comprised of 20–30 amino acid regions that are unusually rich in the hydrophobic amino acid leucine and form a characteristic structural fold.
- Copy choice mechanism of recombination
-
A genetic recombination mechanism in which a new DNA sequence is generated by replication using multiple DNA sequences as templates. The DNA polymerase continues to synthesize a single DNA molecule while jumping from one template strand to another. The choice of templates is largely driven by sequence homologies, allowing the previously synthesized DNA to anneal to similar sequences elsewhere in the genome and thereby redirecting DNA synthesis.
- Chordates
-
An animal phylum that comprises both jawed and jawless vertebrates, and two subphyla of invertebrates: the cephalochordates (such as amphioxus) and the urochordates (such as the sea squirt Ciona intestinalis).
- Deuterostomes
-
An animal superphylum composed of four phyla: the chordates (which include vertebrates), the echinoderms (consisting of starfish, sea urchins and allied species), the hemichordates (acorn worms) and Xenoturbellida (containing two marine worm-like species). Genomes from each of the three main deuterostome phyla have been sequenced.
- Transposons
-
(Also are known as 'jumping genes' and 'selfish DNA'). DNA sequences that encode transposases, the enzymes required to excise the transposon from its original chromosomal location and to integrate it in a different position within the genome. The ends of transposons consist of DNA repeats that serve as recognition sites for the transposase itself.
- Purple sea urchin
-
(Strongylocentrotus purpuratus). An echinoderm that is a well established model system for developmental biology. Sequencing of its genome increased the interest of the broader scientific community (including immunologists) in this invertebrate model system.
- Complementarity determining region 3
-
(CDR3). The region in B and T cell receptors that interacts with the antigen, in which hypervariable sequences are located. CDR3 typically is derived somatically, whereas CDR1 and CDR2 are germline encoded.
- B-1 B cells
-
In mice, this B cell subset is found mainly in the peritoneal and pleural cavities. B-1 B cells are a self-renewing subset with a restricted repertoire of B cell receptors that respond to common bacterial antigens and have a role in autoimmunity.
- Derived evolutionary features
-
Anatomical structures, genes or functional systems are designated as derived when they originate within a sub-lineage. Primitive evolutionary features refer to those that originate from similar features in a common ancestor.
- Invariant natural killer T (iNKT) cells
-
Lymphocytes that express a particular variable gene segment, Vα14 (in mice) and Vα24 (in humans), precisely rearranged to a particular Jα gene segment to yield T cell receptor α-chains with an invariant sequence.
- Novel immune-type receptors
-
(NITRs). Activating or inhibitory receptors that are encoded by large diversified multigene families in bony fish. All NITRs have a variable region and most have a transmembrane region and cytoplasmic tail with signalling motifs.
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Litman, G., Rast, J. & Fugmann, S. The origins of vertebrate adaptive immunity. Nat Rev Immunol 10, 543–553 (2010). https://doi.org/10.1038/nri2807
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DOI: https://doi.org/10.1038/nri2807
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